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10.1101/2021.01.21.21249920 | Survey of Contaminated Percutaneous Injuries in Anesthesia Practitioners | BackgroundAnesthesia practitioners are at inherent risk for percutaneous injuries by blood-contaminated needles and sharp objects. These exposures may result in transmission of HIV and hepatitis viruses. Data about this occupational hazard from contaminated needles and sharp devices is limited and decades old. We conducted a web-based survey to assess the occurrence, reporting, characteristics, and outcome of contaminated percutaneous injuries (CPI) in anesthesia residents, fellows, and attendings.
MethodsAfter institutional research board approval, an email was sent to 217 anesthesia practitioners requesting their participation in an online survey about contaminated percutaneous injuries. Responses were collected from February through March 2020. Results are reported as absolute numbers and proportions with 95% confidence interval (CI).
ResultsThe overall survey response rate was 51% (110/217). 59% (65/110) (95% CI, 50-68) of participants reported having one or more contaminated percutaneous injury during their years of anesthesia practice (42% (21/50) of residents, 50% (4/8) of fellows, 77% (40/52) of anesthesia attendings). Prevalence of injuries related to attendings years of anesthesia practice was 69% (95% CI, 44-94) for 5-10 years, 62.5% (95% CI, 29-96) for 10-15 years, and 79% (95% CI, 63- 95) for greater than 15 years of practice.
35% (95% CI, 26-44) of participants reported having one or more CPI within the last 5 years (40% of residents, 50% of fellows, 29% of attendings). Occurrence of CPI within the last 5 years based on attending anesthesiologist years of practice was 57% for less than 5 years, 37.5% for 10-15 years, and 20% for 15-20 years of practice. 75% (95% CI, 65-85) reported the incident at the time of injury. 59% (95% CI, 48-70) of injuries were due to hollow bore needles. 50% (95% CI, 39-61) of total injuries were high risk. 26% of injured anesthesia practitioners received post-exposure prophylaxis and there were zero seroconversions.
ConclusionMost anesthesiologists will sustain a contaminated percutaneous injury during their careers. Incidence of these injuries decreases with years of practice. Occurrence of these injuries is high among anesthesia residents, with the majority reporting their injuries. Half of the injuries are high risk with a quarter requiring postexposure prophylaxis. More education and interventions are needed to reduce percutaneous injuries and improve reporting. | anesthesia |
10.1101/2021.01.18.21250017 | Validation of the new pathology staging system for progressive supranuclear palsy | Progressive supranuclear palsy (PSP) is a neurodegenerative disorder associated with neuroglial accumulation of 4-repeat tau protein. Kovacs et al. have recently proposed a new semi-quantitative staging system to categorise the severity of PSP pathology, using the distribution of tau aggregates as it progresses from subcortical to cerebellar and cortical regions. Here, we test the new PSP pathology staging system in an independent series of PSP, and test the potential association between pathology stage and clinical severity at death. We include tissue from 35 people with a clinical diagnosis of PSP (including N=25 with Richardsons syndrome and N=10 with other phenotypes). Donors had attended longitudinal clinical studies at the Cambridge Centre Parkinson-plus including assessment of clinical severity by the PSP rating scale (PSPRS) and cognitive performance by the revised Addenbrookes Cognitive Examination (ACE-R). We rated tau pathology from none-to-severe in six regions. We focused on (I) astrocytic tau inclusions in striatum, frontal and occipital regions, and (II) neuronal and oligodendroglia tau inclusions in globus pallidus, subthalamic nucleus, and cerebellum. Thirty-two cases (91%) readily conformed to the new staging system, ranging from stage 2 to 6. Staging system applied to brains from people with different clinical phenotypes of PSP. Neuropathology stages correlated with clinical severity at death using both PSPRS and ACE-R, weighted for the interval between last assessment and donation. Our study supports the proposed sequential distribution of tau aggregates in PSP pathology, and the hypothesised relationship between clinical and neuropathological severity. For future studies, in order to standardise rating between centres, we propose a set of operational criteria for region-specific thresholds or tau burden, and a visual guide. | pathology |
10.1101/2021.01.21.21250225 | A phase IV, multi-centre, randomized clinical trial comparing two pertussis-containing vaccines in pregnant women in England and vaccine responses in their infants | BackgroundPertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants antigen-specific immunoglobulin G (IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP5-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis [five antigens] and inactivated polio) or TdaP3-IPV in pregnancy (three pertussis antigens).
MethodsThis multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England from 2014-2016. Women were randomized to receive TdaP5-IPV (n=77) or TdaP3-IPV (n=77) at 28-32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled postpartum.
ResultsFollowing infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP5-IPV (n=67) or TdaP3-IPV (n=63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP5-IPV and TdaP3-IPV vaccinated mothers compared to infants born to unvaccinated mothers (n=45) (geometric mean ratio: 0.71 [0.56-0.90] and 0.78 [0.61-0.98], respectively); by 13 months of age, this difference was no longer observed.
ConclusionBlunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP5-IPV and TdaP3-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy.
Clinical Trials identifierClinicalTrials.gov: NCT02145624 | pediatrics |
10.1101/2021.01.20.21250176 | Effect of a home-based health, nutrition, and responsive stimulation intervention and conditional cash transfers on child development and growth: a cluster-randomized controlled trial in Tanzania | IntroductionEvidence on the effect of community health worker (CHW) interventions and conditional cash transfers (CCTs) on child growth and development in sub-Saharan Africa remains sparse.
MethodsWe conducted a single-blind, cluster-randomized controlled trial of an integrated home-visiting health, nutrition, and responsive stimulation intervention alone and in combination with CCTs to promote antenatal and child clinic attendance from 2017 to 2019 in rural Morogoro region, Tanzania. Pregnant women and caregivers with a child <1{square}year of age were enrolled. Twelve villages were randomized to either a (i) CHW (n=200 participants), (ii) CHW+CCT (n=200), or (iii) control arm (n=193). An intention-to-treat analysis was conducted for the primary trial outcomes of child cognitive, language and motor development assessed with the Bayley Scales of Infant and Toddler Development and child length/height-for-age z-scores (HAZ) at 18-months of follow-up.
ResultsThe CHW and CHW+CCT interventions had beneficial effects on child cognitive development as compared to control (standardized mean difference (SMD): 0.15; 95% confidence interval (CI): 0.05, 0.24) and SMD: 0.18; 95% CI: 0.07, 0.28, respectively). The CHW+CCT intervention also had positive effects on language (SMD: 0.08; 95% CI: 0.01, 0.15) and motor development (SMD: 0.16; 95% CI: 0.03, 0.28). Both CHW and CHW+CCT interventions had no effect on HAZ in the primary analysis; however, there were statistically significant positive effects in multivariable analyses. The CHW+CCT group (mean difference: 3.0 visits; 95% CI: 2.1-4.0) and the CHW group (mean difference: 1.5 visits; 95% CI: 0.6-2.5) attended greater number of child health and growth monitoring clinic visits as compared to the control group.
ConclusionIntegrated CHW home-visiting interventions can improve child cognitive development and may have positive effects on linear growth. Combining CHWs with CCTs may provide additional benefits on clinic visit attendance and selected child development outcomes.
Trial registration numberISRCTN10323949
Key Questions BoxO_ST_ABSWhat is already known?C_ST_ABSO_LICommunity health worker interventions that integrate health, nutrition and responsive stimulation components can improve child development but evidence from sub-Saharan Africa is limited.
C_LIO_LIConditional cash transfers can increase healthcare utilization but effects on child development and growth remain unclear.
C_LI
What are the new findings?O_LIAn integrated home-visiting community health worker intervention benefited child cognitive development and may have improved child linear growth in rural Tanzania.
C_LIO_LICombining conditional cash transfers with the community health worker intervention increased child clinic visit attendance as intended and improved child cognitive, motor, and language development and may have improved child linear growth as compared to control.
C_LI
What do the new findings imply?O_LICommunity health workers can improve child development and possibly child growth outcomes; however, additional research is needed to determine the intensity and frequency of visits to optimize impact as well as the direct and indirect mechanisms through which community health worker interventions work.
C_LIO_LIConditional cash transfers may provide additional benefits on clinic attendance and selected development domains as compared to community health workers alone; however, additional research is needed to directly compare integrated supply-side and demand-side strategies to promote child growth and development.
C_LI | pediatrics |
10.1101/2021.01.20.21250176 | Effect of a home-based health, nutrition, and responsive stimulation intervention and conditional cash transfers on child development and growth: a cluster-randomized controlled trial in Tanzania | IntroductionEvidence on the effect of community health worker (CHW) interventions and conditional cash transfers (CCTs) on child growth and development in sub-Saharan Africa remains sparse.
MethodsWe conducted a single-blind, cluster-randomized controlled trial of an integrated home-visiting health, nutrition, and responsive stimulation intervention alone and in combination with CCTs to promote antenatal and child clinic attendance from 2017 to 2019 in rural Morogoro region, Tanzania. Pregnant women and caregivers with a child <1{square}year of age were enrolled. Twelve villages were randomized to either a (i) CHW (n=200 participants), (ii) CHW+CCT (n=200), or (iii) control arm (n=193). An intention-to-treat analysis was conducted for the primary trial outcomes of child cognitive, language and motor development assessed with the Bayley Scales of Infant and Toddler Development and child length/height-for-age z-scores (HAZ) at 18-months of follow-up.
ResultsThe CHW and CHW+CCT interventions had beneficial effects on child cognitive development as compared to control (standardized mean difference (SMD): 0.15; 95% confidence interval (CI): 0.05, 0.24) and SMD: 0.18; 95% CI: 0.07, 0.28, respectively). The CHW+CCT intervention also had positive effects on language (SMD: 0.08; 95% CI: 0.01, 0.15) and motor development (SMD: 0.16; 95% CI: 0.03, 0.28). Both CHW and CHW+CCT interventions had no effect on HAZ in the primary analysis; however, there were statistically significant positive effects in multivariable analyses. The CHW+CCT group (mean difference: 3.0 visits; 95% CI: 2.1-4.0) and the CHW group (mean difference: 1.5 visits; 95% CI: 0.6-2.5) attended greater number of child health and growth monitoring clinic visits as compared to the control group.
ConclusionIntegrated CHW home-visiting interventions can improve child cognitive development and may have positive effects on linear growth. Combining CHWs with CCTs may provide additional benefits on clinic visit attendance and selected child development outcomes.
Trial registration numberISRCTN10323949
Key Questions BoxO_ST_ABSWhat is already known?C_ST_ABSO_LICommunity health worker interventions that integrate health, nutrition and responsive stimulation components can improve child development but evidence from sub-Saharan Africa is limited.
C_LIO_LIConditional cash transfers can increase healthcare utilization but effects on child development and growth remain unclear.
C_LI
What are the new findings?O_LIAn integrated home-visiting community health worker intervention benefited child cognitive development and may have improved child linear growth in rural Tanzania.
C_LIO_LICombining conditional cash transfers with the community health worker intervention increased child clinic visit attendance as intended and improved child cognitive, motor, and language development and may have improved child linear growth as compared to control.
C_LI
What do the new findings imply?O_LICommunity health workers can improve child development and possibly child growth outcomes; however, additional research is needed to determine the intensity and frequency of visits to optimize impact as well as the direct and indirect mechanisms through which community health worker interventions work.
C_LIO_LIConditional cash transfers may provide additional benefits on clinic attendance and selected development domains as compared to community health workers alone; however, additional research is needed to directly compare integrated supply-side and demand-side strategies to promote child growth and development.
C_LI | pediatrics |
10.1101/2021.01.23.21250358 | An effect of the COVID-19 pandemic: significantly more complicated appendicitis due to delayed presentation of patients! | AIMS OF THE STUDYThe novel coronavirus pandemic has affected emergency department consultations for surgical pathologies. The aim of our study was to compare the number of acute appendicitis cases and the proportion of complicated appendicitis before and during the COVID-19 pandemic.
METHODSWe retrospectively analyzed all data collected from a multi-center database of patients presenting to the emergency department for acute appendicitis during the COVID-19 pandemic from March 12 to June 6, 2020, and compared these data with those from the same periods in 2017, 2018, and 2019. The number of acute appendicitis cases, proportion of complicated appendicitis, and pre- and postoperative patient characteristics were evaluated.
RESULTSA total of 306 patients were included in this evaluation. Sixty-five patients presented during the 2020 COVID-19 pandemic lockdown (group A), and 241 patients in previous years (group B: 2017-2019). The number of consultations for acute appendicitis decreased by almost 20 percent during the pandemic compared with previous periods, with a significant increase in complicated appendicitis (52% in group A versus 20% in group B, p < 0,001.). Comparing the two groups, significant differences were also noted in the duration of symptoms (symptoms > 48h in 61% and 26%, p < 0,001), the intervention time (77 vs 61 minutes, p = 0,002), length of hospital stay (hospitalization of > 2 days in 63% and 32%, p < 0.001) and duration of antibiotic treatment (antibiotics > 3 days in 36% and 24% p = 0.001).
CONCLUSIONSThe COVID-19 pandemic resulted in a decreased number of consultations for acute appendicitis, with a higher proportion of complicated appendicitis, most likely due to patient delay in consulting the emergency department at symptom onset. Patients and general practitioners should be aware of this problem to avoid a time delay from initial symptoms to consultation. | surgery |
10.1101/2021.01.19.21250133 | Are probiotics and prebiotics safe for use during pregnancy and lactation? A systematic review and meta-analysis | Probiotic and prebiotic products have shown potential health benefits, including for the prevention of adverse pregnancy outcomes. The incidence of adverse effects in pregnant people and their infants associated with probiotic/prebiotic/synbiotic intake, however, remains unclear. The objectives of this study were to evaluate the evidence on adverse effects of maternal probiotic, prebiotic and/or synbiotic supplementation during pregnancy and lactation and interpret the findings to help inform clinical decision-making and care of this population. A systematic review was conducted following PRISMA guidelines. Scientific databases were searched using pre-determined terms, and risk of bias assessments were conducted to determine study quality. Inclusion criteria were English language studies, human studies, access to full-text, and probiotic/prebiotic/synbiotic supplementation to the mother and not the infant. 11/100 eligible studies reported adverse effects and were eligible for inclusion in quantitative analysis, and data were visualised in a GOfER diagram. Probiotic and prebiotic products are safe for use during pregnancy and lactation. One study reported increased risk of vaginal discharge and changes in stool consistency (Relative Risk [95% CI]: 3.67 [1.04, 13.0]) when administering Lactobacillus rhamnosus and L. reuteri. Adverse effects associated with probiotic and prebiotic use do not pose any serious health concerns to mother or infant. Our findings and knowledge translation visualisations provide healthcare professionals and consumers with information to make evidence-informed decisions about the use of pre- and probiotics. | obstetrics and gynecology |
10.1101/2021.01.19.21250133 | Are probiotics and prebiotics safe for use during pregnancy and lactation? A systematic review and meta-analysis | Probiotic and prebiotic products have shown potential health benefits, including for the prevention of adverse pregnancy outcomes. The incidence of adverse effects in pregnant people and their infants associated with probiotic/prebiotic/synbiotic intake, however, remains unclear. The objectives of this study were to evaluate the evidence on adverse effects of maternal probiotic, prebiotic and/or synbiotic supplementation during pregnancy and lactation and interpret the findings to help inform clinical decision-making and care of this population. A systematic review was conducted following PRISMA guidelines. Scientific databases were searched using pre-determined terms, and risk of bias assessments were conducted to determine study quality. Inclusion criteria were English language studies, human studies, access to full-text, and probiotic/prebiotic/synbiotic supplementation to the mother and not the infant. 11/100 eligible studies reported adverse effects and were eligible for inclusion in quantitative analysis, and data were visualised in a GOfER diagram. Probiotic and prebiotic products are safe for use during pregnancy and lactation. One study reported increased risk of vaginal discharge and changes in stool consistency (Relative Risk [95% CI]: 3.67 [1.04, 13.0]) when administering Lactobacillus rhamnosus and L. reuteri. Adverse effects associated with probiotic and prebiotic use do not pose any serious health concerns to mother or infant. Our findings and knowledge translation visualisations provide healthcare professionals and consumers with information to make evidence-informed decisions about the use of pre- and probiotics. | obstetrics and gynecology |
10.1101/2021.01.19.21250133 | Are probiotics and prebiotics safe for use during pregnancy and lactation? A systematic review and meta-analysis | Probiotic and prebiotic products have shown potential health benefits, including for the prevention of adverse pregnancy outcomes. The incidence of adverse effects in pregnant people and their infants associated with probiotic/prebiotic/synbiotic intake, however, remains unclear. The objectives of this study were to evaluate the evidence on adverse effects of maternal probiotic, prebiotic and/or synbiotic supplementation during pregnancy and lactation and interpret the findings to help inform clinical decision-making and care of this population. A systematic review was conducted following PRISMA guidelines. Scientific databases were searched using pre-determined terms, and risk of bias assessments were conducted to determine study quality. Inclusion criteria were English language studies, human studies, access to full-text, and probiotic/prebiotic/synbiotic supplementation to the mother and not the infant. 11/100 eligible studies reported adverse effects and were eligible for inclusion in quantitative analysis, and data were visualised in a GOfER diagram. Probiotic and prebiotic products are safe for use during pregnancy and lactation. One study reported increased risk of vaginal discharge and changes in stool consistency (Relative Risk [95% CI]: 3.67 [1.04, 13.0]) when administering Lactobacillus rhamnosus and L. reuteri. Adverse effects associated with probiotic and prebiotic use do not pose any serious health concerns to mother or infant. Our findings and knowledge translation visualisations provide healthcare professionals and consumers with information to make evidence-informed decisions about the use of pre- and probiotics. | obstetrics and gynecology |
10.1101/2021.01.24.21250395 | Functional Comparison of Different Exome Capture-based Methods for Transcriptomic Profiling of Formalin-Fixed Paraffin-Embedded Tumor Samples | BackgroundThe need for fresh frozen (FF) tissue limits implementing RNA sequencing (RNA-seq) in the clinic. The majority of clinical samples are processed in clinical laboratories and stored as formalin-fixed, paraffin-embedded (FFPE) tissues. Exome capture has recently emerged as a promising approach for RNA-seq from FFPE samples. Multiple exome capture platforms are now available. However, their performances have not been systematically compared.
MethodsTranscriptomic analysis of 32 FFPE tumor samples from 11 patients was performed using three exome capture-based methods: Agilent SureSelect V6, TWIST NGS Exome, and IDT XGen Exome Research Panel. We compared these methods to TruSeq RNA-seq of fresh frozen (FF-TruSeq) tumor samples from the same patients. We assessed the recovery of clinically relevant biological features, including the expression of key immune genes, expression outliers often associated with actionable genes, gene expression-based subtypes, and fusions using each of these capture methods.
ResultsThe Spearmans correlation coefficients between global expression profiles of the three capture-based methods and matched FF tumor samples, analyzed using TruSeq RNA-seq, were high (rho = 0.72-0.9, p < 0.05). There was a significant correlation between the expression of key immune genes between individual capture-based methods and FF-TruSeq (rho = 0.76-0.88, p < 0.05). All three exome capture-based methods reliably detected the outlier expression of actionable genes, including ERBB2, MET, NTRK1, and PPARG, initially detected in FF-TruSeq. In urothelial cancer samples, the Agilent assay was associated with the highest molecular subtyping agreement with FF-TruSeq (Cohens k = 0.7, p < 0.01). Both Agilent and IDT detected all the clinically relevant fusions which were initially identified in FF-TruSeq.
