Minimizing loss of life in Covid-19 in a 100 day period in the U.S.A. by personalized-dose vaccination and distribution of a limited vaccine supply - a vaccination strategy model BackgroundWe aimed at minimizing loss of lives in the Covid-19 pandemic in the USA by identifying optimal vaccination strategies during a 100-day period with limited vaccine supplies. While lethality is highest in the elderly, transmission and case numbers are highest in the younger. A strategy of first vaccinating the elderly is widely used, thought to protect the vulnerable, elderly best. Despite lower immunogenicity in the elderly, mRNA vaccines retain high efficacy, implying that in the younger, reduced vaccine doses might suffice, thereby increasing vaccination counts with a given vaccine supply.

MethodsUsing published immunogenicity data of the Moderna mRNA-1273 vaccine, we examined the value of personalized-dose vaccination strategies, using a modeling approach incorporating age-related vaccine immunogenicity, social contact patterns, population structure, Covid-19 case and death rates in the USA in late January 2021. An increase if the number of persons that can be vaccinated and a potential reduction of the individual protective efficacy was accounted for.

ResultsAge-personalized dosing strategies reduced cases faster, shortening the pandemic, reducing the delay to reaching <100000 cases/day from 64 to 30 days and avoiding 25000 deaths within 100 days in the USA. In an "elderly first" vaccination strategy, mortality is higher even in the elderly. Findings were robust with transmission blocking efficacies of reduced dose vaccination between 30% to 90%, and with a vaccine supply from 1 to 3 million full dose vaccinations per day.

ConclusionRapid reduction of Covid-19 case and death rate in the USA in 100 days with a limited vaccine supply is best achieved when personalized, age-tailored dosing for highly effective vaccines is used, according to this vaccination strategy model parameterized to U.S. demographics, Covid-19 transmission and vaccine characteristics. Protecting the vulnerable is most effectively achieved by personalized-dose vaccination of all population segments, while an "elderly first" approach costs more lives, even in the elderly.
Detection and quantification of enteric pathogens in aerosols near open wastewater canals in cities with poor sanitation Urban sanitation infrastructure is inadequate in many low-income countries, leading to the presence of highly concentrated, uncontained fecal waste streams in densely populated areas. Combined with mechanisms of aerosolization, airborne transport of enteric microbes and their genetic material is possible in such settings but remains poorly characterized. We detected and quantified enteric pathogen-associated gene targets in aerosol samples near open wastewater canals (OWCs) or wastewater-impacted surface waters and control sites in La Paz, Bolivia; Kanpur, India; and Atlanta, USA via multiplex reverse-transcription qPCR (37 targets) and ddPCR (13 targets). We detected a wide range of enteric targets, some not previously reported in extramural urban aerosols, with more frequent detections of all enteric targets at higher densities in La Paz and Kanpur near OWCs. We report density estimates ranging up to 4.7 x 102 gc per m3air across all targets including heat stabile enterotoxigenic E. coli, C. jejuni, enteroinvasive E. coli/Shigella spp., Salmonella spp., norovirus, and Cryptosporidium spp. An estimated 25%, 76%, and 0% of samples containing positive pathogen detects were accompanied by culturable E. coli in La Paz, Kanpur, and Atlanta, respectively, suggesting potential for viability of enteric microbes at the point of sampling. Airborne transmission of enteric pathogens merits further investigation in cities with poor sanitation.

SYNOPSISWe detected and quantified molecular targets associated with important enteric pathogens in outdoor aerosols in cities with poor sanitation to assess the potential role of the aeromicrobiological pathway in enteric infection transmission in such settings.
Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant BackgroundThere has been an unprecedented global effort to produce safe and effective vaccines against SARS-CoV-2. However, production challenges, supply shortages and unequal global reach, together with an increased number of breakthrough infections due to waning of immunity and the emergence of new variants of concern (VOC), have prolonged the pandemic. To boost the immune response, several heterologous vaccination regimes have been tested and have shown increased antibody responses compared to homologous vaccination. Here we evaluated the effect of mRNA vaccine booster on immunogenicity in individuals who had been vaccinated with two doses of inactivated vaccines.