ConclusionAll exome capture-based methods had comparable performance and concordance with FF-TruSeq. These findings provide a path for the transcriptomic profiling of vast numbers of FFPE currently stored in biobanks. For specific applications such as fusion detection and gene expression-based subtyping, some methods performed better. By enabling the interrogation of FFPE tumor samples, our findings open the door for implementing RNA-seq in the clinic to guide precision oncology approaches. | oncology |
10.1101/2021.01.22.21250298 | The ferroxidase HEPHaestin in Lung cancer: Pathological Significance and Prognostic Value | Iron is a fundamental nutrient utilized by living cells to support several key cellular processes. Despite its paramount role to sustain cell survival, excess of labile iron availability can inflict severe cell damage via reactive oxygen species generation which, in turn, can promote neoplastic transformation. The lung is particularly sensitive to iron-induced oxidative stress, given the high oxygen tensions herein present. Moreover, cigarette smoke as well as air pollution particulate can function as vehicles of iron supply, leading to an iron dysregulation condition shown to be crucial in the pathogenesis of several respiratory diseases including lung cancer. Hephaestin (HEPH) belongs to a group of exocytoplasmic ferroxidases emerged to contribute to cellular iron homeostasis by favouring its export. Although HEPH can affect the concentration of intracellular iron labile pool, its expression in lung cancer and its influence on prognosis have not been investigated.
In this study we explored the expression pattern and prognostic value of HEPH in the most prevalent histotypes of lung cancers including lung adenocarcinoma and lung squamous cell carcinoma across in silico analyses using UALCAN, Gepia and Kaplan-Meier plotter bioninformatics. We took advantage of TIMER to assess the correlation between HEPH and tumour infiltrating immune and non-immune cells. Then we performed immunohistochemical analysis to dissect the presence of HEPH either in "healthy" and tumor lung tissues. Overall, our data suggest a positive correlation between higher level of HEPH expression with a favorable prognosis in both cancer histotypes. | oncology |
10.1101/2021.01.19.21250105 | Gene-level analysis of rare variants in 363,977 whole exome sequences reveals an association of GIGYF1 loss of function with diabetes | Sequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and type 2 diabetes (T2D) diagnosis in 363,977 exome-sequenced participants in the UK Biobank. We identified associations for variants in GCK, HNF1A and PDX1, which are known to be involved in Mendelian forms of diabetes. Notably, we uncovered novel associations for GIGYF1, a gene not previously implicated by human genetics, in diabetes. GIGYF1 predicted loss of function (pLOF) variants associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 x 10-12) and HbA1c (4.33 mmol/mol, p = 1.28 x 10-14) as well as T2D diagnosis (OR = 4.15, p= 6.14 x10-11). Multiple rare variants contributed to these associations, including singleton variants. GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. The association of GIGYF1 pLOF with T2D diagnosis replicated in an independent cohort from the Geisinger Health System. In addition, a common variant association for glucose and T2D was identified at the GIGYF1 locus. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.
Author SummaryGenetic studies focused on high impact variants in protein-coding regions of the genome can provide valuable insight into the biology of human disease. As these variants tend to be rare, studying them requires large cohort sizes and methods to aggregate variants that are likely to have a similar biological impact. We studied how rare genetic variants contribute to type 2 diabetes (T2D) using sequencing data from 363,977 participants in the UK Biobank, employing methods to aggregate variants at the level of individual genes. As well as identifying genes known to be involved in inherited forms of diabetes, we uncovered a novel association for GIGYF1. GIGYF1 loss of function associated with increased risk of T2D and increased levels of the diabetes biomarkers glucose and HbA1c. This association was also seen in an independent dataset. GIGYF1 encodes a protein that binds a negative regulator of the insulin receptor that has not been well-characterized in the literature. By highlighting the importance of GIGYF1 in modulating insulin signaling these results may lead to new therapeutic approaches for diabetes as well as a new appreciation for GIGYF1 loss of function as a genetic risk factor for T2D. | genetic and genomic medicine |
10.1101/2021.01.19.21250105 | Gene-level analysis of rare variants in 363,977 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes | Sequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and type 2 diabetes (T2D) diagnosis in 363,977 exome-sequenced participants in the UK Biobank. We identified associations for variants in GCK, HNF1A and PDX1, which are known to be involved in Mendelian forms of diabetes. Notably, we uncovered novel associations for GIGYF1, a gene not previously implicated by human genetics, in diabetes. GIGYF1 predicted loss of function (pLOF) variants associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 x 10-12) and HbA1c (4.33 mmol/mol, p = 1.28 x 10-14) as well as T2D diagnosis (OR = 4.15, p= 6.14 x10-11). Multiple rare variants contributed to these associations, including singleton variants. GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. The association of GIGYF1 pLOF with T2D diagnosis replicated in an independent cohort from the Geisinger Health System. In addition, a common variant association for glucose and T2D was identified at the GIGYF1 locus. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.
Author SummaryGenetic studies focused on high impact variants in protein-coding regions of the genome can provide valuable insight into the biology of human disease. As these variants tend to be rare, studying them requires large cohort sizes and methods to aggregate variants that are likely to have a similar biological impact. We studied how rare genetic variants contribute to type 2 diabetes (T2D) using sequencing data from 363,977 participants in the UK Biobank, employing methods to aggregate variants at the level of individual genes. As well as identifying genes known to be involved in inherited forms of diabetes, we uncovered a novel association for GIGYF1. GIGYF1 loss of function associated with increased risk of T2D and increased levels of the diabetes biomarkers glucose and HbA1c. This association was also seen in an independent dataset. GIGYF1 encodes a protein that binds a negative regulator of the insulin receptor that has not been well-characterized in the literature. By highlighting the importance of GIGYF1 in modulating insulin signaling these results may lead to new therapeutic approaches for diabetes as well as a new appreciation for GIGYF1 loss of function as a genetic risk factor for T2D. | genetic and genomic medicine |
10.1101/2021.01.20.21250183 | Large-scale validation of the Prediction model Risk Of Bias ASsessment Tool (PROBAST) using a short form: high risk of bias models show poorer discrimination | ObjectiveTo assess whether the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and a shorter version of this tool can identify clinical prediction models (CPMs) that perform poorly at external validation.
Study Design and SettingWe evaluated risk of bias (ROB) on 102 CPMs from the Tufts CPM Registry, comparing PROBAST to a short form consisting of six PROBAST items anticipated to best identify high ROB. We then applied the short form to all CPMs in the Registry with at least 1 validation and assessed the change in discrimination (dAUC) between the derivation and the validation cohorts (n=1,147).
ResultsPROBAST classified 98/102 CPMS as high ROB. The short form identified 96 of these 98 as high ROB (98% sensitivity), with perfect specificity. In the full CPM registry, 529/556 CPMs (95%) were classified as high ROB, 20 (4%) low ROB, and 7 (1%) unclear ROB. Median change in discrimination was significantly smaller in low ROB models (dAUC -0.9%, IQR -6.2%-4.2%) compared to high ROB models (dAUC -11.7%, IQR -33.3%-2.6%; p<0.001).
ConclusionHigh ROB is pervasive among published CPMs. It is associated with poor performance at validation, supporting the application of PROBAST or a shorter version in CPM reviews.
What is newO_LIHigh risk of bias is pervasive among published clinical prediction models
C_LIO_LIHigh risk of bias identified with PROBAST is associated with poorer model performance at validation
C_LIO_LIA subset of questions can distinguish between models with high and low risk of bias
C_LI | health informatics |
10.1101/2021.01.18.21250029 | Mask adherence and rate of COVID-19 across the United States | Mask wearing has been advocated by public health officials as a way to reduce the spread of COVID-19. In the United States, policies on mask wearing have varied from state to state over the course of the pandemic. Even as more and more government leaders encourage or even mandate mask wearing, many citizens still resist the notion. Our research examines mask wearing policy and adherence in association with COVID-19 case rates. We used state-level data on mask wearing policy for the general public and on proportion of residents who stated they always wear masks in public. For all 50 states and the District of Columbia (DC), these data were abstracted by month for April September 2020 to measure their impact on COVID-19 rates in the subsequent month (May October 2020). Monthly COVID-19 case rates (number of cases per capita over two weeks) >200 per 100,000 residents were considered high. Fourteen of the 15 states with no mask wearing policy for the general public through September reported a high COVID-19 rate. Of the 8 states with at least 75% mask adherence, none reported a high COVID-19 rate. States with the lowest levels of mask adherence were most likely to have high COVID-19 rates in the subsequent month, independent of mask policy or demographic factors. Mean COVID-19 rates for states with at least 75% mask adherence in the preceding month was 109.26 per 100,000 compared to 249.99 per 100,000 for those with less adherence. Our analysis suggests high adherence to mask wearing could be a key factor in reducing the spread of COVID-19. This association between high mask adherence and reduced COVID-19 rates should influence policy makers and public health officials to focus on ways to improve mask adherence across the population in order to mitigate the spread of COVID-19. | health policy |
10.1101/2021.01.18.21250029 | Mask adherence and rate of COVID-19 across the United States | Mask wearing has been advocated by public health officials as a way to reduce the spread of COVID-19. In the United States, policies on mask wearing have varied from state to state over the course of the pandemic. Even as more and more government leaders encourage or even mandate mask wearing, many citizens still resist the notion. Our research examines mask wearing policy and adherence in association with COVID-19 case rates. We used state-level data on mask wearing policy for the general public and on proportion of residents who stated they always wear masks in public. For all 50 states and the District of Columbia (DC), these data were abstracted by month for April September 2020 to measure their impact on COVID-19 rates in the subsequent month (May October 2020). Monthly COVID-19 case rates (number of cases per capita over two weeks) >200 per 100,000 residents were considered high. Fourteen of the 15 states with no mask wearing policy for the general public through September reported a high COVID-19 rate. Of the 8 states with at least 75% mask adherence, none reported a high COVID-19 rate. States with the lowest levels of mask adherence were most likely to have high COVID-19 rates in the subsequent month, independent of mask policy or demographic factors. Mean COVID-19 rates for states with at least 75% mask adherence in the preceding month was 109.26 per 100,000 compared to 249.99 per 100,000 for those with less adherence. Our analysis suggests high adherence to mask wearing could be a key factor in reducing the spread of COVID-19. This association between high mask adherence and reduced COVID-19 rates should influence policy makers and public health officials to focus on ways to improve mask adherence across the population in order to mitigate the spread of COVID-19. | health policy |
10.1101/2021.01.21.21250270 | Clarifying Values: An Updated and Expanded Systematic Review and Meta-Analysis | BackgroundPatient decision aids should help people make evidence-informed decisions aligned with their values. There is limited guidance about how to achieve such alignment.
PurposeTo describe the range of values clarification methods available to patient decision aid developers, synthesize evidence regarding their relative merits, and foster collection of evidence by offering researchers a proposed set of outcomes to report when evaluating the effects of values clarification methods.
Data SourcesMEDLINE, EMBASE, PubMed, Web of Science, the Cochrane Library, CINAHL
Study SelectionWe included articles that described randomized trials of one or more explicit values clarification methods. From 30,648 records screened, we identified 33 articles describing trials of 43 values clarification methods.
Data ExtractionTwo independent reviewers extracted details about each values clarification method and its evaluation.
Data SynthesisCompared to control conditions or to implicit values clarification methods, explicit values clarification methods decreased the frequency of values-disgruent choices (risk difference -0.04 95% CI [-0.06 to -0.02], p<.001) and decisional regret (standardized mean difference -0.20 95% CI [-0.29 to -0.11], p<0.001). Multicriteria decision analysis led to more values-congruent decisions than other values clarification methods (Chi-squared(2)=9.25, p=.01). There were no differences between different values clarification methods regarding decisional conflict (Chi-squared(2)=6.08, p=.05).
LimitationsSome meta-analyses had high heterogeneity. We grouped values clarification methods into broad categories.
ConclusionsCurrent evidence suggests patient decision aids should include an explicit values clarification method. Developers may wish to specifically consider multicriteria decision analysis. Future evaluations of values clarification methods should report their effects on decisional conflict, decisions made, values congruence, and decisional regret. | health systems and quality improvement |
10.1101/2021.01.23.21250359 | Association between clinical characteristics and laboratory findings with outcome of hospitalized COVID-19 patients, a report from northeast of Iran | Coronavirus disease 2019 (COVID-19) was first discovered in December 2019 in China and has rapidly spread worldwide. Clinical characteristics, laboratory findings, and their association with the outcome of patients with COVID-19 can be decisive in management and early diagnosis. Data were obtained retrospectively from medical records of 397 hospitalized COVID-19 patients between February and May 2020 in Imam Reza hospital, northeast of Iran. Clinical and laboratory features were evaluated among survivors and non-survivors. The correlation between variables and duration of hospitalization and admission to the Intensive Care Unit (ICU) was determined. Male sex, age, hospitalization duration, and admission to ICU were significantly related to mortality rate. Headache was a more common feature in patients who survived (p = 0.017). It was also related to a shorter stay in the hospital (p = 0.032) as opposed to patients who experienced chest pain (p = 0.033). Decreased levels of consciousness and dyspnea were statistically more frequent in non-survivors (p = 0.003 and p = 0.011, respectively). Baseline white blood cell count (WBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were significantly higher in non-survivors (p < 0.001). Patients with higher WBC and CRP levels were more likely to be admitted to ICU (p = 0.009 and p = 0.001, respectively). Evaluating clinical and laboratory features can help clinicians find ways for risk stratifying patients and even make predictive tools. Chest pain, decreased level of consciousness, dyspnea, and increased CRP and WBC levels seem to be the most potent predictors of severe prognosis. | infectious diseases |
10.1101/2021.01.24.21250408 | Harnessing testing strategies and public health measures to avert COVID-19 outbreaks during ocean cruises | To ensure the safe operation of schools, workplaces, nursing homes, and other businesses during COVID-19 pandemic there is an urgent need to develop cost-effective public health strategies. Here we focus on the cruise industry which was hit early by the COVID-19 pandemic, with more than 40 cruise ships reporting COVID-19 infections. We apply mathematical modeling to assess the impact of testing strategies together with social distancing protocols on the spread of the novel coronavirus during ocean cruises using an individual-level stochastic model of the transmission dynamics of COVID-19. We model the contact network, the potential importation of cases arising during shore excursions, the temporal course of infectivity at the individual level, the effects of social distancing strategies, different testing scenarios characterized by the tests sensitivity profile, and the testing frequency. Our findings indicate that PCR testing at embarkation and daily testing of all individuals aboard, together with increased social distancing and other public health measures, should allow for rapid detection and isolation of COVID-19 infections and dramatically reducing the probability of onboard COVID-19 community spread. In contrast, relying only on PCR testing at embarkation would not be sufficient to avert outbreaks, even when implementing substantial levels of social distancing measures. | infectious diseases |
10.1101/2021.01.22.21250042 | Detection of SARS-CoV-2 infection by rapid antigen test in comparison with RT-PCR in a public setting | BackgroundRapid and accurate detection of SARS-CoV-2 infection is essential in limiting the spread of infection during the ongoing COVID-19 pandemic. The aim of this study was to determine the accuracy of the STANDARD Q COVID-19 Ag test (SD BIOSENSOR) by comparison with RT-PCR in a public setting.
MethodIndividuals aged 18 years or older who had booked an appointment for a RT-PCR test on December 26-31, 2020 at a public test center in Copenhagen, Denmark, were invited to participate. An oropharyngeal swab was collected for RT-PCR analysis, immediately followed by a nasopharyngeal swab examined by the STANDARD Q COVID-19 Ag test (SD BIOSENSOR). Sensitivity, specificity, positive and negative predictive values of the antigen test were calculated with test results from RT-PCR as reference.
ResultsOverall, 4697 individuals were included (female n=2456, 53.3%; mean age: 44.7 years, SD: 16.9 years); 196 individuals were tested twice or more. Among 4811 paired conclusive test results from the RT-PCR and antigen tests, 221 (4.6%) RT-PCR tests were positive. The overall sensitivity and specificity of the antigen test were 69.7% and 99.5%, the positive and negative predictive values were 87.0% and 98.5%. Ct values were significantly higher among individuals with false negative antigen tests compared to true positives.
ConclusionThe sensitivity, specificity, and predictive values found indicate that the STANDARD Q COVID-19 Ag is a good supplement to RT-PCR testing. | infectious diseases |
10.1101/2021.01.21.21249176 | Distinct Autoimmune Antibody Signatures Between Hospitalized Acute COVID-19 Patients, SARS-CoV-2 Convalescent Individuals, and Unexposed Pre-Pandemic Controls | Increasing evidence suggests that autoimmunity may play a role in the pathophysiology of SARS-CoV-2 infection during both the acute and long COVID phases of disease. However, an assessment of autoimmune antibodies in convalescent SARS-CoV-2 patients has not yet been reported.
MethodologyWe compared the levels of 18 different IgG autoantibodies (AABs) between four groups: (1) unexposed pre-pandemic subjects from the general population (n = 29); (2) individuals hospitalized with acute moderate-severe COVID-19 (n = 20); (3) convalescent SARS-COV-2-infected subjects with asymptomatic to mild viral symptoms during the acute phase with samples obtained between 1.8 and 7.3 months after infection (n = 9); and (4) unexposed pre-pandemic subjects with systemic lupus erythematous (SLE) (n = 6). Total IgG and IgA levels were also measured from subjects in groups 1-3 to assess non-specific pan-B cell activation.
ResultsAs expected, in multivariate analysis, AABs were detected at much higher odds in SLE subjects (5 of 6, 83%) compared to non-SLE pre-pandemic controls (11 of 29, 38%) [odds ratio (OR) 19.4,95% CI, 2.0 - 557.0, p = 0.03]. AAB detection (percentage of subjects with one or more autoantibodies) was higher in SARS-CoV-2 infected convalescent subjects (7 of 9, 78%) [OR 17.4, 95% CI, 2.0 - 287.4, p = 0.02] and subjects with acute COVID-19 (12 of 20, 60%) compared with non-SLE pre-pandemic controls, but was not statistically significant among the latter [OR 1.8,95% CI, 0.6 - 8.1, p = 0.23]. Within the convalescent subject group, AABs were detected in 5/5 with reported persistent symptoms and 2/4 without continued symptoms (p = 0.17). The multivariate computational algorithm Partial Least Squares Determinant Analysis (PLSDA) was used to determine if distinct AAB signatures distinguish subject groups 1-3. Of the 18 autoantibodies measured, anti-Beta 2-Glycoprotein, anti-Proteinase 3-ANCA, anti-Mi-2 and anti-PM/Scl-100 defined the convalescent group; anti-Proteinase 3-ANCA, anti-Mi-2, anti-Jo-1 and anti-RNP/SM defined acute COVID-19 subjects; and anti-Proteinase 3-ANCA, anti-Mi-2, anti-Jo-1, anti-Beta 2-Glycoprotein distinguished unexposed controls. The AABs defining SARS-COV-2 infected from pre-pandemic subjects are widely associated with myopathies, vasculitis, and antiphospholipid syndromes, conditions with some similarities to COVID-19. Compared to pre-pandemic non-SLE controls, subjects with acute COVID-19 had higher total IgG concentration (p-value=0.006) but convalescent subjects did not (p-value=0.08); no differences in total IgA levels were found between groups.
ConclusionsOur findings support existing studies suggesting induction of immune responses to self-epitopes during acute, severe COVID-19 with evidence of general B cell hyperactivation. Also, the preponderance of AAB positivity among convalescent individuals up to seven months after infection indicates potential initiation or proliferation, and then persistence of self-reactive immunity without severe initial disease. These results underscore the importance of further investigation of autoimmunity during SARS-CoV-2 infection and its role in the onset and persistence of post-acute sequelae of COVID-19. | infectious diseases |
10.1101/2021.01.22.21249716 | An interactive COVID-19 virus Mutation Tracker (CovMT) with a particular focus on critical mutations in the Receptor Binding Domain (RBD) region of the Spike protein | Almost one year has passed since the appearance of SARS-CoV-2, causing the COVID-19 pandemic. The number of confirmed SARS-Cov-2 cases worldwide has now reached [~]92 million, with 2 million reported deaths (https://covid19.who.int). Nearly 400,000 SARS-Cov-2 genomes were sequenced from COVID-19 samples and added to public resources such as GISAID (https://gisaid.org). With the vaccines becoming available or entering trials (https://covid19.trackvaccines.org), it is vital to keep track of mutations in the genome of SARS-CoV-2, especially in the Spike proteins Receptor Binding Domain (RBD) region, which could have a potential impact on disease severity and treatment strategies.1-3 In the wake of a recent increase in cases with a potentially more infective RBD mutation (N501Y) in the United Kingdom, countries worldwide are concerned about the spread of this or similar variants. Impressive sampling and timely increase in sequencing efforts related to COVID-19 in the United Kingdom (UK) helped detect and monitor the spread of the new N501Y variant. Similar sequencing efforts are needed in other countries for timely tracking of this or different variants. To track geographic sequencing efforts and mutations, with a particular focus on RBD region of the Spike protein, we present our daily updated COVID-19 virus Mutation Tracker system, see https://www.cbrc.kaust.edu.sa/covmt. | infectious diseases |
10.1101/2021.01.22.21249945 | Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients | BackgroundReports of persistent symptoms after hospitalization with COVID-19 have raised concern of a "long COVID" syndrome. This study aimed at characterizing acute and persistent symptoms in non- hospitalized patients with polymerase chain reaction (PCR) confirmed COVID-19.
MethodsCohort study of 445 non-hospitalized participants identified via the Danish Civil Registration System with a SARS-CoV-2-positive PCR-test and available biobank samples for genetic analyses. Participants received a digital questionnaire on demographics and COVID-19-related symptoms. Persistent symptoms: symptoms >four weeks (in sensitivity analyses >12 weeks).
Results445 participants were included, of whom 34% were asymptomatic. Most common acute symptoms were fatigue, headache, and sneezing, while fatigue and reduced smell and taste were reported as most severe. Persistent symptoms, most commonly fatigue and memory and concentration difficulties, were reported by 36% of 198 symptomatic participants with follow-up >four weeks. Risk factors for persistent symptoms included female sex (women 44% vs. men 24%, odds ratio 2.7, 95%CI:1.4-5.1, p=0.003) and BMI (odds ratio 1.1, 95%CI:1.0-1.2, p=0.001).
ConclusionAmong non-hospitalized PCR-confirmed COVID-19 patients one third were asymptomatic while one third of symptomatic participants had persistent symptoms illustrating the heterogeneity of disease presentation. These findings should be considered in future health care planning and policy making related to COVID-19. | infectious diseases |
10.1101/2021.01.21.21249825 | SARS-CoV-2 Control on a Large Urban College Campus Without Mass Testing | ObjectiveA small percentage of universities and colleges conduct mass SARS-CoV-2 testing. However, universal testing is resource-intensive, strains national testing capacity, and false negative tests can encourage unsafe behaviors.
ParticipantsA large urban university campus.
MethodsVirus control centered on three pillars: mitigation, containment, and communication, with testing of symptomatic and a random subset of asymptomatic students.
ResultsRandom surveillance testing demonstrated a prevalence among asymptomatic students of 0.4% throughout the term. There were two surges in cases that were contained by enhanced mitigation and communication combined with targeted testing. Cumulative cases totaled 445 for the term, most resulting from unsafe undergraduate student behavior and among students living off-campus. A case rate of 232/10,000 undergraduates equaled or surpassed several peer institutions that conducted mass testing.
ConclusionsAn emphasis on behavioral mitigation and communication can control virus transmission on a large urban campus combined with a limited and targeted testing strategy. | infectious diseases |
10.1101/2021.01.20.20243782 | COVID-19 Diagnostic Testing For All - Using Non-Dilutive Saliva Sample Collection, Stabilization and Ambient Transport Devices | COVID-19 testing is not accessible for millions during this pandemic despite our best efforts. Without greatly expanded testing of asymptomatic individuals, contact tracing and subsequent isolation of spreaders remains as a means for control. In an effort to increase RT-PCR assay testing for the presence of the novel beta-coronavirus SARS-CoV-2 as well as improve sample collection safety, GenTegra LLC has introduced two products for saliva collection and viral RNA stabilization: GTR-STM (GenTegra Saliva Transport Medium) and GTR-STMdk (GenTegra Saliva Transport Medium Direct to PCR). Both products contain a proprietary formulation based on GenTegras novel "Active Chemical Protection" (ACP) technology that gives non-dilutive, error-free saliva sample collection using RNA stabilization chemicals already dried in the collection tube.
GTR-STM can be used for safer saliva-based sample collection at home (or at a test site). Following saliva collection, the sample-containing GTR-STM can be kept at ambient temperature during shipment to an authorized CLIA lab for analysis. SARS-CoV-2 viral RNA in GTR-STM is stable for over a month at ambient temperature, easily surviving the longest transit times from home to lab. GTR-STM enhances patient comfort, convenience, compliance and reduces infectious virus exposure to essential medical and lab professionals.
Alternatively, the GTR-STMdk direct-into-PCR product can be used to improve lab throughput and reduce reagent costs for saliva sample collection and testing at any lab site with access to refrigeration. GTR-STMdk reduces lab process time by 25% and reagent costs by 30% compared to other approaches. Since GTR-STMdk retains SARS-CoV-2 viral RNA stability for three days at ambient temperature, it is optimized for lab test site rather than at home saliva collection. SARS-COV-2 viral RNA levels as low as 0.4 genome equivalents/uL are detected in saliva samples using GTR-STMdk. The increased sensitivity of SARS-CoV-2 detection can expand COVID-19 testing to include asymptomatic individuals using pooled saliva.
One Sentence SummaryGTR-STM and Direct-into-PCR GTR-STMdk offer substantive improvements in SARS-CoV-2 viral RNA stability, safety, and RT-PCR process efficiency for COVID-19 testing by using a non-dilutive saliva sample collection system for individuals at home or onsite respectively. | infectious diseases |
10.1101/2021.01.22.21249811 | High-altitude is associated with better short-term survival in critically ill COVID-19 patients admitted to the ICU | BackgroundThe novel human coronavirus, SARS-CoV-2, has affected at least 218 countries worldwide. Some geographical and environmental factors are positively associated with a better or worse prognosis concerning COVID-19 disease and with lower or higher SARS-CoV-2 transmission. High altitude exposure has been associated with lower SARS-CoV-2 attack rates; nevertheless, the role of chronic high-altitude exposure on the clinical outcome of critically ill COVID-19 patients has not been studied.
ObjectiveTo compare the clinical course and outcomes of critically ill patients with COVID-19 hospitalized in two intensive care units (ICU) located at low and high altitude.
Exposure and OutcomeTo explore the effect of two different elevations (10 m vs 2,850 m above sea level) on COVID-19 clinical outcome and survival.
MethodsA prospective cohort, two-center study in confirmed COVID-19 adult patients admitted to a low altitude (Sea level) and high altitude (2,850 m) ICU units in Ecuador was conducted. Two hundred and thirty confirmed COVID-19 patients were enrolled from March 15th to July 15th, 2020. Sociodemographic, clinical, laboratory and imaging parameters including supportive therapies, pharmacological treatments and medical complications were reported and compared between the low and high-altitude groups.
ResultsThe median age of all the patients was 60 years, 64.8% were men and 35.2% were women. A total of 105 (45.7%) patients had at least one underlying comorbidity, the most frequent being chronic diseases, such as hypertension (33.5%), diabetes (16.5%), and chronic kidney failure (5.7%). The APACHE II scale at 72 hours was especially higher in the low-altitude group with a median of 18 points (IQR: 9.5-24.0), compared to 9 points (IQR: 5.0-22.0) obtained in the group of high altitude. There is evidence of a difference in survival in favor of the high-altitude group (p = 0.006), the median survival being 39 days, compared to 21 days in the low altitude group.
ConclusionThere has been a substantial improvement in survival amongst people admitted to the high-altitude critical care unit. High altitude living was associated with improved survival, especially among patients with no comorbidities. COVID-19 patients admitted to the high-altitude ICU unit have improved severity-of-disease classification system scores at 72 hours and reported better respiratory and ventilatory profiles than the low altitude group. | intensive care and critical care medicine |
10.1101/2021.01.20.21250109 | Numbers of close contacts of individuals infected with SARS-CoV-2 and their association with government intervention strategies. | BackgroundContact tracing is conducted with the primary purpose of interrupting transmission from individuals who are likely to be infectious to others. Secondary analyses of data on the numbers of close contacts of confirmed cases could also: provide an early signal of increases in contact patterns that might precede larger than expected case numbers; evaluate the impact of government interventions on the number of contacts of confirmed cases; or provide data information on contact rates between age cohorts for the purpose of epidemiological modelling.
MethodsWe analysed data from 140,204 contacts of 39861 cases in Ireland from 1st May to 1st December 2020. Only close contacts were included in the analysis. A close contact was defined as any individual who had had > 15 minutes face-to-face (<2 m) contact with a case; any household contact; or any individual sharing a closed space for longer than 2 hours, in any setting.
ResultsThe number of contacts per case was overdispersed, the mean varied considerably over time, and was temporally associated with government interventions. Negative binomial regression models highlighted greater numbers of contacts within specific population demographics, after correcting for temporal associations. Separate segmented regression models of the number of cases over time and the average number of contacts per case indicated that a breakpoint indicating a rapid decrease in the number of contacts per case in October 2020 preceded a breakpoint indicating a reduction in the number of cases by 11 days.
DiscussionThese data were collected for a specific purpose and therefore any inferences must be made with caution. The data are representative of contact rates of cases, and not of the overall population. However, the data may be a more accurate indicator of the likely degree of onward transmission than might be the case if a random sample of the population were taken. Furthermore, since we analysed only the number of close contacts, the total number of contacts per case would have been higher. Nevertheless, this analysis provides useful information for monitoring the impact of government interventions on the number of contacts; for helping pre-empt increases or decreases in case numbers, and for triangulating assumptions regarding the contact mixing rates between different age cohorts for epidemiological modelling. | epidemiology |
10.1101/2021.01.24.21250411 | Disaggregating proportional multistate lifetables by population heterogeneity to estimate intervention impacts on inequalities | BackgroundSimulation models can be used to quantify the projected health impact of interventions. Quantifying heterogeneity in these impacts, for example by socioeconomic status, is important to understand impacts on health inequalities.
We aim to disaggregate one type of Markov macro-simulation model, the proportional multistate lifetable, ensuring that under business-as-usual (BAU) the sum of deaths across disaggregated strata in each time step returns the same as the initial non-disaggregated model. We then demonstrate the application by deprivation quintiles for New Zealand (NZ), for: hypothetical interventions (50% lower all-cause mortality, 50% lower coronary heart disease mortality) and a dietary intervention to substitute 59% of sodium with potassium chloride in the food supply.
MethodsWe developed a disaggregation algorithm that iteratively rescales mortality, incidence and case fatality rates by time-step of the model to ensure correct total population counts were retained at each step.
To demonstrate the algorithm on deprivation quintiles in NZ, we used the following inputs: overall (non-disaggregated) all-cause mortality &morbidity rates, coronary heart disease incidence &case fatality rates; stroke incidence &case fatality rates. We also obtained rate ratios by deprivation for these same measures. Given all-cause and cause-specific mortality rates by deprivation quintile, we derived values for the incidence, case fatality and mortality rates for each quintile, ensuring rate ratios across quintiles and the total population mortality and morbidity rates were returned when averaged across groups.
The three interventions were then run on top of these scaled BAU scenarios.
ResultsThe algorithm exactly disaggregated populations by strata in BAU. The intervention scenario life years and health adjusted life years (HALYs) gained differed slightly when summed over the deprivation quintile compared to the aggregated model, due to the stratified model (appropriately) allowing for differential background mortality rates by strata. Modest differences in health gains (health adjusted life years) resulted from rescaling of sub-population mortality and incidence rates to ensure consistency with the aggregate population.
ConclusionPolicy makers ideally need to know the effect of population interventions estimated both overall, and by socioeconomic and other strata. We demonstrate a method and provide code to do this routinely within proportional multistate lifetable simulation models and similar Markov models. | epidemiology |
10.1101/2021.01.24.21250406 | On mobility trends analysis of COVID-19 dissemination in Mexico City | This work presents a forecast of the spread of the new coronavirus in Mexico City based on a mathematical model with metapopulation structure by using Bayesian Statistics inspired in a data-driven approach. The mobility of humans on a daily basis in Mexico City is mathematically represented by a origin-destination matrix using the open mobility data from Google and a Transportation Mexican Survey. This matrix, is incorporated in a compartmental model. We calibrate the model against borough-level incidence data collected between February 27, 2020 and October 27, 2020 using Bayesian inference to estimate critical epidemiological characteristics associated with the coronavirus spread. Since working with metapopulation models lead to rather high computational time consume, we do a clustering analysis based on mobility trends in order to work on these clusters of borough separately instead of taken all the boroughs together at once. This clustering analysis could be implemented in smaller or lager scale in different part of the world. In addition, this clustering analysis is divided in the phases that the government of Mexico City has set up to restrict the individuals movement in the city. Also, we calculate the reproductive number in Mexico City using the next generation operator method and the inferred model parameters. The analysis of mobility trends can be helpful in public health decisions. | epidemiology |
10.1101/2021.01.23.21250376 | Predictive power of SARS-CoV-2 wastewater surveillance for diverse populations across a large geographical range | The COVID-19 pandemic has exacerbated the disparities in healthcare delivery in the US. Many communities had, and continue to have, limited access to COVID-19 testing, making it difficult to track the spread and impact of COVID-19 in early days of the outbreak. To address this issue we monitored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA at the population-level using municipal wastewater influent from 19 cities across the state of Minnesota during the COVID-19 outbreak in Summer 2020. Viral RNA was detected in wastewater continually for 20-weeks for cities ranging in populations from 500 to >1, 000, 000. Using a novel indexing method, we were able to compare the relative levels of SARS-CoV-2 RNA for each city during this sampling period. Our data showed that viral RNA trends appeared to precede clinically confirmed cases across the state by several days. Lag analysis of statewide trends confirmed that wastewater SARS-CoV-2 RNA levels preceded new clinical cases by 15-17 days. At the regional level, new clinical cases lagged behind wastewater viral RNA anywhere from 4-20 days. Our data illustrates the advantages of monitoring at the population-level to detect outbreaks. Additionally, by tracking infections with this unbiased approach, resources can be directed to the most impacted communities before the need outpaces the capacity of local healthcare systems. | epidemiology |
10.1101/2021.01.23.21250376 | Predictive power of SARS-CoV-2 wastewater surveillance for diverse populations across a large geographical range | The COVID-19 pandemic has exacerbated the disparities in healthcare delivery in the US. Many communities had, and continue to have, limited access to COVID-19 testing, making it difficult to track the spread and impact of COVID-19 in early days of the outbreak. To address this issue we monitored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA at the population-level using municipal wastewater influent from 19 cities across the state of Minnesota during the COVID-19 outbreak in Summer 2020. Viral RNA was detected in wastewater continually for 20-weeks for cities ranging in populations from 500 to >1, 000, 000. Using a novel indexing method, we were able to compare the relative levels of SARS-CoV-2 RNA for each city during this sampling period. Our data showed that viral RNA trends appeared to precede clinically confirmed cases across the state by several days. Lag analysis of statewide trends confirmed that wastewater SARS-CoV-2 RNA levels preceded new clinical cases by 15-17 days. At the regional level, new clinical cases lagged behind wastewater viral RNA anywhere from 4-20 days. Our data illustrates the advantages of monitoring at the population-level to detect outbreaks. Additionally, by tracking infections with this unbiased approach, resources can be directed to the most impacted communities before the need outpaces the capacity of local healthcare systems. | epidemiology |
10.1101/2021.01.24.21250405 | Mathematical Relationship between Effective Reproduction Number Rt and Epidemic Curve of Daily Cases -- Demonstration and Details | The strict mathematical relationship between Rt and the curve of daily cases f(t) is shown. Up-to-date and statistically robust Rt from the curve of daily cases can be estimated as soon as new cases are added to the curve. That is equivalent to estimating Rt by averaging all detected cases of infection, without any distortion induced by the difficulty of following and weighting trees of secondary cases from original ones, and without needing to wait for secondary cases to manifest infection. With this method, if Rt scaled numbers are of interest, only the average duration of infectivity of subjects has to be estimated directly, but independently of linking secondary cases to primary ones. A new index, instantaneous reproduction number Rist is introduced, which does not depend on the duration of infectivity of subjects. Rist, Rt and the doubling/halving time of the epidemics may be estimated by simple computations at the very detection time of new daily cases. Any smoothed curve of daily cases gives smooth Rt and Rist. No phase lag on Rt estimate is introduced by this method. | epidemiology |
10.1101/2021.01.21.21250226 | Determinants of the incidence and mortality rates of COVID-19 during the first six months of the pandemic; A cross-country study | COVID-19 pandemic raises an extraordinary challenge to the healthcare systems globally. The governments are taking key measures to constrain the corresponding health, social, and economic impacts, however, these measures vary depending on the nature of the crisis and country-specific circumstances.
ObjectivesConsidering different incidence and mortality rates across different countries, we aimed at explaining variance of these variables by performing accurate and precise multivariate analysis with aid of suitable predictors, accordingly, the model would proactively guide the governmental responses to the crisis.
MethodsUsing linear and exponential time series analysis, this research aimed at studying the incidence and mortality rates of COVID-19 in 18 countries during the first six months of the pandemic, and further utilize multivariate techniques to explain the variance in monthly exponential growth rates of cases and deaths with aid of a set of different predictors: the recorded Google mobility trends towards six categories of places, daily average temperature, daily humidity, and key socioeconomic attributes of each country.
ResultsThe analysis showed that changes in mobility trends were the most significant predictors of the incidence and mortality rates, temperature and humidity were also significant but to a much lesser extent, on the other hand, the socioeconomic attributes did not contribute significantly to explaining different incidence and mortality rates across countries.
ConclusionChanges in mobility trends across countries dramatically affected the incidence and mortality rates across different countries, thus, it might be used as a proxy measure of contact frequency. | epidemiology |
10.1101/2021.01.24.21250416 | Social, economic, and environmental factors influencing the basic reproduction number of COVID-19 across countries | ObjectiveTo assess whether the basic reproduction number (R0) of COVID-19 is different across countries and what national-level demographic, social, and environmental factors characterize initial vulnerability to the virus.