MethodsThe levels of specific antibodies against the receptor-binding domain (RBD) of the spike protein from wild-type virus and the Beta, Delta and Omicron variants were measured in healthy individuals who had received two doses of homologous inactivated (BBIBP-CorV or CoronoVac) or mRNA (BNT162b2 or mRNA-1273) vaccines, and in donors who were given an mRNA vaccine boost after two doses of either vaccine. Pre-vaccinated healthy donors, or individuals who had been infected and subsequently received the mRNA vaccine were also included as controls. In addition, specific memory B and T cell responses were measured in a subset of samples.

ResultsA booster dose of an mRNA vaccine significantly increased the level of specific antibodies that bind to the RBD domain of the wild-type (6-fold) and VOCs including Delta (8-fold) and Omicron (14-fold), in individuals who had previously received two doses of inactivated vaccines. The level of specific antibodies in the heterologous vaccination group was furthermore similar to that in individuals receiving a third dose of homologous mRNA vaccines or boosted with mRNA vaccine after natural infection. Moreover, this heterologous vaccination regime significantly enhanced the specific memory B and T cell responses.

ConclusionsHeterologous prime-boost immunization with inactivated vaccine followed by an mRNA vaccine boost markedly increased the levels of specific antibodies and B and T cell responses and may thus increase protection against emerging SARS-CoV-2 variants including Omicron. KRAS mutations impact clinical outcome in metastatic non-small cell lung cancer PurposeThere is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PD) and immune checkpoint blockade (ICB) with pembrolizumab. Here we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (stage IV) non-small cell lung cancer (NSCLC).

MethodsAll consecutive patients molecularly assessed and diagnosed between 2016-2018 with stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. Primary study outcome was overall survival (OS).

ResultsOut of 580 stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.288, 95% CI 1.091-1.521, p = 0.003). When treated with first-line platinum doublet (n = 195), KRASMUT is a negative factor for survival (p = 0.018) with median OS 9 months vs KRASWT 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95%CI 1.124-2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1high KRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significant (p = 0.006) better outcome than KRASWT with a median OS 23 vs 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95%CI 0.148-0.822, p = 0.016).

ConclusionsKRAS mutations is a positive predictive factor for treatment with pembrolizumab and a negative predictive factor for platinum doublet chemotherapy as well as general OS in stage IV NSCLC. The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. Impact of COVID 19 on the quality of life (QoL) of patients living with Sickle Cell Disorder (SCD) in Lagos Nigeria The study aimed to assess the impact of the COVID-19 pandemic on Quality of Life (QoL) in persons living with Sickle Cell Disorder (SCD) in Lagos, Nigeria and to determine how they coped during the pandemic, particularly during the period of total lockdown with the additional "SHIELDING" measures to which they had to adhere. Data was collected using a standardized protocol PedsQL, Sickle Cell Disease Module version.3.0 designed for youth within the ages of (13-18) years, (19-35) years and their parents/Guardian if underage. The survey captured data on patients pain impact, hurts, management, treatments, communication with their caregivers and their Guardians perception. The survey was performed online, or Face-to-Face/telephone interview if online was not possible. Contacts of patients and parents were obtained from the database of Sickle Cell Foundation Nigeria. A total of 105 (80 patients and 25 parents) participants responded to the survey. The age distribution of respondents was highest at 56 % in the age bracket of 13 - 18 years old. Pain crisis were very common amongst patients. The survey revealed that the type of treatment or care received at these times determined whether or not the patients visited the hospital when they had pain crises. In addition, as patients reports an increase in ill-treatment they experienced in the hands of health care givers, so did the fear of accessing treatment during the COVID pandemic. It was observed that the frequency of pain crises experienced by SCD patients was proportional to the patients quality of life (the higher the frequency of pains, the worse the QoL). As a follow-up, a more detailed study would be required, as this study was limited in the capturing of the demographics, sex and number of participants; Considering the number of persons living with SCD that visit the Sickle Cell Foundation Nigeria, (about 3,000 patients), the number of responses in this study was low (105). It is believed that a higher number of responses would have given more information about the Sickle Cell burden and the QoL of persons living with SCD in Lagos during the COVID-19 pandemic. Lagos was the epicentre of the COVID-19 pandemic in Nigeria. A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