MethodsWe fit logistic growth curves to reported daily case numbers, up to the first epidemic peak. This fitting estimates R0. We then use a generalized additive model to discern the effects, and include 5 random effect covariates to account for potential differences in testing and reporting that can bias the estimated R0.
FindingsWe found that the mean R0 is 1.70 (S.D. 0.57), with a range between 1.10 (Ghana) and 3.52 (South Korea). We identified four factors-population between 20-34 years old (youth), population residing in urban agglomerates over 1 million (city), social media use to organize offline action (social media), and GINI income inequality-as having strong relationships with R0. An intermediate level of youth and GINI inequality are associated with high R0, while high city population and high social media use are associated with high R0. Environmental and climate factors were not found to have strong relationships with R0.
ConclusionStudies that aim to measure the effectiveness of interventions should account for the intrinsic differences between populations. | epidemiology |
10.1101/2021.01.22.21250304 | Rates of serious clinical outcomes in survivors of hospitalisation with COVID-19: a descriptive cohort study within the OpenSAFELY platform | BackgroundPatients with COVID-19 are thought to be at higher risk of cardiometabolic and pulmonary complications, but quantification of that risk is limited. We aimed to describe the overall burden of these complications in survivors of severe COVID-19.
MethodsWorking on behalf of NHS England, we used linked primary care records, death certificate and hospital data from the OpenSAFELY platform. We constructed three cohorts: patients discharged following hospitalisation with COVID-19, patients discharged following hospitalisation with pneumonia in 2019, and a frequency-matched cohort from the general population in 2019. We studied eight cardiometabolic and pulmonary outcomes. Absolute rates were measured in each cohort and Cox regression models were fitted to estimate age/sex adjusted hazard ratios comparing outcome rates between discharged COVID-19 patients and the two comparator cohorts.
ResultsAmongst the population of 31,716 patients discharged following hospitalisation with COVID-19, rates for majority of outcomes peaked in the first month post-discharge, then declined over the following four months. Patients in the COVID-19 population had markedly increased risk of all outcomes compared to matched controls from the 2019 general population, especially for pulmonary embolism (HR 12.86; 95% CI: 11.23 - 14.74). Outcome rates were more similar when comparing patients discharged with COVID-19 to those discharged with pneumonia in 2019, although COVID-19 patients had increased risk of type 2 diabetes (HR 1.23; 95% CI: 1.05 - 1.44).
InterpretationCardiometabolic and pulmonary adverse outcomes are markedly raised following hospitalisation for COVID-19 compared to the general population. However, the excess risks were more comparable to those seen following hospitalisation with pneumonia. Identifying patients at particularly high risk of outcomes would inform targeted preventive measures.
FundingWellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, UK Research and Innovation, Health and Safety Executive. | epidemiology |
10.1101/2021.01.22.21250304 | Rates of serious clinical outcomes in survivors of hospitalisation with COVID-19: a descriptive cohort study within the OpenSAFELY platform | BackgroundPatients with COVID-19 are thought to be at higher risk of cardiometabolic and pulmonary complications, but quantification of that risk is limited. We aimed to describe the overall burden of these complications in survivors of severe COVID-19.
MethodsWorking on behalf of NHS England, we used linked primary care records, death certificate and hospital data from the OpenSAFELY platform. We constructed three cohorts: patients discharged following hospitalisation with COVID-19, patients discharged following hospitalisation with pneumonia in 2019, and a frequency-matched cohort from the general population in 2019. We studied eight cardiometabolic and pulmonary outcomes. Absolute rates were measured in each cohort and Cox regression models were fitted to estimate age/sex adjusted hazard ratios comparing outcome rates between discharged COVID-19 patients and the two comparator cohorts.
ResultsAmongst the population of 31,716 patients discharged following hospitalisation with COVID-19, rates for majority of outcomes peaked in the first month post-discharge, then declined over the following four months. Patients in the COVID-19 population had markedly increased risk of all outcomes compared to matched controls from the 2019 general population, especially for pulmonary embolism (HR 12.86; 95% CI: 11.23 - 14.74). Outcome rates were more similar when comparing patients discharged with COVID-19 to those discharged with pneumonia in 2019, although COVID-19 patients had increased risk of type 2 diabetes (HR 1.23; 95% CI: 1.05 - 1.44).
InterpretationCardiometabolic and pulmonary adverse outcomes are markedly raised following hospitalisation for COVID-19 compared to the general population. However, the excess risks were more comparable to those seen following hospitalisation with pneumonia. Identifying patients at particularly high risk of outcomes would inform targeted preventive measures.
FundingWellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, UK Research and Innovation, Health and Safety Executive. | epidemiology |
10.1101/2021.01.22.21250304 | Rates of serious clinical outcomes in survivors of hospitalisation with COVID-19: a descriptive cohort study within the OpenSAFELY platform | BackgroundPatients with COVID-19 are thought to be at higher risk of cardiometabolic and pulmonary complications, but quantification of that risk is limited. We aimed to describe the overall burden of these complications in survivors of severe COVID-19.
MethodsWorking on behalf of NHS England, we used linked primary care records, death certificate and hospital data from the OpenSAFELY platform. We constructed three cohorts: patients discharged following hospitalisation with COVID-19, patients discharged following hospitalisation with pneumonia in 2019, and a frequency-matched cohort from the general population in 2019. We studied eight cardiometabolic and pulmonary outcomes. Absolute rates were measured in each cohort and Cox regression models were fitted to estimate age/sex adjusted hazard ratios comparing outcome rates between discharged COVID-19 patients and the two comparator cohorts.
ResultsAmongst the population of 31,716 patients discharged following hospitalisation with COVID-19, rates for majority of outcomes peaked in the first month post-discharge, then declined over the following four months. Patients in the COVID-19 population had markedly increased risk of all outcomes compared to matched controls from the 2019 general population, especially for pulmonary embolism (HR 12.86; 95% CI: 11.23 - 14.74). Outcome rates were more similar when comparing patients discharged with COVID-19 to those discharged with pneumonia in 2019, although COVID-19 patients had increased risk of type 2 diabetes (HR 1.23; 95% CI: 1.05 - 1.44).
InterpretationCardiometabolic and pulmonary adverse outcomes are markedly raised following hospitalisation for COVID-19 compared to the general population. However, the excess risks were more comparable to those seen following hospitalisation with pneumonia. Identifying patients at particularly high risk of outcomes would inform targeted preventive measures.
FundingWellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, UK Research and Innovation, Health and Safety Executive. | epidemiology |
10.1101/2021.01.22.21249308 | Using Non-Pharmaceutical Interventions and High Isolation of Asymptomatic Carriers to Contain the Spread of SARS-CoV-2 in Nursing Homes | ObjectiveUsing a pandemic influenza model modified for COVID-19, this study investigated the degree of control over pre-symptomatic transmission that common non-pharmaceutical interventions (NPIs) would require to reduce the spread in long-term care facilities.
MethodsWe created a stochastic compartmental SEIR model with Poisson-distributed transition states that compared the effect of R0, common NPIs, and isolation rates of pre-symptomatic carriers primarily on attack rate, peak cases, and timing in a 200-resident nursing home. Model sensitivity was assessed with 1st order Sobol indices.
ResultsThe most rigorous NPIs decreased the peak number of infections by 4.3 and delayed the peak by 9.7 days in the absence of pre-symptomatic controls. Reductions in attack rate were not likely, even with rigorous application of all defined NPIs, unless pre-symptomatic carriers were identified and isolated at rates exceeding 76%. Attack rate was most sensitive to the pre-symptomatic isolation rate (Sobol index > 0.7) and secondarily to R0.
ConclusionsCommon NPIs delayed and reduced epidemic peaks. Reducing attack rates ultimately required efficient isolation of pre-symptomatic cases, including rapid antigen tests on a nearly daily basis. This must be accounted for in testing and contact tracing plans for group living settings. | epidemiology |
10.1101/2021.01.22.21249726 | Development of quantitative frailty and mortality prediction models on older patients as a palliative care needs assessment tool | BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.
ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.
MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.
ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.
ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es. | palliative medicine |
10.1101/2021.01.22.21249726 | Development of quantitative frailty and mortality prediction models on older patients as a palliative care needs assessment tool | BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.
ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.
MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.
ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.
ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es. | palliative medicine |
10.1101/2021.01.22.21249726 | Complementary frailty and mortality prediction models on older patients as a tool for assessing palliative care needs | BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.
ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.
MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.
ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.
ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es. | palliative medicine |
10.1101/2021.01.25.21250437 | Tracking the mental health of home-carers during the first COVID-19 national lockdown: evidence from a nationally representative UK survey | BackgroundUnpaid carers who look after another member of their household (home-carers) have poorer mental health than the general population. The first COVID-19 national lockdown led to an increasing reliance on home-carers and we investigate the short and longer-term impact of lockdown on their mental health.
MethodsData from 9,737 adult participants (aged 16+) from the UK Household Longitudinal Study (Understanding Society) were used to explore changes in 12-item General Health Questionnaire (GHQ-12) score between (a) pre-pandemic (2019) and early lockdown (April 2020) and (b) early and later (July 2020) lockdown.
ResultsGHQ-12 scores among home-carers were higher pre-lockdown and increased more than for non-carers from 2019 to April 2020 with further increases for home-carers compared with non-carers between April and July. Compared with respondents caring for a spouse/partner, those caring for a child under 18 had a particularly marked increase in GHQ-12 score between 2019 and April, as did those caring for someone with learning difficulties. Home-carers of children under 18 improved from April to July while those caring for adult children saw a marked worsening of their mental health. Home-carers with greater care burden saw larger increases in GHQ-12 score from 2019 to April and from April to July, and increases through both periods were greater for home-carers who had formal help prior to lockdown but then lost it.
ConclusionsThe mental health of home-carers deteriorated more during lockdown than non-carers. Policies that reinstate support for them and their care-recipients will benefit the health of both vulnerable groups.
What is already known on this topicO_LICarers have poorer mental health than the general population.
C_LIO_LIAmong carers who live with the care recipient (home-carers), some subgroups have poorer mental health than others: female versus male; those who provide more hours of care and have been caring for longer; spousal carers compared with those caring for children (including adult), parents, or other relationships; those caring for individuals whose impairment results in behavioural disturbances, than those who care for individuals with physical or long-term health conditions.
C_LI
What this study addsO_LIIn a large representative UK survey, the decline in mental health during lockdown was greater among home-carers than for the general population, and stayed poorer through to July, even as the general populations mental health recovered slightly.
C_LIO_LICompared with respondents who were caring for a spouse/partner, those caring for a child under 18 had a particularly marked increase in GHQ-12 score between 2019 and April while those caring for an adult child experienced a substantial decline in their mental health between the beginning and end of the first lockdown (April to July).
C_LIO_LIThe increase in GHQ-12 in April from 2019 was highest among those caring for someone with a learning disability and lowest for those caring for someone with a problem related to old age.
C_LIO_LIHome-carers who had a greater care burden, in terms of hours of care provided, or lost formal support during lockdown, had poorer mental health.
C_LI | public and global health |
10.1101/2021.01.22.21249968 | An external validation of the QCovid risk prediction algorithm for risk of mortality from COVID-19 in adults: national validation cohort study in England | BackgroundTo externally validate a risk prediction algorithm (QCovid) to estimate mortality outcomes from COVID-19 in adults in England.
MethodsPopulation-based cohort study using the ONS Public Health Linked Data Asset, a cohort based on the 2011 Census linked to Hospital Episode Statistics, the General Practice Extraction Service Data for pandemic planning and research, radiotherapy and systemic chemotherapy records. The primary outcome was time to COVID-19 death, defined as confirmed or suspected COVID-19 death as per death certification. Two time periods were used: (a) 24th January to 30th April 2020; and (b) 1st May to 28th July 2020. We evaluated the performance of the QCovid algorithms using measures of discrimination and calibration for each validation time period.
FindingsThe study comprises 34,897,648 adults aged 19-100 years resident in England. There were 26,985 COVID-19 deaths during the first time-period and 13,177 during the second. The algorithms had good calibration in the validation cohort in both time periods with close correspondence of observed and predicted risks. They explained 77.1% (95% CI: 76.9% to 77.4%) of the variation in time to death in men in the first time-period (R2); the D statistic was 3.76 (95% CI: 3.73 to 3.79); Harrells C was 0.935 (0.933 to 0.937). Similar results were obtained for women, and in the second time-period. In the top 5% of patients with the highest predicted risks of death, the sensitivity for identifying deaths in the first time period was 65.9% for men and 71.7% for women. People in the top 20% of predicted risks of death accounted for 90.8% of all COVID-19 deaths for men and 93.0% for women.
InterpretationThe QCovid population-based risk algorithm performed well, showing very high levels of discrimination for COVID-19 deaths in men and women for both time periods. It has the potential to be dynamically updated as the pandemic evolves and therefore, has potential use in guiding national policy.
FundingNational Institute of Health Research
RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSPublic policy measures and clinical risk assessment relevant to COVID-19 need to be aided by rigorously developed and validated risk prediction models. A recent living systematic review of published risk prediction models for COVID-19 found most models are subject to a high risk of bias with optimistic reported performance, raising concern that these models may be unreliable when applied in practice. A population-based risk prediction model, QCovid risk prediction algorithm, has recently been developed to identify adults at high risk of serious COVID-19 outcomes, which overcome many of the limitations of previous tools.
Added value of this studyCommissioned by the Chief Medical Officer for England, we validated the novel clinical risk prediction model (QCovid) to identify risks of short-term severe outcomes due to COVID-19. We used national linked datasets from general practice, death registry and hospital episode data for a population-representative sample of over 34 million adults. The risk models have excellent discrimination in men and women (Harrells C statistic>0.9) and are well calibrated. QCovid represents a new, evidence-based opportunity for population risk-stratification.
Implications of all the available evidenceQCovid has the potential to support public health policy, from enabling shared decision making between clinicians and patients in relation to health and work risks, to targeted recruitment for clinical trials, and prioritisation of vaccination, for example. | public and global health |
10.1101/2021.01.24.21250397 | Using an Ecological and Biological Framing for an Anti-racist Covid-19 Approach | In the United States and the United Kingdom COVID-19 has disproportionately affected Black, Indigenous and People of Colour (BIPOC) and Black, Asian and Minority Ethnic (BAME) people respectively. Multiple studies identify environmental factors such as overcrowded housing and poor workplace conditions as contributing factors for the disproportionate COVID-19 rates amongst BAME and BIPOC communities. This paper will show that to fully understand the phenomenon, both an ecological and biological approach is needed. An ecological approach highlights how a persons habitat and the experiences within it mediate their susceptibility to disease. Moreover, to understand how this mediation works, this paper will use allostatic load as a biological pathway to link a person to their habitat and the poor health outcomes that contributed to COVID-19 susceptibility. In introducing this new approach, the paper will serve as an anti-racist framework for understanding how COVID-19 affected BAME and BIPOC communities. It is anti-racist by centring poor health outcomes on the habitats people are forced to live in due to structural racism rather than the physiology of a persons race or ethnicity. This is important in order to avoid similar crises in the future and to improve the health of marginalised communities. | public and global health |
10.1101/2021.01.24.21250401 | Impact of gastric resection and enteric anastomotic configuration on delayed gastric emptying after pancreaticoduodenectomy: a network meta-analysis of randomized trials | IntroductionDelayed gastric emptying (DGE) is frequent after pancreaticoduodenectomy (PD). Several randomised controlled trials (RCTs) have explored operative strategies to minimise DGE, however, the optimal combination of gastric resection approach, anastomotic route, and configuration, role of Braun enteroenterostomy remains unclear.
MethodsMEDLINE, Embase, and CENTRAL databases were systematically searched for RCTs comparing gastric resection (Classic Whipple, pylorus-resecting, and pylorus-preserving), anastomotic route (antecolic vs retrocolic) and configuration (Billroth II vs Roux-en-Y), and enteroenterostomy (Braun vs no Braun). A random-effects, Bayesian network meta-analysis with non-informative priors was conducted to determine the optimal combination of approaches to PD for minimising DGE.
ResultsTwenty-four RCTs, including 2526 patients and 14 approaches were included. There was some heterogeneity, although inconsistency was low. The overall incidence of DGE was 25.6% (n = 647). Pylorus-resecting, antecolic, Billroth II with Braun enteroenterostomy was associated with the lowest rates of DGE and ranked the best in 35% of comparisons. Classic Whipple, retrocolic, Billroth II with Braun ranked the worst for DGE in 32% of comparisons. Pairwise meta-analysis of retrocolic vs antecolic route of gastro-jejunostomy found increased risk of DGE with the retrocolic route (OR 2.1, 95% CrI; 0.92 - 4.7). Pairwise meta-analysis of Braun enteroenterostomy found a trend towards lower DGE rates with Braun compared to no Braun (OR 1.9, 95% CrI; 0.92 - 3.9). Having a Braun enteroenterostomy ranked the best in 96% of comparisons.
ConclusionBased on existing RCT evidence, a pylorus-resecting, antecolic, Billroth II with Braun enteroenterostomy may be associated with the lowest rates of DGE. | surgery |
10.1101/2021.01.24.21250413 | Protocol for a realist review of the influence of cultural factors on understanding the role of feedback in developing clinical competencies of health professional students in Asia. | IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.
In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.
The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.
Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.
Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.
Ethics and DisseminationAs this study is a literature review, ethics approval is not required.
The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).
Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI | medical education |
10.1101/2021.01.24.21250413 | Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. | IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.
In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.
The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.
Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.
Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.
Ethics and DisseminationAs this study is a literature review, ethics approval is not required.
The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).
Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI | medical education |
10.1101/2021.01.23.21250015 | Bidirectional Associations between Short or Long Sleep Duration and Cognitive Function: the China Health and Retirement Longitudinal Study | IMPORTANCEThe bidirectional association between sleep duration and cognitive function has not been conclusively demonstrated.
OBJECTIVETo investigate the longitudinal association between sleep duration and cognitive function among middle-aged and elderly Chinese participants.
Design, SETTING, AND PARTICIPANTSA national representative and prospective longitudinal study in China. 7984 participants aged 45 years and above were assessed at baseline between June 2011 and March 2012 (wave 1) and 2013 (wave 2), 2015 (wave 3) and 2018 (wave4).
MAIN OUCOMES AND MEASURESSelf-reported nighttime sleep duration was evaluated by interview. Cognitive function was evaluated via assessments of global cognition, which reflected the ability of episodic memory, visuospatial construction, calculation, orientation and attention.
ResultsRegarding the 7984 participants in wave 4, the mean (SD) age was 64.7 (8.4), 3862 (48.4) were male, and 6453 (80.7) lived in rural area. There were 14981, 11768 (78.6%), 10192 (68.0%), 7984 (53.3%) participants in the four waves of the study, respectively. Latent growth models showed both sleep duration and global cognition worsen over time. Cross-lagged models indicated that long or short sleep duration in the previous wave was associated lower global cognition in the next wave (standardized {beta}=-0.066; 95%CI: -0.073, -0.059; P<0.001; Wave 1 to 2), and lower global cognition in the previous wave was associated with long or short sleep duration in the next wave (standardized {beta}=-0.106; 95%CI: -0.116, -0.096; P<0.001; Wave 1 to 2). Global cognition was probably the major driver in this reciprocal associations.
CONCLUSIONS AND REVELANCEThere were bidirectional associations between long or short sleep duration and cognitive function. Lower cognitive function had a stronger association with worse cognitive function than the reverse. A moderate sleep duration is always recommended. Moreover, attention should be paid on the declined cognition and cognitive therapy among older adults with short or long sleep duration. | neurology |
10.1101/2021.01.24.21250391 | Existence of SARS-CoV-2 RNA on ambient particulate matter samples: A nationwide study in Turkey | Coronavirus disease 2019 (COVID-19) is caused by the SARS-CoV-2 virus and has been affecting the world since the end of 2019. Turkey is severely affected with the first case being reported on March 11th 2020. Ambient particulate matter (PM) samples in various size ranges were collected from 13 sites including urban and urban background locations and hospital gardens in 10 cities across Turkey between the 13th of May and the 14th of June, 2020 to investigate a possible presence of SARS-CoV-2 RNA on ambient PM. A total of 155 daily samples (TSP, n=80; PM2.5, n=33; PM2.5-10, n=23; PM10, n=19; and 6 size segregated, n=48) were collected using various samplers in each city. The N1 gene and RdRP gene expressions were analyzed for the presence of SARS-CoV-2 as suggested by the Centers for Disease Control and Prevention (CDC). According to RT-PCR and 3D-RT-PCR analysis, dual RdRP and N1 gene positivity were detected in 20 (9.8 %) of the samples. The highest percentage of virus detection on PM samples was from hospital gardens in Tekirda[g], Zonguldak, and [I]stanbul--especially in PM2.5 mode. Samples collected from two urban sites were also positive. Findings of this study have suggested that SARS-CoV-2 may be transported by ambient particles especially at sites close to the infection hot-spots. However, whether this has an impact on the spread of the virus infection remains to be determined.
Significance StatementAlthough there are several studies reporting the existence of SARS-CoV-2 in indoor aerosols is established, it remains unclear whether the virus is transported by ambient atmospheric particles. The presence of the SARS-CoV-2 RNA in ambient particles collected from characteristic sites within various size ranges was investigated, and positive results were found in urban sites especially around Turkish hospitals. In this context, this study offers a new discussion on the transmission of the virus via ambient particles. | occupational and environmental health |
10.1101/2021.01.24.21250391 | Existence of SARS-CoV-2 RNA on ambient particulate matter samples: A nationwide study in Turkey | Coronavirus disease 2019 (COVID-19) is caused by the SARS-CoV-2 virus and has been affecting the world since the end of 2019. Turkey is severely affected with the first case being reported on March 11th 2020. Ambient particulate matter (PM) samples in various size ranges were collected from 13 sites including urban and urban background locations and hospital gardens in 10 cities across Turkey between the 13th of May and the 14th of June, 2020 to investigate a possible presence of SARS-CoV-2 RNA on ambient PM. A total of 155 daily samples (TSP, n=80; PM2.5, n=33; PM2.5-10, n=23; PM10, n=19; and 6 size segregated, n=48) were collected using various samplers in each city. The N1 gene and RdRP gene expressions were analyzed for the presence of SARS-CoV-2 as suggested by the Centers for Disease Control and Prevention (CDC). According to RT-PCR and 3D-RT-PCR analysis, dual RdRP and N1 gene positivity were detected in 20 (9.8 %) of the samples. The highest percentage of virus detection on PM samples was from hospital gardens in Tekirda[g], Zonguldak, and [I]stanbul--especially in PM2.5 mode. Samples collected from two urban sites were also positive. Findings of this study have suggested that SARS-CoV-2 may be transported by ambient particles especially at sites close to the infection hot-spots. However, whether this has an impact on the spread of the virus infection remains to be determined.
Significance StatementAlthough there are several studies reporting the existence of SARS-CoV-2 in indoor aerosols is established, it remains unclear whether the virus is transported by ambient atmospheric particles. The presence of the SARS-CoV-2 RNA in ambient particles collected from characteristic sites within various size ranges was investigated, and positive results were found in urban sites especially around Turkish hospitals. In this context, this study offers a new discussion on the transmission of the virus via ambient particles. | occupational and environmental health |
10.1101/2021.01.24.21250385 | Launching a saliva-based SARS-CoV-2 surveillance testing program on a university campus | Regular surveillance testing of asymptomatic individuals for SARS-CoV-2 has played a vital role in SARS-CoV-2 outbreak prevention on college and university campuses. Here we describe the voluntary saliva testing program instituted at the University of California, Berkeley during an early period of the SARS-CoV-2 pandemic in 2020. The program was administered as a research study ahead of clinical implementation, enabling us to launch surveillance testing while continuing to optimize the assay. Results of both the testing protocol itself and the study participants experience show how the program succeeded in providing routine, robust testing capable of contributing to outbreak prevention within a campus community and offer strategies for encouraging participation and a sense of civic responsibility. | health systems and quality improvement |
10.1101/2021.01.24.21250385 | Launching a saliva-based SARS-CoV-2 surveillance testing program on a university campus | Regular surveillance testing of asymptomatic individuals for SARS-CoV-2 has played a vital role in SARS-CoV-2 outbreak prevention on college and university campuses. Here we describe the voluntary saliva testing program instituted at the University of California, Berkeley during an early period of the SARS-CoV-2 pandemic in 2020. The program was administered as a research study ahead of clinical implementation, enabling us to launch surveillance testing while continuing to optimize the assay. Results of both the testing protocol itself and the study participants experience show how the program succeeded in providing routine, robust testing capable of contributing to outbreak prevention within a campus community and offer strategies for encouraging participation and a sense of civic responsibility. | health systems and quality improvement |
10.1101/2021.01.24.21250385 | Launching a saliva-based SARS-CoV-2 surveillance testing program on a university campus | Regular surveillance testing of asymptomatic individuals for SARS-CoV-2 has played a vital role in SARS-CoV-2 outbreak prevention on college and university campuses. Here we describe the voluntary saliva testing program instituted at the University of California, Berkeley during an early period of the SARS-CoV-2 pandemic in 2020. The program was administered as a research study ahead of clinical implementation, enabling us to launch surveillance testing while continuing to optimize the assay. Results of both the testing protocol itself and the study participants experience show how the program succeeded in providing routine, robust testing capable of contributing to outbreak prevention within a campus community and offer strategies for encouraging participation and a sense of civic responsibility. | health systems and quality improvement |
10.1101/2021.01.21.21250207 | Analytical and clinical evaluation of antibody tests for SARS-CoV-2 serosurveillance studies used in Finland in 2020 | BackgroundSensitive and highly specific antibody tests are critical for detection of SARS-CoV-2 antibodies especially in populations where seroprevalence is low.
AimTo set up, optimize and evaluate the analytical and clinical performance of a new in-house microsphere immunoassay for measurement of IgG antibodies to SARS-CoV-2 nucleoprotein for assessment of population seroprevalence in Finland.
MethodsWe set up a new in-house microsphere immunoassay (FMIA) with SARS-CoV-2 nucleoprotein and optimized its analytical performance. For evaluation of clinical performance, we tested sera collected in a well-characterized cohort of PCR positive-confirmed SARS-CoV-2 patients (n=89) with mostly mild symptoms, and before the COVID-19 pandemic (n=402), for nucleoprotein specific IgG concentrations by FMIA and a commercial chemiluminescent immunoassay and for neutralizing antibodies by the microneutralization test.
ResultsThe analytical performance of FMIA was established in terms of sensitivity, linearity and precision. FMIA discriminated between COVID-19 patient and control samples with high specificity (100%) and sensitivity (100%). We generated FMIA seropositivity cut-offs, 0.46 and 1.71 U/ml, for low- and high-seroprevalence settings, respectively. In addition, we obtained high level of agreement between FMIA results and results by the microneutralization test.
ConclusionThe fluorescent microsphere immunoassay showed excellent analytical and clinical performance and is well suited for serosurveillance studies of SARS-CoV-2. However, to optimize analytical sensitivity and clinical specificity of the assay, different seropositivity thresholds depending on the intended use of the assay and the target population, may be needed. | infectious diseases |
10.1101/2021.01.23.21249922 | SARS-CoV-2 seroprevalence among healthcare workers in general hospitals and clinics in Japan | Coronavirus disease 2019 (COVID-19) has become a serious public health problem worldwide. However, little is known about the prevalence of COVID-19 among healthcare workers in Japan. We aimed to examine the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies among 2,160 healthcare workers in general hospitals and clinics in Japan. The prevalence of SARS-CoV-2 immunoglobulin G was 1.2% in August and October 2020, which is relatively higher than that in the general population in Japan. Because of the higher risk of COVID-19 infection, healthcare workers should be the top priority for further social support and vaccination against SARS-CoV-2. | infectious diseases |
10.1101/2021.01.22.21249953 | Prediction of In-hospital Mortality among Adults with COVID-19 Infection | Prediction of mortality from COVID-19 infection might help triage patients to hospitalization and intensive care. To estimate the risk of inpatient mortality, we analyzed the data of 13,190 adult patients in the New York City Health + Hospitals system admitted for COVID-19 infection from March 1 to June 30, 2020. They had a mean age 58 years, 40% were Latinx, 29% Black, 9% White and 22% of other races/ethnicities and 2,875 died. We used Machine learning (Gradient Boosted Decision Trees; XGBoost) to select predictors of inpatient mortality from demographics, vital signs and lab tests results from initial encounters. XGBoost identified O2 saturation, systolic and diastolic blood pressure, pulse rate, respiratory rate, age, and BUN with an Area Under the Receiver Operating Characteristics Curve = 94%. We applied CART to find cut-points in these variables, logistic regression to calculate odds-ratios for those categories, and assigned points to the categories to develop a score. A score = 0 indicates a 0.8% (95% confidence interval, 0.5 - 1.0%) risk of dying and [≥] 12 points indicates a 98% (97-99%) risk, and other scores have intermediate risks. We translated the models into an online calculator for the probability of mortality with 95% confidence intervals (as pictured):
O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/21249953v2_ufig1.gif" ALT="Figure 1">
View larger version (31K):
[email protected]@bbe826org.highwire.dtl.DTLVardef@8652a9org.highwire.dtl.DTLVardef@9d04b3_HPS_FORMAT_FIGEXP M_FIG C_FIG danielevanslab.shinyapps.io/COVID_mortality/ | infectious diseases |
10.1101/2021.01.22.21249953 | An Online Risk Calculator for Rapid Prediction of In-hospital Mortality from COVID-19 Infection | Prediction of mortality from COVID-19 infection might help triage patients to hospitalization and intensive care. To estimate the risk of inpatient mortality, we analyzed the data of 13,190 adult patients in the New York City Health + Hospitals system admitted for COVID-19 infection from March 1 to June 30, 2020. They had a mean age 58 years, 40% were Latinx, 29% Black, 9% White and 22% of other races/ethnicities and 2,875 died. We used Machine learning (Gradient Boosted Decision Trees; XGBoost) to select predictors of inpatient mortality from demographics, vital signs and lab tests results from initial encounters. XGBoost identified O2 saturation, systolic and diastolic blood pressure, pulse rate, respiratory rate, age, and BUN with an Area Under the Receiver Operating Characteristics Curve = 94%. We applied CART to find cut-points in these variables, logistic regression to calculate odds-ratios for those categories, and assigned points to the categories to develop a score. A score = 0 indicates a 0.8% (95% confidence interval, 0.5 - 1.0%) risk of dying and [≥] 12 points indicates a 98% (97-99%) risk, and other scores have intermediate risks. We translated the models into an online calculator for the probability of mortality with 95% confidence intervals (as pictured):
O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/21249953v2_ufig1.gif" ALT="Figure 1">
View larger version (31K):
[email protected]@bbe826org.highwire.dtl.DTLVardef@8652a9org.highwire.dtl.DTLVardef@9d04b3_HPS_FORMAT_FIGEXP M_FIG C_FIG danielevanslab.shinyapps.io/COVID_mortality/ | infectious diseases |
10.1101/2021.01.24.21250392 | Comparison of Carotid Intima Media Thickness between Women with History of Preeclampsia and Normal Pregnancy: A Meta-Analysis of Systematic Review | BackgroundWomen with a history of preeclampsia are twice as likely to experience long term cardiovascular disease (CVD) compared to women with unaffected pregnancy. The pathophysiology of preeclampsia is not well understood, however there is general agreement that, similar to cardiovascular disease, endothelial dysfunction plays a crucial role. On a clinical level, preeclampsia and atherosclerotic cardiovascular disease share common risk factors. Carotid intima media thickness (CIMT) is ultrasound-based imaging, non-invasive, simple and reproducible method of subclinical atherosclerosis evaluation. Nowadays, there were studies concerning of CIMT among preeclamptic women, although the results were different.
ObjectiveTo prove that CIMT among women with histories of preeclampsia was greater compared to normal pregnancy.
MethodsWe conducted a meta-analysis of studies that reported CIMT, in women who had preeclampsia and had normal pregnancy. Studies were identified through three databases: PubMed, Google Scholar dan SAGE Journals with publication year of 2010- 2020. Heterogeneity was assessed using the I2 statistic. Standardized mean difference was used as measured of effect size.
ResultsNine eligible studies were included in the meta-analysis. This meta-analysis consisted of 439 women with preeclampsia histories and 526 women with normal pregnancy histories. Women who had preeclampsia had significantly higher CIMT compared to those with normal pregnancy with standardized mean difference -0.38 and 95% confidence interval (CI) -0.68 to -0.07 (p=0.02).
ConclusionCIMT was greater among women with histories of preeclampsia compared to normal pregnancy.
Prospero registration numberID 228825. | cardiovascular medicine |
10.1101/2021.01.23.21249978 | Do Not Attempt Resuscitation (DNAR) status in people with suspected COVID-19: Secondary analysis of the PRIEST observational cohort study | BackgroundCardiac arrest is common in people admitted with suspected COVID-19 and has a poor prognosis. Do Not Attempt Resuscitation (DNAR) orders can reduce the risk of futile resuscitation attempts but have raised ethical concerns.
ObjectivesWe aimed to describe the characteristics and outcomes of adults admitted to hospital with suspected COVID-19 according to their DNAR status and identify factors associated with an early DNAR decision.
MethodsWe undertook a secondary analysis of 13977 adults admitted to hospital with suspected COVID-19 and included in the Pandemic Respiratory Infection Emergency System Triage (PRIEST) study. We recorded presenting characteristics and outcomes (death or organ support) up to 30 days. We categorised patients as early DNAR (occurring before or on the day of admission) or late/no DNAR (no DNAR or occurring after the day of admission). We undertook descriptive analysis comparing these groups and multivariable analysis to identify independent predictors of early DNAR.
ResultsWe excluded 1249 with missing DNAR data, and identified 3929/12748 (31%) with an early DNAR decision. They had higher mortality (40.7% v 13.1%) and lower use of any organ support (11.6% v 15.7%), but received a range of organ support interventions, with some being used at rates comparable to those with late or no DNAR (e.g. non-invasive ventilation 4.4% v 3.5%). On multivariable analysis, older age (p<0.001), active malignancy (p<0.001), chronic lung disease (p<0.001), limited performance status (p<0.001), and abnormal physiological variables were associated with increased recording of early DNAR. Asian ethnicity was associated with reduced recording of early DNAR (p=0.001).
ConclusionsEarly DNAR decisions were associated with recognised predictors of adverse outcome, and were inversely associated with Asian ethnicity. Most people with an early DNAR decision survived to 30 days and many received potentially life-saving interventions.
RegistrationISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533 | emergency medicine |
10.1101/2021.01.23.21249978 | Do Not Attempt Resuscitation (DNAR) status in people with suspected COVID-19: Secondary analysis of the PRIEST observational cohort study | BackgroundCardiac arrest is common in people admitted with suspected COVID-19 and has a poor prognosis. Do Not Attempt Resuscitation (DNAR) orders can reduce the risk of futile resuscitation attempts but have raised ethical concerns.
ObjectivesWe aimed to describe the characteristics and outcomes of adults admitted to hospital with suspected COVID-19 according to their DNAR status and identify factors associated with an early DNAR decision.
MethodsWe undertook a secondary analysis of 13977 adults admitted to hospital with suspected COVID-19 and included in the Pandemic Respiratory Infection Emergency System Triage (PRIEST) study. We recorded presenting characteristics and outcomes (death or organ support) up to 30 days. We categorised patients as early DNAR (occurring before or on the day of admission) or late/no DNAR (no DNAR or occurring after the day of admission). We undertook descriptive analysis comparing these groups and multivariable analysis to identify independent predictors of early DNAR.
ResultsWe excluded 1249 with missing DNAR data, and identified 3929/12748 (31%) with an early DNAR decision. They had higher mortality (40.7% v 13.1%) and lower use of any organ support (11.6% v 15.7%), but received a range of organ support interventions, with some being used at rates comparable to those with late or no DNAR (e.g. non-invasive ventilation 4.4% v 3.5%). On multivariable analysis, older age (p<0.001), active malignancy (p<0.001), chronic lung disease (p<0.001), limited performance status (p<0.001), and abnormal physiological variables were associated with increased recording of early DNAR. Asian ethnicity was associated with reduced recording of early DNAR (p=0.001).
ConclusionsEarly DNAR decisions were associated with recognised predictors of adverse outcome, and were inversely associated with Asian ethnicity. Most people with an early DNAR decision survived to 30 days and many received potentially life-saving interventions.
RegistrationISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533 | emergency medicine |
10.1101/2021.01.22.21250346 | Prevalent comorbidities among young and underprivileged: Death portrait of COVID-19 among 235 555 hospitalized patients in Brazil | BackgroundCOVID-19 has been alarmingly spreading worldwide, with Brazil ranking third in total number of cases and second in deaths. Being a continental country, which comprises many ethnic groups and an engrained social inequality, the pandemic evidenced this heterogeneous discrepancy. We aimed to estimate the impact of associated risk factors, isolated or combined, on COVID-19 severeness, detecting specific epidemiological profiles for multiple age ranges in hospitalized Brazilians.
MethodsIn this large retrospective cohort study, we used open-access data from the Ministry of Health of Brazil with COVID-19 confirmed hospitalized patients annotated in SRAG system between February and August 2020, a total of 235555 entries. The association of COVID-19 death with socio-demographic and clinical characteristics was analysed and presented as odds ratios adjusted by confounding co-variables. We also presented marginal mean aOR values for high-order interactions either by or not another fixed level or condition. We kept all other variables in the multivariate logistic models in their mean values or equal proportions.
FindingsYounger individuals with one or more comorbidities had an adjusted odds ratio up to four-fold compared to those without it, in the same age interval. Younger diabetic patients either self-declared as brown ethnicity (aOR 5{middle dot}58, 95% CI 4{middle dot}97-6{middle dot}25; p<0{middle dot}0001) or with some other associated comorbidities, mainly chronic hematologic disease (21{middle dot}09, 13{middle dot}64-32{middle dot}6; p<0{middle dot}0001) and obesity (aOR 21{middle dot}7, 95% CI not calculated; p<0{middle dot}0001), resulted in outstanding death risk. Age over 60, particularly over 90 (28{middle dot}91, 24{middle dot}5-34{middle dot}11; p<0.001), usage of invasive ventilatory support (16{middle dot}23, 14{middle dot}05-18{middle dot}75; p<0{middle dot}001), admission to intensive care units (3{middle dot}14, 2{middle dot}82-3{middle dot}48; p<0{middle dot}001), multiple respiratory symptoms (3{middle dot}24, 2{middle dot}79-3{middle dot}75; p<0{middle dot}0001), black ethnicity (1{middle dot}78, 1{middle dot}52-2{middle dot}07; p<0{middle dot}05), and diagnosis previous to hospitalization (1{middle dot}32, 1{middle dot}19-1{middle dot}47; p<0{middle dot}05) were associated with higher death odds. As protective factors, with roughly one third less death risk, we found hospitalization duration of (4, 7] days and illness onset to hospitalization over 6 days.