O_TBL View this table:
org.highwire.dtl.DTLVardef@134f5d7org.highwire.dtl.DTLVardef@1f8149forg.highwire.dtl.DTLVardef@11dbf0org.highwire.dtl.DTLVardef@7e854borg.highwire.dtl.DTLVardef@61272f_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

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org.highwire.dtl.DTLVardef@53a9f0org.highwire.dtl.DTLVardef@b9e76dorg.highwire.dtl.DTLVardef@108bd12org.highwire.dtl.DTLVardef@b500ddorg.highwire.dtl.DTLVardef@14be1d8_HPS_FORMAT_FIGEXP  M_TBL C_TBL Funding and Support in Kind

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org.highwire.dtl.DTLVardef@d86811org.highwire.dtl.DTLVardef@1985973org.highwire.dtl.DTLVardef@118ca5corg.highwire.dtl.DTLVardef@8d7839org.highwire.dtl.DTLVardef@1cff6e1_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderThe pilot at North Bristol Trust (NBT) is overseen by Neuromusculoskeletal (NMSK) Division governance. NBT NMSK Division takes responsibility for ensuring that the design of the study meets appropriate standards and that arrangements are in place to ensure appropriate conduct and reporting. Governance oversight for Hospital at Home was registered with NBT NMSK, and for primary care with Horfield Health Centre.

Roles and Responsibilities

Study Flow Chart

O_TBL View this table:
org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL Decreased tissue stiffness in glioblastoma by MR Elastography is associated with increased cerebral blood flow PURPOSEUnderstanding how mechanical properties relate to functional changes in glioblastomas may help explain different treatment response between patients. The aim of this study was to map differences in biomechanical and functional properties between tumor and healthy tissue, to assess any relationship between them and to study their spatial distribution.

METHODSTen patients with glioblastoma and 17 healthy subjects were scanned using MR Elastography, perfusion and diffusion MRI. Stiffness and viscosity measurements G' and G'', cerebral blood flow (CBF), apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in patients contrast-enhancing tumor, necrosis, edema, and gray and white matter, and in gray and white matter for healthy subjects. A regression analysis was used to predict CBF as a function of ADC, FA, G' and G''.

RESULTSMedian G' and G'' in contrast-enhancing tumor were 13% and 37% lower than in normal-appearing white matter (P<0.01), and 8% and 6% lower in necrosis than in contrast-enhancing tumor, respectively (P<0.05). Tumors showed both inter-patient and intra-patient heterogeneity. Measurements approached values in normal-appearing tissue when moving outward from the tumor core, but abnormal tissue properties were still present in regions of normal-appearing tissue. Using both a linear and a random-forest model, prediction of CBF was improved by adding MRE measurements to the model (P<0.01).

CONCLUSIONSThe inclusion of MRE measurements in statistical models helped predict perfusion, with stiffer tissue associated with lower perfusion values. COMPARISON OF sPLA2-IIA PERFORMANCE WITH HIGH-SENSITIVE CRP, NEUTROPHIL PERCENTAGE, PCT AND LACTATE TO IDENTIFY BACTERIAL INFECTION: A PROSPECTIVE STUDY Early bacterial infection (BI) identification in resource-limiting Emergency Departments (ED) is challenging especially in low- and middle-income counties (LMIC). Misdiagnosis predisposes to antibiotic overuse and propagates antimicrobial resistance. This study evaluates new emerging biomarkers, secretory phospholipase A2 group IIA (sPLA2-IIA), and compares with other biomarkers on their performance characteristic of BI detection in Malaysia, an LMIC. A prospective cohort study was conducted involving 151 consecutive patients admitted to the ED. A single measurement was taken upon patient arrival in ED and was analysed for serum levels of sPLA2-IIA, high-sensitive C-reactive protein (CRP), procalcitonin (PCT), neutrophil percentage (N%), and lactate. All biomarkers performance was compared for the outcomes using area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. The performance of sPLA2-IIA (AUROC 0.93 [95% CI: 0.89-0.97]; Sn 80% [95% CI: 72-87] Sp 94% [95% CI: 81-89]) was the highest among all. It was comparable with high-sensitive CRP (AUROC 0.93 [95% CI: 0.88-0.97]; Sn 75% [95% CI: 66-83]; Sp 91 [95% CI: 77-98]) but had a higher Sn and Sp. The sPLA2-IIA was also found superior to N%, PCT, and lactate. This finding suggested sPLA2-IIA was recommended biomarkers for BI detection in LMIC. Preexisting diabetes and COVID-associated hyperglycaemia in patients with COVID-19 pneumonia AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSAimC_ST_ABSThe aim of the current study was to compare clinical characteristics, laboratory findings and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or preexisting diabetes.