InterpretationWe found evidence for increased COVID-19 risk in two distinct groups: younger patients with prevalent comorbidities, especially in brown ethnicity, and patients with black ethnicity. We speculate that the pro-inflammatory synergism of COVID-19 and comorbidities, promoting an overproduction of cytokines, is partially the cause of higher mortality in this young group. Brazilian black and brown are underprivileged populations, with structural social inequality, limited healthcare access and, thus, remarkable disease vulnerability. Our study supplies essential data to patient stratification upon admission, optimizing hospital management, and to guide public policy determinations, including group prioritization for COVID-19 vaccination in Brazil.
FundingNone.
O_TEXTBOXResearch in context
Evidence before this studyCOVID-19 is still very active, having spread to over two hundred countries and caused more than one million deaths worldwide. Its current situation requires large-scale studies to assess the impact of preexisting comorbidities, symptoms, and socioeconomic issues regarding mortality rate, especially where lack of control is evident. We searched PubMed, Google Scholar, medRxiv, and bioRxiv on Dec 12, 2020, for studies published in English or Brazilian Portuguese, estimating the impact of several risk factors in COVID-19 prognosis. We used the search terms "Brazil" or "risk factors" or "ethnicity" or "cohort" or "diabetes mellitus" or "mortality" or "symptoms" or "comorbidities", and related synonyms, combined with "SARS-CoV-2" or "COVID-19". Many pre-existing conditions have shown to directly impact patient prognosis, out of which cancer, chronic kidney disease, chronic obstructive pulmonary disease, cardiovascular disease, obesity, and diabetes, among others, are well established in SARS-CoV-2 infection severeness. Some studies reported an increased death risk for non-white Brazilians, but no large scale cohort analyzing the impact of one or more associated risk factors in younger Brazilians patients were found.
Added value of this studyWe found that the impact of having one or two or more risk factors on mortality are progressively higher in ages (60, 80], (40, 60], (20, 40], and (0, 20], compared with people of the same age interval without comorbidities. We also found that young brown individuals with diabetes, as well as black ethnicity on its own, are population subgroups at remarkably higher risk for severe COVID-19 in Brazil. Furthermore, advanced age, usage of ventilatory support, admission to intensive care units, multiple respiratory symptoms, and diagnosis previous to hospitalization were associated with higher death odds. As protective factors, we found hospitalization duration of (4, 7] days and illness onset to hospitalization over 6 days.
Implications of all the available evidenceWe identified multiple epidemiological profiles associated with death risk in different age ranges in Brazilian COVID-19 hospitalized patients. These findings unveil that a large part of Brazilian working-age population is at a higher risk for SARS-CoV-2 death, a neglected situation that is further exacerbating inequalities, leading to a striking sociodemographic and economic impact. We hope that our analysis aids patient risk stratification, hospital management optimization, and public policy determination, including prioritization for COVID-19 vaccination in Brazil.
C_TEXTBOX | epidemiology |
10.1101/2021.01.21.21250045 | Mental health and wellbeing amongst people with informal caring responsibilities across different time points during the COVID-19 pandemic: A population-based propensity score matching analysis | AimsDue to a prolonged period of national and regional lockdown measures during the coronavirus (COVID-19) pandemic, there has been an increase reliance on informal care and a consequent increase in care intensity for informal carers. In light of this, the current study compared the experiences of carers and non-carers on various mental health and wellbeing measures across 5 key time points during the pandemic.
MethodsData analysed were from the UCL COVID -19 Social Study. Our study focused on 5 time points in England: (i) the first national lockdown (March-April 2020; N=12,053); (ii) the beginning of lockdown rules easing (May 2020; N=24,374); (iii) further easing (July 2020; N=21,395); (iv) new COVID-19 restrictions (September 2020; N=4,792); and (v) the three-tier system restrictions (October 2020; N=4,526). We considered 5 mental health and wellbeing measures-depression, anxiety, loneliness, life satisfaction and sense of worthwhile. Propensity score matching were applied for the analyses.
ResultsWe found that informal carers experienced higher levels of depressive symptoms and anxiety than non-carers across all time points. During the first national lockdown, carers also experienced a higher sense of life being worthwhile. No association was found between informal caring responsibilities and levels of loneliness and life satisfaction.
ConclusionGiven that carers are an essential national health care support, especially during a pandemic, it is crucial to integrate carers needs into healthcare planning and delivery. These results highlight there is a pressing need to provide adequate and targeted mental health support for carers during and following this pandemic. | public and global health |
10.1101/2021.01.22.21250320 | High-throughput sequencing of SARS-CoV-2 in wastewater provides insights into circulating variants | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged from a zoonotic spill-over event and has led to a global pandemic. The public health response has been predominantly informed by surveillance of symptomatic individuals and contact tracing, with quarantine, and other preventive measures have then been applied to mitigate further spread. Non-traditional methods of surveillance such as genomic epidemiology and wastewater-based epidemiology (WBE) have also been leveraged during this pandemic. Genomic epidemiology uses high-throughput sequencing of SARS-CoV-2 genomes to inform local and international transmission events, as well as the diversity of circulating variants. WBE uses wastewater to analyse community spread, as it is known that SARS-CoV-2 is shed through bodily excretions. Since both symptomatic and asymptomatic individuals contribute to wastewater inputs, we hypothesized that the resultant pooled sample of population-wide excreta can provide a more comprehensive picture of SARS-CoV-2 genomic diversity circulating in a community than clinical testing and sequencing alone. In this study, we analysed 91 wastewater samples from 11 states in the USA, where the majority of samples represent Maricopa County, Arizona (USA). With the objective of assessing the viral diversity at a population scale, we undertook a single-nucleotide variant (SNV) analysis on data from 52 samples with >90% SARS-CoV-2 genome coverage of sequence reads, and compared these SNVs with those detected in genomes sequenced from clinical patients. We identified 7973 SNVs, of which 5680 were "novel" SNVs that had not yet been identified in the global clinical-derived data as of 17th June 2020 (the day after our last wastewater sampling date). However, between 17th of June 2020 and 20th November 2020, almost half of the SNVs have since been detected in clinical-derived data. Using the combination of SNVs present in each sample, we identified the more probable lineages present in that sample and compared them to lineages observed in North America prior to our sampling dates. The wastewater-derived SARS-CoV-2 sequence data indicates there were more lineages circulating across the sampled communities than represented in the clinical-derived data. Principal coordinate analyses identified patterns in population structure based on genetic variation within the sequenced samples, with clear trends associated with increased diversity likely due to a higher number of infected individuals relative to the sampling dates. We demonstrate that genetic correlation analysis combined with SNVs analysis using wastewater sampling can provide a comprehensive snapshot of the SARS-CoV-2 genetic population structure circulating within a community, which might not be observed if relying solely on clinical cases. | infectious diseases |
10.1101/2021.01.20.21250179 | Assessing the drivers of syphilis among men who have sex with men in Switzerland reveals a key impact of testing frequency: A modelling study | BackgroundOver the last decade, syphilis diagnoses among men-who-have-sex-with-men (MSM) have strongly increased in Europe. Understanding the drivers of the ongoing epidemic may aid to curb transmissions.
Methods and FindingsWe set up an epidemiological model to assess the drivers of syphilis in MSM in Switzerland between 2006 and 2017. We stratified the model by syphilis stage, HIV-diagnosis, and behavioral factors to account for syphilis infectiousness and risk for transmission. In the main model, we used reported non-steady partners (nsP) as the main proxy for sexual risk. We parameterized the model using data from the Swiss HIV Cohort Study, Swiss Voluntary Counselling and Testing center, cross-sectional surveys among the Swiss MSM population, and published syphilis notifications from the Federal Office of Public Health.
The main model reproduced the increase in syphilis diagnoses from 168 cases in 2006 to 418 cases in 2017. It estimated that between 2006 and 2017, MSM with HIV diagnosis had 45.9 times the median syphilis incidence of MSM without HIV diagnosis. Defining risk as condomless anal intercourse with nsP decreased model accuracy (sum of squared weighted residuals, 378.8 vs 148.3). Counterfactual scenarios suggested that increasing screening of MSM without HIV diagnosis and with nsP from once every two-years to twice per year may reduce syphilis incidence (at most 12.8% reduction by 2017). Whereas, increasing screening among MSM with HIV diagnosis and with nsP from once per year to twice per year may substantially reduce syphilis incidence over time (at least 63.5% reduction by 2017).
ConclusionsThe model suggests that reporting nsP regardless of condom use is suitable for risk stratification when modelling syphilis transmission. More frequent screening of MSM with HIV diagnosis, particularly those with nsP may aid to curb syphilis transmission. | infectious diseases |
10.1101/2021.01.19.21250064 | SARS-CoV-2 Airborne Surveillance Using Non-Powered Cold Traps | BackgroundCOVID-19 pandemic is a worldwide challenge requiring efficient containment strategies. High-throughput SARS-CoV-2 testing and legal restrictions are not effective in order to get the current outbreak under control. Emerging SARS-CoV-2 variants with a higher transmissibility require efficient strategies for early detection and surveillance.
MethodsSARS-CoV-2 RNA levels were determined by quantitative RT-PCR in aerosols collected by non-powered cold traps. SARS-CoV-2 spreading kinetics and indoor hotspots could be identified in isolation units and at public places within a high-endemic area. These included an outpatient endoscopy facility, a concert hall, and a shopping mall.
ResultsIndoor COVID-19 hotspots were found in non-ventilated areas and in zones that are predisposed to a buoyancy (chimney) effect. SARS-CoV-2 RNA in those aerosols reached concentrations of 105 copies/mL. Extensive outdoor air ventilation reliably eliminates SARS-CoV-2 aerosol contamination.
ConclusionsThe method presented herein could predict SARS-CoV-2 indoor hotspots and may help to characterize SARS-CoV-2 spreading kinetics. Moreover, it can be used for the surveillance of emerging SARS-CoV-2 variants. Due to low costs and easy handling, the procedure might enable efficient algorithms for COVID-19 prevention and screening. | infectious diseases |
10.1101/2021.01.16.21249901 | REPEATABILITY OF A CALIBRATED DIGITAL SPECTROPHOTOMETER FOR DENTAL SHADE EVALUATION IN CURRENT, FORMER AND NEVER SMOKERS STUDY PROTOCOL | Despite the negative impact of cigarette smoking on oral health and teeth appearance, there is no data available on dental shade changes in smokers who quit smoking. Dental discoloration caused by smoking may be permanent, with minimal restoration after stopping smoking. If this is valid, former smokers can show dental shade values equivalent to those of current smokers.
The aim of this study is to compare the dental shade assessment by digital spectrophotometry (VITA Easyshade V) in current, former and never smokers and to verify the short (7 days) and long-term (30 days) repeatability of these measurements.
Confirmation of good reproducibility of VITA Easyshade V with clear objective discrimination of dental shade measurements among current, former, and never smokers will improve the power of this measurement giving more confidence in clinical research findings of dental shades in these populations.
It is also anticipated that results from the study will expand the application of this measurements to include medical and regulatory research applied to combustion-free tobacco products (e.g. e-cigarettes, heated tobacco products, oral tobacco/nicotine products, etc.), smoking cessation medications, and to consumer care product for oral hygiene and dental aesthetics. | dentistry and oral medicine |
10.1101/2021.01.16.21249901 | REPEATABILITY OF A CALIBRATED DIGITAL SPECTROPHOTOMETER FOR DENTAL SHADE EVALUATION IN CURRENT, FORMER AND NEVER SMOKERS STUDY PROTOCOL | Despite the negative impact of cigarette smoking on oral health and teeth appearance, there is no data available on dental shade changes in smokers who quit smoking. Dental discoloration caused by smoking may be permanent, with minimal restoration after stopping smoking. If this is valid, former smokers can show dental shade values equivalent to those of current smokers.
The aim of this study is to compare the dental shade assessment by digital spectrophotometry (VITA Easyshade V) in current, former and never smokers and to verify the short (7 days) and long-term (30 days) repeatability of these measurements.
Confirmation of good reproducibility of VITA Easyshade V with clear objective discrimination of dental shade measurements among current, former, and never smokers will improve the power of this measurement giving more confidence in clinical research findings of dental shades in these populations.
It is also anticipated that results from the study will expand the application of this measurements to include medical and regulatory research applied to combustion-free tobacco products (e.g. e-cigarettes, heated tobacco products, oral tobacco/nicotine products, etc.), smoking cessation medications, and to consumer care product for oral hygiene and dental aesthetics. | dentistry and oral medicine |
10.1101/2021.01.20.21250152 | High density lipoprotein cholesterol and risk of subsequent COVID-19 hospitalisation: the UK Biobank study | ObjectiveThere is growing evidence of, and biological plausibility for, elevated levels of high-density lipoprotein cholesterol (HDL-C), being related to lower rates of severe infection. Accordingly, we tested whether pre-pandemic HDL-C within the normal range is associated with subsequent COVID-19 hospitalisations and death.
ApproachWe analysed data on 317,306 participants from UK Biobank, a prospective cohort study, baseline data for which were collected between 2006 and 2010. Follow-up for COVID-19 was via hospitalisation records and a national mortality registry.
ResultsAfter controlling for a series of confounding factors which included health behaviours, inflammatory markers, and socio-economic status, higher levels of HDL-C were related to a lower risk of later hospitalisation for COVID-19. The effect was linear (p-value for trend 0.001) such that a 0.2 mmol/L increase in HDL-C was associated with a corresponding 9% reduction in risk (odds ratio; 95% confidence interval: 0.91; 0.86, 0.96). A very similar pattern of association was apparent when COVID-19 mortality was the outcome of interest (odds ratio per 0.2 mmol/l increase in HDL-C: 0.90; 0.81, 1.00); again, a stepwise effect was evident (p-value for trend 0.03).
ConclusionsThese novel results for HDL-C and COVID-19 events warrant testing in other studies. | epidemiology |
10.1101/2021.01.20.21250152 | High density lipoprotein cholesterol and risk of subsequent COVID-19 hospitalisation: the UK Biobank study | ObjectiveThere is growing evidence of, and biological plausibility for, elevated levels of high-density lipoprotein cholesterol (HDL-C), being related to lower rates of severe infection. Accordingly, we tested whether pre-pandemic HDL-C within the normal range is associated with subsequent COVID-19 hospitalisations and death.
ApproachWe analysed data on 317,306 participants from UK Biobank, a prospective cohort study, baseline data for which were collected between 2006 and 2010. Follow-up for COVID-19 was via hospitalisation records and a national mortality registry.
ResultsAfter controlling for a series of confounding factors which included health behaviours, inflammatory markers, and socio-economic status, higher levels of HDL-C were related to a lower risk of later hospitalisation for COVID-19. The effect was linear (p-value for trend 0.001) such that a 0.2 mmol/L increase in HDL-C was associated with a corresponding 9% reduction in risk (odds ratio; 95% confidence interval: 0.91; 0.86, 0.96). A very similar pattern of association was apparent when COVID-19 mortality was the outcome of interest (odds ratio per 0.2 mmol/l increase in HDL-C: 0.90; 0.81, 1.00); again, a stepwise effect was evident (p-value for trend 0.03).
ConclusionsThese novel results for HDL-C and COVID-19 events warrant testing in other studies. | epidemiology |
10.1101/2021.01.20.21250156 | Adjustment for energy intake in nutritional research: a causal inference perspective | BackgroundFour models are commonly used to adjust for energy intake when estimating the causal effect of a dietary component on an outcome; (1) the standard model adjusts for total energy intake, (2) the energy partition model adjusts for remaining energy intake, (3) the nutrient density model rescales the exposure as a proportion of total energy, and (4) the residual model indirectly adjusts for total energy by using a residual. It remains underappreciated that each approach evaluates a different estimand and only partially accounts for proxy confounding by common dietary causes.
ObjectiveTo clarify the implied causal estimand and interpretation of each model and evaluate their performance in reducing dietary confounding.
DesignSemi-parametric directed acyclic graphs and Monte Carlo simulations were used to identify the estimands and interpretations implied by each model and explore their performance in the absence or presence of dietary confounding.
ResultsThe standard model and the mathematically identical residual model estimate the average relative causal effect (i.e., a substitution effect) but provide biased estimates even in the absence of confounding. The energy partition model estimates the total causal effect but only provides unbiased estimates in the absence of confounding or when all other nutrients have equal effects on the outcome. The nutrient density model has an obscure interpretation but attempts to estimate the average relative causal effect rescaled as a proportion of total energy intake. Accurate estimates of both the total and average relative causal effects may instead be estimated by simultaneously adjusting for all dietary components, an approach we term the all-components model.
ConclusionLack of awareness of the estimand differences and accuracy of the four modelling approaches may explain some of the apparent heterogeneity among existing nutritional studies and raise serious questions regarding the validity of meta-analyses where different estimands have been inappropriately pooled. | epidemiology |
10.1101/2021.01.19.21250027 | Natural Progression of Routine Laboratory Markers following Spinal Trauma: A Longitudinal, Multi-Cohort Study | ObjectiveTo track and quantify the natural course of hematological markers over the first year following spinal cord injury.
MethodsData on hematological markers, demographics, and injury characteristics were extracted from medical records of a clinical trial (Sygen) and an ongoing observational cohort study (Murnau Study). The primary outcomes were concentration/levels/amount of commonly collected hematological markers at multiple time-points. Two-way ANOVA and mixed-effects regression techniques were used to account for the longitudinal data and adjust for potential confounders. Trajectories of hematological markers contained in both data sources were compared using the slope of progression.
ResultsAt baseline ([≤] 2 weeks post-injury), most hematological markers were at pathological levels, but returned to normal values over the course of six to twelve months post-injury. The baseline levels and longitudinal trajectories were dependent on injury severity. More complete injuries were associated with more pathological values (e.g. hematocrit, ANOVA test; Chisq = 77.10, df = 3, adjusted p-value<0.001, and Chisq = 94.67, df = 3, adjusted p-value<0.001, in the Sygen and Murnau studies, respectively). Comparing the two databases revealed some differences in the hematological markers, which are likely attributable to differences in study design, sample size, and standard of care.
ConclusionsDue to trauma-induced physiological perturbations, hematological markers undergo marked changes over the course of recovery, from initial pathological levels that normalize within a year. The findings from this study are important as they provide a benchmark for clinical decision making and prospective clinical trials. All results can be interactively explored on the Haemosurveillance website (https://jutzelec.shinyapps.io/Haemosurveillance/).
Code availabilityhttps://github.com/jutzca/Systemic-effects-of-Spinal-Cord-Injury | epidemiology |
10.1101/2021.01.19.21250097 | Contact patterns before and during the UK's Autumn 2020 COVID-19 lockdown among university students and staff | IntroductionUK universities re-opened in September 2020, despite the on-going coronavirus epidemic. During the first term, various national social distancing measures were introduced, including banning groups of >6 people and the second lockdown in November. COVID-19 can spread rapidly in university-settings, and students adherence to social distancing measures is critical for controlling transmission.
MethodsWe measured university staff and student contact patterns via an online, longitudinal survey capturing self-reported contacts on the previous day. We investigated the change in contacts associated with COVID-19 guidance periods: post-first lockdown (23/06/2020-03/07/2020), relaxed guidance period (04/07/2020-13/09/2020), "rule-of-six" period (14/09/2020-04/11/2020), and the second lockdown (05/11/2020-25/11/2020).
Results722 staff (4199 responses) (mean household size: 2.6) and 738 students (1906 responses) (mean household size: 4.5) were included in the study. Contact number decreased with age. Staff in single-person households reported fewer contacts than individuals in 2-and 3-person households, and individuals in 4-and 5-person households reported more contacts.
For staff, daily contacts were higher in the relaxed guidance and "rule-of-six" periods (means: 3.2 and 3.5, respectively; medians: 3) than the post-first lockdown and second lockdown periods (means: 4.5 and 5.4, respectively; medians: 2). Few students responded until 05/10/2020, after which the median student contacts was 2 and the mean was 5.7, until the second lockdown when it dropped to 3.1.
DiscussionUniversity staff and students responded to national guidance by altering their social contacts. The response in staff and students was similar, suggesting that students are able to adhere to social distancing guidance while at university. | epidemiology |
10.1101/2021.01.19.21250097 | University students and staff able to maintain low daily contact numbers during various COVID-19 guideline periods | IntroductionUK universities re-opened in September 2020, despite the on-going coronavirus epidemic. During the first term, various national social distancing measures were introduced, including banning groups of >6 people and the second lockdown in November. COVID-19 can spread rapidly in university-settings, and students adherence to social distancing measures is critical for controlling transmission.
MethodsWe measured university staff and student contact patterns via an online, longitudinal survey capturing self-reported contacts on the previous day. We investigated the change in contacts associated with COVID-19 guidance periods: post-first lockdown (23/06/2020-03/07/2020), relaxed guidance period (04/07/2020-13/09/2020), "rule-of-six" period (14/09/2020-04/11/2020), and the second lockdown (05/11/2020-25/11/2020).
Results722 staff (4199 responses) (mean household size: 2.6) and 738 students (1906 responses) (mean household size: 4.5) were included in the study. Contact number decreased with age. Staff in single-person households reported fewer contacts than individuals in 2-and 3-person households, and individuals in 4-and 5-person households reported more contacts.
For staff, daily contacts were higher in the relaxed guidance and "rule-of-six" periods (means: 3.2 and 3.5, respectively; medians: 3) than the post-first lockdown and second lockdown periods (means: 4.5 and 5.4, respectively; medians: 2). Few students responded until 05/10/2020, after which the median student contacts was 2 and the mean was 5.7, until the second lockdown when it dropped to 3.1.
DiscussionUniversity staff and students responded to national guidance by altering their social contacts. The response in staff and students was similar, suggesting that students are able to adhere to social distancing guidance while at university. | epidemiology |
10.1101/2021.01.20.21250195 | Integrating Operant and Cognitive Behavioral Economics to Inform Infectious Disease Response: Prevention, Testing, and Vaccination in the COVID-19 Pandemic | The role of human behavior to thwart transmission of infectious diseases like COVID-19 is evident. Yet, many areas of psychological and behavioral science are limited in the ability to mobilize to address exponential spread or provide easily translatable findings for policymakers. Here we describe how integrating methods from operant and cognitive approaches to behavioral economics can provide robust policy relevant data. Adapting well validated methods from behavioral economic discounting and demand frameworks, we evaluate in four crowdsourced samples (total N = 1,366) behavioral mechanisms underlying engagement in preventive health behaviors. We find that people are more likely to social distance when specified activities are framed as high risk, that describing delay until testing (rather than delay until results) increases testing likelihood, and that framing vaccine safety in a positive valence improves vaccine acceptance. These findings collectively emphasize the flexibility of methods from diverse areas of behavioral science for informing public health crisis management. | public and global health |
10.1101/2021.01.20.21250195 | Integrating Operant and Cognitive Behavioral Economics to Inform Infectious Disease Response: Prevention, Testing, and Vaccination in the COVID-19 Pandemic | The role of human behavior to thwart transmission of infectious diseases like COVID-19 is evident. Yet, many areas of psychological and behavioral science are limited in the ability to mobilize to address exponential spread or provide easily translatable findings for policymakers. Here we describe how integrating methods from operant and cognitive approaches to behavioral economics can provide robust policy relevant data. Adapting well validated methods from behavioral economic discounting and demand frameworks, we evaluate in four crowdsourced samples (total N = 1,366) behavioral mechanisms underlying engagement in preventive health behaviors. We find that people are more likely to social distance when specified activities are framed as high risk, that describing delay until testing (rather than delay until results) increases testing likelihood, and that framing vaccine safety in a positive valence improves vaccine acceptance. These findings collectively emphasize the flexibility of methods from diverse areas of behavioral science for informing public health crisis management. | public and global health |
10.1101/2021.01.20.21250145 | Impact of COVID-19 Pandemic on Inpatient Rehabilitation and the Original Infection Control Measures for Rehabilitation Team | ObjectiveThis study aimed to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on inpatient rehabilitation, and to determine the effectiveness of the original infection control measures implemented for the rehabilitation team.
MethodsIn this single-center, retrospective, observational study, we calculated multiple rehabilitation indices of patients discharged from our rehabilitation ward between February 28 and May 25, 2020 when Hokkaido was initially affected by COVID-19, and compared them with those calculated during the same period in 2019. Fishers exact test and the Mann-Whitney U test were used for statistical analysis. We also verified the impact of implementing the original infection control measures for the rehabilitation team on preventing nosocomial infections.
ResultsA total of 93 patients (47 of 2020 group, 46 of 2019 group) were included. The median age was 87 and 88 years, respectively, with no differences in age, sex, and main disease between the groups. Training time per day in the ward in 2020 was significantly lower than that in 2019 (p = 0.013). No significant differences were found in the qualitative evaluation indices of Functional Independence Measure (FIM) score at admission, FIM gain, length of ward stay, FIM efficiency, and rate of discharge to home. None of the patients or staff members had confirmed COVID-19 during the study period.
ConclusionsEarly COVID-19 pandemic in Hokkaido affected the quantitative index for inpatient rehabilitation but not the qualitative indices. No symptomatic nosocomial COVID-19 infections were observed with our infection control measures. | rehabilitation medicine and physical therapy |
10.1101/2021.01.20.21250141 | Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs | ObjectivesRecent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease, characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but sJIA-PAP patients also commonly experience features of drug reaction such as atypical rashes and eosinophilia. We sought to investigate immunopathology and identify biomarkers in sJIA, MAS, and sJIA-PAP.
MethodsWe used SOMAscan to measure >1300 analytes in sera from healthy controls and patients with sJIA, MAS, sJIA-PAP and other related diseases. We verified selected findings by ELISA and lung immunostaining. Because the proteome of a sample may reflect multiple states (sJIA, MAS, sJIA-PAP), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.
ResultsProteome alterations in active sJIA and MAS overlapped substantially, including known sJIA biomarkers like SAA and S100A9, and novel elevations of heat shock proteins and glycolytic enzymes. IL-18 was elevated in all sJIA groups, particularly MAS and sJIA-PAP. We also identified an MAS-independent sJIA-PAP signature notable for elevated ICAM5, MMP7, and allergic/eosinophilic chemokines, which were all previously associated with lung damage. Immunohistochemistry localized ICAM5 and MMP7 in sJIA-PAP lung. ICAM5s ability to distinguish sJIA-PAP from sJIA/MAS was independently validated.
ConclusionsSerum proteins support an sJIA-to-MAS continuum, help distinguish sJIA, sJIA/MAS, and sJIA-PAP, and suggest etiologic hypotheses. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP. | rheumatology |
10.1101/2021.01.20.21250141 | Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers | ObjectivesRecent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease, characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but sJIA-PAP patients also commonly experience features of drug reaction such as atypical rashes and eosinophilia. We sought to investigate immunopathology and identify biomarkers in sJIA, MAS, and sJIA-PAP.
MethodsWe used SOMAscan to measure >1300 analytes in sera from healthy controls and patients with sJIA, MAS, sJIA-PAP and other related diseases. We verified selected findings by ELISA and lung immunostaining. Because the proteome of a sample may reflect multiple states (sJIA, MAS, sJIA-PAP), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.
ResultsProteome alterations in active sJIA and MAS overlapped substantially, including known sJIA biomarkers like SAA and S100A9, and novel elevations of heat shock proteins and glycolytic enzymes. IL-18 was elevated in all sJIA groups, particularly MAS and sJIA-PAP. We also identified an MAS-independent sJIA-PAP signature notable for elevated ICAM5, MMP7, and allergic/eosinophilic chemokines, which were all previously associated with lung damage. Immunohistochemistry localized ICAM5 and MMP7 in sJIA-PAP lung. ICAM5s ability to distinguish sJIA-PAP from sJIA/MAS was independently validated.
ConclusionsSerum proteins support an sJIA-to-MAS continuum, help distinguish sJIA, sJIA/MAS, and sJIA-PAP, and suggest etiologic hypotheses. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP. | rheumatology |
10.1101/2021.01.17.21249822 | Early Detection of Alzheimer's Disease with Low-Cost Neuropsychological Tests: A Novel Predict-Diagnose Approach using Recurrent Neural Networks | Alzheimers Disease (AD) is the most expensive and currently incurable disease that affects a large number of the elderly globally. One in five Medicare dollars is spent on AD-related tests and treatments. Accurate AD diagnosis is critical but often involves invasive and expensive tests that include brain scans and spinal taps. Recommending these tests for only patients who are likely to develop the disease will save families of cognitively normal individuals and hospitals from unnecessary expenditures. Moreover, many of the subjects chosen for clinical trials for AD therapies never develop any cognitive impairment and prove not to be ideal candidates for those trials. It is thereby critical to find inexpensive ways to first identify individuals who are likely to develop cognitive impairment and focus attention on them for in-depth testing, diagnosing, and clinical trial participation. Research shows that AD is a slowly progressing disease. This slow progression allows for early detection and treatment, but more importantly, gives the opportunity to predict the likelihood of disease development from early indications of memory lapses. Neuropsychological tests have been shown to be effective in identifying cognitive impairment. Relying exclusively on a set of longitudinal neuropsychological test data available from the ADNI database, this paper has developed Recurrent Neural Networks (RNN) to diagnose the current and predict the future cognitive states of individuals. The RNNs use sequence prediction techniques to predict test scores for two to four years in the future. The predicted scores and predictions of cognitive states based on them showed a high level of accuracy for a group of test subjects, when compared with their known future cognitive assessments conducted by ADNI. This shows that a battery of neuropsychological tests can be used to track the cognitive states of people above a certain age and identify those who are likely to develop cognitive impairment in the future. This ability to triage individuals into those who are likely to remain normal and those who will develop cognitive impairment in the future, advances the quest to find appropriate candidates for invasive tests like spinal taps for disease identification, and the ability to identify suitable candidates for clinical trials. | neurology |
10.1101/2021.01.21.21249764 | Pervasive transmission of E484K and emergence of VUI-NP13L with evidence of SARS-CoV-2 co-infection events by two different lineages in Rio Grande do Sul, Brazil | Emergence of novel SARS-CoV-2 lineages are under the spotlight of the media, scientific community and governments. Recent reports of novel variants in the United Kingdom, South Africa and Brazil (B.1.1.28-E484K) have raised intense interest because of a possible higher transmission rate or resistance to the novel vaccines. Nevertheless, the spread of B.1.1.28 (E484K) and other variants in Brazil is still unknown. In this work, we investigated the population structure and genomic complexity of SARS-CoV-2 in Rio Grande do Sul, the southernmost state in Brazil. Most samples sequenced belonged to the B.1.1.28 (E484K) lineage, demonstrating its widespread dispersion. We were the first to identify two independent events of co-infection caused by the occurrence of B.1.1.28 (E484K) with either B.1.1.248 or B.1.91 lineages. Also, clustering analysis revealed the occurrence of a novel cluster of samples circulating in the state (named VUI-NP13L) characterized by 12 lineage-defining mutations. In light of the evidence for E484K dispersion, co-infection and emergence of VUI-NP13L in Rio Grande do Sul, we reaffirm the importance of establishing strict and effective social distancing measures to counter the spread of potentially more hazardous SARS-CoV-2 strains.
HighlightsO_LIThe novel variant B.1.1.28 (E484K) previously described in Rio de Janeiro is currently spread across the southernmost state of Brazil;
C_LIO_LIThe novel variant VUI-NP13L was also identified by causing a local outbreak in Rio Grande do Sul;
C_LIO_LIB.1.1.28 (E484K) is able to establish successful coinfection events co-occurring simultaneously with different lineages of SARS-CoV-2.
C_LI | genetic and genomic medicine |
10.1101/2021.01.20.21250151 | Weighted burden analysis in 200 000 exome-sequenced UK Biobank subjects characterises effects of rare genetic variants on BMI | IntroductionA number of genes have been identified in which rare variants can cause obesity. Here we analyse a sample of exome sequenced subjects from UK Biobank using BMI as a phenotype.
MethodsThere were 199,807 exome sequenced subjects for whom BMI was recorded. Weighted burden analysis of rare, functional variants was carried out, incorporating population principal components and sex as covariates. For selected genes, additional analyses were carried out to clarify the contribution of different categories of variant. Statistical significance was summarised as the signed log 10 of the p value (SLP), given a positive sign if the weighted burden score was positively correlated with BMI.
ResultsTwo genes were exome-wide significant, MC4R (SLP = 15.79) and PCSK1 (SLP = 6.61). In MC4R, disruptive variants were associated with an increase in BMI of 2.72 units and probably damaging nonsynonymous variants with an increase of 2.02 units. In PCSK1, disruptive variants were associated with a BMI increase of 2.29 and protein-altering variants with an increase of 0.34. Results for other genes were not formally significant after correction for multiple testing, although SIRT1, ZBED6 and NPC2 were noted to be of potential interest.
ConclusionBecause the UK Biobank consists of a self-selected sample of relatively healthy volunteers, the effect sizes noted may be underestimates. The results demonstrate the effects of very rare variants on BMI and suggest that other genes and variants will be definitively implicated when the sequence data for additional subjects becomes available.
This research has been conducted using the UK Biobank Resource. | genetic and genomic medicine |
10.1101/2021.01.20.21249267 | Consultagene: Pre- and Post-Pandemic Experience with a Web-based Platform and Remote Delivery of Genetic Services | Changes in genetics and genomics sequencing in recent years have created increased demand for genetics professionals, including clinical geneticists and genetic counselors. A significant workforce shortage of these professionals has become widely recognized. This shortage is driven by several factors, including the increased role of genetics in healthcare due to precision medicine initiatives and demand outside of medical practices in clinical and direct-to-consumer genetic testing companies that require genetics professionals for education and counseling.
We developed the Consultagene virtual platform for delivery of genetic care, counseling, and education to address some of these issues that have become global challenges in the field of clinical genetics and to bridge existing gaps at the point of care. The platform provides access to specific content based upon the referral indication including educational videos and resource links, allows document sharing, health and history information gathering and appointment scheduling with persistent access to the materials via secure data infrastructure. Having the platform coupled with access to our tele- and video consultation service allows clients convenient on-demand access to genetic education and services as needed.
This report describes the Consultagene platform development and use prior to and during the COVID-19 pandemic, some of the identified strengths and weaknesses of such a platform, and the current applications in the new environment where telemedicine practice has rapidly expanded.
Topic SummaryConsultagene is the first academic virtual platform to integrate a comprehensive range of genetics services including genetics education, genetics consultation, and genetic counseling. Consultagene addresses the increasing demands and unmet, evolving needs for genetic services due to widely available genomic sequencing and the platform seamlessly adapted to the pandemic-induced adjustments to clinical practice. | genetic and genomic medicine |
10.1101/2021.01.22.21249971 | Weekly SARS-CoV-2 sentinel in primary schools, kindergartens and nurseries, June to November 2020, Germany | A 12-week sentinel programme monitored SARS-CoV-2 in primary schools, kindergartens and nurseries. Out of 3169 oropharyngeal swabs, only two tested positive on rRT-PCR while general incidence rates were surging. Thus, children attending respective institutions are not significantly contributing to the pandemic spread when appropriate infection control measures are in place. | infectious diseases |
10.1101/2021.01.21.21250249 | Evaluation of six commercial SARS-CoV-2 Enzyme-Linked Immunosorbent assays for clinical testing and serosurveillance. | BackgroundSerological testing for SARS-CoV-2 complements nucleic acid tests for patient diagnosis and enables monitoring of population susceptibility to inform the COVID-19 pandemic response. As we move into the era of vaccines, the detection of neutralising antibody will become increasingly important. Many serological tests have been developed under emergency use authorization, but their reliability remains unclear.
MethodsWe evaluated the performance of six commercially-available Enzyme-linked Immunosorbent Assays (ELISAs), including a surrogate virus neutralization test, for detection of SARS-CoV-2 immunoglobulins (IgA, IgM, IgG), total or neutralising antibodies and a subset of results were compared to microneutralisation.
ResultsFor sera collected > 14 days post-symptom onset the Wantai total Ab performed best with highest sensitivity 100% (95% confidence interval: 94.6-100) followed by 93.1% for Euroimmun NCP-IgG,93.1% for GenScript Surrogate Virus Neutralization Test, 90.3% for Euroimmun S1-IgG, 88.9% for Euroimmun S1-IgA and 83.3% for Wantai IgM. Specificity for the best performing assay was 99.5% and for the lowest 97.1%.
ConclusionWantai ELISA, detecting total immunoglobulins against SARS-CoV-2 receptor binding domain, had the best performance. Antibody target, timing and longevity of the immune response, and the objectives of testing should be considered in test choice. ELISAs should be used within a confirmatory testing algorithm to ensure reliable results. ELISAs provide high quality results, with flexibility for test numbers without the need for manufacturer specific analyzers. | infectious diseases |
10.1101/2021.01.21.21249203 | SARS-CoV-2 recruits a haem metabolite to evade antibody immunity | The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD. | infectious diseases |
10.1101/2021.01.21.21249623 | Genomic insights into early SARS-CoV-2 strains isolated in Reunion Island | The relative isolation of many island communities provides some protection from the COVID-19 pandemic, as imported cases can be limited and traced effectively. Until recently, this was true for the population of the French overseas department, Reunion Island, where only limited numbers of autochthonous cases were observed prior to August 2020. Since the report of the first case of COVID-19, contact tracing has been carried out for each new case identified in Reunion Island to identify transmission and clusters. To contribute to the public health response and understand the diffusion of SARS-Cov-2 strains in Reunion Island, we established in-house genome sequencing capability in Reunion using Oxford nanopore technology (MinION) as an inexpensive option for genomic typing of SARS-CoV-2 lineages on the island, and cross-validated typing results between viral isolation methods and different sequencing technologies. The results of our work during the early phase of the epidemics are presented herein.
Article Summary LineThe COVID-19 pandemic has had an unprecedented impact on the global community. Here we provide epidemiological and genomic details of the early stages of the pandemic on Reunion Island. | infectious diseases |
10.1101/2021.01.20.21250173 | The usefulness of a quantitative olfactory test for the detection of COVID-19. | BackgroundDuring the COVID-19 pandemic, olfactory dysfunction (anosmia or hyposmia) has been reported by many patients and recognized as a prevalent and early symptom of infection. This finding has been associated with viral-induced olfactory neuron dysfunction rather than the nasal congestion typically found in cold- or flu-like states. In literature, the prevalence of anosmia varies from 15% to 85%, and the studies, in general, were based on the subjective evaluation of patients self-reports of loss of smell (yes or no question). In the present study, we quantitatively evaluated olfactory dysfunction and the prevalence of fever in symptomatic patients suspected of having COVID-19 using a scratch-and-sniff olfactory test and infrared temperature testing with RT-PCR as the gold-standard comparator method to diagnose COVID-19 infection.
MethodsOutpatients had their forehead temperature checked with an infrared non-contact thermometer (temperature guns). After that, they received two olfactory smell identification test (SIT) cards (u-Smell-it; CT, USA) that each had 5 scent windows and were asked to scratch with a pencil and sniff each of the 10 small circles containing the microencapsulated fragrances and mark the best option on a response card. Nasopharyngeal swabs were then collected for Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) to determine if the patients were positive or negative for COVID-19 infection. We considered the number of hits (correct answers) [≤] 5 as positive for loss of smell (LOS) in the olfactory test; [≥] 6 hits was considered negative for LOS (i.e. normal olfactory function). All data were analyzed using Excel and Matlab software.
ResultsIn the present study, 165 patients were eligible for the olfactory test and nasopharyngeal swab collection RT-PCR. Five patients were excluded because of inconclusive PCR results (n=2) and missing data (n=3). A total of 160 patients completed all the protocols. The RT-PCR positivity rate for COVID-19 was 27.5% (n=44), and PCR+ patients scored significantly worse in the olfactory test (5.5{+/-}3.5) compared to RT-PCR-patients (8.2{+/-}1.8, p<0.001). 0/44 PCR+ patients presented with a fever ([≥]37.8{degrees}C). In contrast an olfactory SIT had a specificity of 94.8% (95% CI, 89.1 - 98.1), sensitivity of 47.7% (95% CI, 32.7 - 63.3), accuracy of 0.82 (95% CI, 0.75 - 0.87), positive predictive value of 77.8% (95% CI, 59.6 - 88.8), negative predictive value of 82.7% (85% CI, 78.7 - 86.7), and odds ratio of 16.7.
ConclusionOur results suggest that temperature checking failed to detect COVID-19 infection, while an olfactory test may be useful to help identify COVID-19 infection in symptomatic patients. | infectious diseases |
10.1101/2021.01.20.21250143 | Comparison study of commercial COVID-19 RT-PCR kits propose an approach to evaluate their performances | With the increasing number of COVID-19 cases in Indonesia, scalable and high-throughput diagnostic testing is essential nationwide. Currently, RT-PCR has been the preferred method of viral detection and many manufacturers offer commercial kits for routine clinical diagnostics. In response to the incoming of various kits, there is a need to assess their performance and compatibility of use in clinical laboratories. Kit characteristics impact the testing workflow of these laboratories and some factors can render a kit to perform sub-optimally, leading to false results that are misleading for public safety. Here, we evaluated six commercial kits that are predominantly distributed to appointed testing facilities across Indonesia. Their performance was assessed based on their ease of use, availability, robustness and accuracy for scalable testing in a manual set-up. Our findings demonstrated that all six kits are suitable for use in routine diagnostics, but their considerations for use may vary according to different use-cases. To better guide considerations in procurement of kits, our study provided a systematic approach for laboratories to assess the performance of new incoming kits. | infectious diseases |
10.1101/2021.01.22.21250282 | Model-driven mitigation measures for reopening schools during the COVID-19 pandemic | Reopening schools is an urgent priority as the COVID-19 pandemic drags on. To explore the risks associated with returning to in-person learning and the value of mitigation measures, we developed stochastic, network-based models of SARS-CoV-2 transmission in primary and secondary schools. We find that a number of mitigation measures, alone or in concert, may reduce risk to acceptable levels. Student cohorting, in which students are divided into two separate populations that attend in-person classes on alternating schedules, can reduce both the likelihood and the size of outbreaks. Proactive testing of teachers and staff can help catch introductions early, before they spread widely through the school. In secondary schools, where the students are more susceptible to infection and have different patterns of social interaction, control is more difficult. Especially in these settings, planners should also consider testing students once or twice weekly. Vaccinating teachers and staff protects these individuals and may have a protective effect on students as well. Other mitigations, including mask-wearing, social distancing, and increased ventilation, remain a crucial component of any reopening plan. | epidemiology |
10.1101/2021.01.22.21250282 | Model-driven mitigation measures for reopening schools during the COVID-19 pandemic | Reopening schools is an urgent priority as the COVID-19 pandemic drags on. To explore the risks associated with returning to in-person learning and the value of mitigation measures, we developed stochastic, network-based models of SARS-CoV-2 transmission in primary and secondary schools. We find that a number of mitigation measures, alone or in concert, may reduce risk to acceptable levels. Student cohorting, in which students are divided into two separate populations that attend in-person classes on alternating schedules, can reduce both the likelihood and the size of outbreaks. Proactive testing of teachers and staff can help catch introductions early, before they spread widely through the school. In secondary schools, where the students are more susceptible to infection and have different patterns of social interaction, control is more difficult. Especially in these settings, planners should also consider testing students once or twice weekly. Vaccinating teachers and staff protects these individuals and may have a protective effect on students as well. Other mitigations, including mask-wearing, social distancing, and increased ventilation, remain a crucial component of any reopening plan. | epidemiology |
10.1101/2021.01.22.21250282 | Model-driven mitigation measures for reopening schools during the COVID-19 pandemic | Reopening schools is an urgent priority as the COVID-19 pandemic drags on. To explore the risks associated with returning to in-person learning and the value of mitigation measures, we developed stochastic, network-based models of SARS-CoV-2 transmission in primary and secondary schools. We find that a number of mitigation measures, alone or in concert, may reduce risk to acceptable levels. Student cohorting, in which students are divided into two separate populations that attend in-person classes on alternating schedules, can reduce both the likelihood and the size of outbreaks. Proactive testing of teachers and staff can help catch introductions early, before they spread widely through the school. In secondary schools, where the students are more susceptible to infection and have different patterns of social interaction, control is more difficult. Especially in these settings, planners should also consider testing students once or twice weekly. Vaccinating teachers and staff protects these individuals and may have a protective effect on students as well. Other mitigations, including mask-wearing, social distancing, and increased ventilation, remain a crucial component of any reopening plan. | epidemiology |
10.1101/2021.01.21.21249999 | A 3D CNN Classification Model for Accurate Diagnosis of Coronavirus Disease 2019 using Computed Tomography Images | The coronavirus disease (COVID-19) has been spreading rapidly around the world. As of August 25, 2020, 23.719 million people have been infected in many countries. The cumulative death toll exceeds 812,000. Early detection of COVID-19 is essential to provide patients with appropriate medical care and protect uninfected people. Leveraging a large computed tomography (CT) database from 1,112 patients provided by China Consortium of Chest CT Image Investigation (CC-CCII), we investigated multiple solutions in detecting COVID-19 and distinguished it from other common pneumonia (CP) and normal controls. We also compared the performance of different models for complete and segmented CT slices. In particular, we studied the effects of CT-superimposition depths into volumes on the performance of our models. The results show that the optimal model can identify the COVID-19 slices with 99.76% accuracy (99.96% recall, 99.35% precision and 99.65% F1-score). The overall performance for three-way classification obtained 99.24% accuracy and the area under the receiver operating characteristic curve (AUROC) of 0.9986. To the best of our knowledge, our method achieves the highest accuracy and recall with the largest public available COVID-19 CT dataset. Our model can help radiologists and physicians perform rapid diagnosis, especially when the healthcare system is overloaded. | epidemiology |
10.1101/2021.01.21.21250215 | Data Driven High Resolution Modeling and Spatial Analyses of the COVID-19 Pandemic in Germany | The SARS-CoV-2 virus has spread around the world with over 90 million infections to date, and currently many countries are fighting the second wave of infections. With neither sufficient vaccination capacity nor effective medication, non-pharmaceutical interventions (NPIs) remain the measure of choice. However, NPIs place a great burden on society, the mental health of individuals, and economics. Therefore the cost/benefit ratio must be carefully balanced and a target-oriented small-scale implementation of these NPIs could help achieve this balance. To this end, we introduce a modified SEIR-class compartment model and parametrize it locally for all 412 districts of Germany. The NPIs are modeled at district level by time varying contact rates. This high spatial resolution makes it possible to apply geostatistical methods to analyse the spatial patterns of the pandemic in Germany and to compare the results of different spatial resolutions. We find that the modified SEIR model can successfully be fitted to the COVID-19 cases in German districts, states, and also nationwide. We propose the correlation length as a further measure, besides the weekly incidence rates, to describe the current situation of the epidemic. | epidemiology |
10.1101/2021.01.20.21250194 | Prediction of Celiac Disease Severity and Associated Endocrine Morbidities through Deep Learning-based Image Analytics. | ObjectiveDevelop a deep learning-based methodology using the foundations of systems pathology to generate highly accurate predictive tools for complex gastrointestinal diseases, using celiac disease (CD) as a prototype.
DesignTo predict the severity of CD, defined by Marsh-Oberhuber classification, we used deep learning to develop a model based on histopathologic features.
ResultsThe study was based on a pediatric cohort of 124 patients identified with different classes of CD severity. The model predicted CD with an overall 88.7% accuracy with the highest for Marsh IIIc (91.0%; 95% sensitivity; 91% specificity). The model identified EECs as a defining feature of children with Marsh IIIc CD and endocrinopathies which was confirmed using immunohistochemistry.
ConclusionThis deep learning image analysis platform has broad applications in disease treatment, management, and prognostication and paves the way for precision medicine.
SummaryO_ST_ABSWhat is already known about this subject?C_ST_ABS- Deep Learning has the potential to generate predictive models for complex gastrointestinal diseases.
What are the new findings?- Our deep learning-based model used the foundations of systems pathology to generate a highly accurate predictive tool for complex gastrointestinal diseases, using a celiac disease (CD) pediatric cohort as a prototype.
- The model predicated CD severity with high accuracy and identified enteroendocrine cells as a defining feature of children with severe CD and endocrinopathies.
How might it impact on clinical practice in the foreseeable future?- Assessment of histopathological markers at the time of diagnosis that can predict risk of severity or complications can have broad applications in disease treatment, management, and prognostication and pave the way for precision medicine. | gastroenterology |
10.1101/2021.01.21.21249496 | Management of conductive deafness from Otitis Media with Effusion (known as glue ear) in children using bone conduction headsets when grommet operations were unavailable during COVID-19. | BackgroundOtitis Media with Effusion (OME) causing hearing impairments affects [~]1 in 10 children starting school in UK/ Europe. 80% have at least one episode with most having conductive hearing loss. Studies showed children with OME hear better with bone conducting headsets. During COVID-19 we investigated whether children with deafness secondary OME, without access to audiology or grommet surgery, could be aided with bone conduction kits and the HearGlueEar app.
MethodsStarting July 2020, during COVID-19, children aged 3-11 years with OME and on a grommet waiting list were invited to a single arm, prospective study. They received the kit, instructions and HearGlueEar app by post. By 3 weeks parents were asked to charge and pair the devices, attend a remote consultation and complete an OMQ-14 questionnaire. Remote follow-up lasted 3 months. Outcomes: ability to use the equipment, complete the questionnaire about childs hearing and behaviour before and with the equipment, declining grommet surgery or where deafness resolved, and give opinion about the intervention.
Findings26 children enrolled. Families used the kit at home and school. Most found remote consultations positive and convenient. OMQ-14 responses were 90% positive. Comments were: "Other people have said, wow his speech is clearer.", "It is making a real difference at home.", "He said over and over again, "I can hear everybody, wow, wow, wow.", "It is no exaggeration to say this has made an astronomical improvement to his quality of life". One child reported "I can hear my best friend again". "She is getting on really well with the headphones - pairing them with the iPad at home is simply brilliant." Three families continued with the headset to avoid grommets.
InterpretationPosting a bone conduction kit, HearGlueEar app and remote consultation is effective support for children with deafness secondary to OME.
FundingNone | pediatrics |
10.1101/2021.01.21.20248810 | Reduction of brooding and more general depressive symptoms after fMRI neurofeedback targeting a melancholic functional-connectivity biomarker | Depressive disorders contribute heavily to global disease burden; This is possibly because patients are usually treated homogeneously, despite having heterogeneous symptoms with differing underlying neural mechanisms. On the contrary, treatment that directly influences the neural circuit relevant to an individual patients subset of symptoms might more precisely and thus effectively aid in the alleviation of their specific symptoms. We tested this hypothesis, using fMRI functional connectivity neurofeedback to target a neural biomarker that objectively relates to a specific subset (melancholic) of depressive symptoms and that is generalizable across independent cohorts of patients. The targeted biomarker was the functional connectivity between the left dorsolateral prefrontal cortex and left precuneus, which has been shown in a data-driven manner to be less anticorrelated in patients with melancholic depression than in healthy controls. We found that the more a participant normalized this biomarker, the more related (brooding and more general depressive), but not unrelated (trait anxiety), symptoms were reduced. Thus, one-to-one correspondence between a normalized neural network and decreased depressive symptoms was demonstrated. These results were found in two experiments that took place several years apart by different experimenters, indicating their reproducibility. Indicative of their potential clinical utility, effects remained one-two months later. | psychiatry and clinical psychology |
10.1101/2021.01.20.21250107 | Psychiatric, Emotional, and Brain Volumetric Footprints of Childhood Conduct in Healthy Young Adults | BackgroundConduct Disorder (CD) is defined as aggressive, antisocial, and rule-breaking behavior during childhood, and a major risk factor for developing an antisocial personality disorder. However, nearly half the patients develop into seemingly normal status. We aimed to identify psychiatric, emotional, and brain volumetric and functional footprints of childhood CD in healthy young adults with a prior history of CD.
Methods40 subjects with a prior history of CD (CC) and 1166 control subjects (HC) were identified from the Human Connectome Project. Their psychiatric, emotional, impulsivity, and personality traits were extracted. An emotion task fMRI activation of amygdala and hippocampus, as well as whole-brain and hippocampal/amygdalar segmentation volumetry were analyzed. We then statistically assessed the between-group differences and associations between the assessments and the hippocampal or amygdala nuclei measurements.
ResultsAfter correcting for multiple comparisons, we found higher anger aggression, antisocial personality problems, aggressive and rule-breaking behaviors, anxiety, attention-deficit/hyperactivity, intrusive, externalizing, neuroticism, and lower agreeableness in the CC group. The neuroimaging analysis also revealed larger subregions of the left hippocampus in CC group. Significant group x assessment association was found for aggression and left hippocampal presubiculum and basal nuclei of left amygdala.
DiscussionHealthy young adults with a prior history of CD still exhibit some forms of antisocial-like behavior, without evidence of emotional recognition disturbances, and with larger left hippocampal subregions. These larger hippocampal and amygdala volumes may play a protective role in CC subjects. | psychiatry and clinical psychology |
10.1101/2021.01.20.21250107 | Childhood Conduct History is Linked to Amygdalohippocampal Changes in Healthy Adults: A Neuroimaging Behavioral Study | BackgroundConduct Disorder (CD) is defined as aggressive, antisocial, and rule-breaking behavior during childhood, and a major risk factor for developing an antisocial personality disorder. However, nearly half the patients develop into seemingly normal status. We aimed to identify psychiatric, emotional, and brain volumetric and functional footprints of childhood CD in healthy young adults with a prior history of CD.
Methods40 subjects with a prior history of CD (CC) and 1166 control subjects (HC) were identified from the Human Connectome Project. Their psychiatric, emotional, impulsivity, and personality traits were extracted. An emotion task fMRI activation of amygdala and hippocampus, as well as whole-brain and hippocampal/amygdalar segmentation volumetry were analyzed. We then statistically assessed the between-group differences and associations between the assessments and the hippocampal or amygdala nuclei measurements.
ResultsAfter correcting for multiple comparisons, we found higher anger aggression, antisocial personality problems, aggressive and rule-breaking behaviors, anxiety, attention-deficit/hyperactivity, intrusive, externalizing, neuroticism, and lower agreeableness in the CC group. The neuroimaging analysis also revealed larger subregions of the left hippocampus in CC group. Significant group x assessment association was found for aggression and left hippocampal presubiculum and basal nuclei of left amygdala.
DiscussionHealthy young adults with a prior history of CD still exhibit some forms of antisocial-like behavior, without evidence of emotional recognition disturbances, and with larger left hippocampal subregions. These larger hippocampal and amygdala volumes may play a protective role in CC subjects. | psychiatry and clinical psychology |
10.1101/2021.01.20.21250204 | Rule of thumb in human intelligence for assessing the COVID-19 outbreak in Japan | BackgroundThe COVID-19 outbreak in Japan exhibited its third peak at the end of 2020. Mathematical modelling and developed AI cannot explain several peaks in a single year.
ObjectThis study was conducted to evaluate a rule of thumb for prediction from past wave experiences.
MethodWe rescaled the number of newly infected patients as 100% at the peak and checked similarities among waves. Then we extrapolated the courses of the third and later waves.
ResultsResults show some similarity around the second and the third waves. Based on this similarity, we expected the bottom of the third wave will show 2131 newly positive patients including asymptomatic patients at around the end of February, 2021.
Discussion and ConclusionWe can infer the course of the third wave from similarity with the second wave. Mathematical modelling has been unable to do it, even when AI was used for prediction. Performance of the rule of thumb used with human intelligence might be superior to that of AI under these circumstances. | public and global health |
10.1101/2021.01.21.21250256 | Adherence to the CONSORT statement and risk of bias assessment in Randomized Controlled Trials in rehabilitation journals: a protocol for a meta-research study | ObjectiveThe aim of this study will be to assess the adherence to the reporting quality standards set forth in the CONSORT Statement checklist of a random sample of randomized controlled trials (RCTs) published in rehabilitation journals, and to assess the association between this adherence and the risk of bias of these RCTs.
Methods and AnalysisA cross-sectional analysis is planned on a random sample of 200 RCTs published between 2011and 2020 in the 68 journals indexed under "rehabilitation" category in InCites Journal Citation Report.
Randomization will be stratified by publication date and journal ranking (quartile range; Q1-2 and Q3-4) to include an equal number of studies from 2011 to 2015 (Q1-Q2=50 and Q3-Q4=50) and from 2016 to 2020 (Q1-Q2=50 and Q3-Q4=50). RCT with parallel group design will be included. Observational or cohort studies, interim analyses, economic analyses of RCTs, RCT protocols, quasi-experimental design post-trial follow-up studies, subgroup and secondary analyses of previously reported RCTs, RCT with cross-over design, pilot feasibility RCTs, n-of-1 trials, cluster trials, editorials, letters and news reports will be excluded. The primary analysis will address the completeness of the reporting for each study and the relationship between CONSORT adherence and risk of bias. This will be a descriptive analysis through descriptive statistics and graphical representation.
Ethics and DisseminationSeveral studies have shown the positive influence of reporting guidelines on the completeness of research reporting but no one investigated the use and the appropriateness of reporting guidelines in physical therapy research. Therefore, this study will add relevant knowledge that may contribute to improve further the reporting of rehabilitation research. The results of this research will be published in a peer-reviewed journal and will be presented at relevant (inter)national scientific events. | rehabilitation medicine and physical therapy |