MethodsA cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n=112) or COVID-associated hyperglycaemia (n=55) was studied. Clinical outcomes and laboratory findings were analysed according to the presence of the two conditions. The time to viral clearance was assessed during the follow-up after hospital discharge.

ResultPatients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities and higher levels of inflammatory markers and indicators of multi-organ injury than those with preexisting diabetes. No differences between preexisting diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, humoral response against SARS-CoV-2 or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p=0.001), even after adjustment for age, sex and other selected variables associated with COVID-19 severity. Furthermore, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p=0.063) between COVID-associated hyperglycaemia and the time to swab negativization.

ConclusionsThe recognition of hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity. Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium PurposeBy optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Muller glia.

MethodIn clinical OCT (61 eyes, 44 AMD patients, 79.4 {+/-} 7.7 years; 29 female; follow-up = 4.7 {+/-} 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy (GA), 6; 3 neovascular AMD (nvAMD). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semi-quantitatively by one observer (none, some cells, all cells).

ResultsTrajectories of RPE plume and cellular debris paralleled Muller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Muller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.

ConclusionGain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Muller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PrecisHyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation. Sensitivity of Estimated Tacrolimus Population Pharmacokinetic Profile to Inaccurate Assumptions about Dose Timing and Absorption: An Investigation in Real-World and Simulated Data A population pharmacokinetic (PK) study with 363 subjects was performed using real-world data extracted from electronic heath records (EHRs) to estimate the tacrolimus population PK profile. As population PK studies for oral medications performed using EHR data often assume a regular dosing schedule as prescribed without incorporating exact dosing time, we assessed the sensitivity of the PK parameter estimates to assumptions about dose timing using last-dose times extracted by our own natural language processing system, medExtractR. We also investigated the sensitivity of estimations to absorption rate constants that are often fixed at a published value in tacrolimus population PK analysis. There was no appreciable difference in parameters estimates with vs. without last-dose time incorporated in the data and our sensitivity analysis revealed little difference between parameters estimated assuming a range of absorption rate constants. We also conducted simulation studies to investigate how drug PK profiles and experimental designs such as concentration measurements affects sensitivity to incorrect assumptions about dose timing and absorption rates. Our findings suggest that drugs with a slower elimination rate (or a longer half-life) are less sensitive to dose timing errors and that experimental designs which only allow for trough blood concentrations are usually insensitive to deviation in absorption rate. Full vaccination is imperative to suppress SARS-CoV-2 delta variant mutation frequency COVID-19 vaccination resistance has become a major challenge to prevent global SARS-CoV-2 transmission. Here we report that the vaccination coverage rate is inversely correlated to the mutation frequency of the full genome (R2=0.878) and spike gene (R2=0.829) of SARS-CoV-2 delta variants in 16 countries, suggesting that full vaccination against COVID-19, with other mitigation strategies, is critical to suppress emergent mutations. Neutrality analysis of DH and Zengs E tests suggested that directional selection was the major driving force of delta variant evolution. To eliminate the homogenous effects (population expansion, selective sweep etc.), the synonymous (Dsyn) and nonsynonymous (Dnonsyn) polymorphisms of the delta variant spike gene were estimated with Tajimas D statistic. Both D ratio (Dnonsyn/Dsyn) and {Delta}D (Dsyn-Dnonsyn) have positive correlation with the full vaccination rate (R2= 0.723 and 0.505, respectively) in 19 countries, indicating that purifying selection pressure of SARS-CoV-2 spike gene increased as the vaccination coverage rate increased. Taken together, our data suggests that vaccination plays an important role in the purifying selection force of spike protein of SARS-CoV-2 delta variants. Early prediction of preeclampsia in pregnancy with circulating cell-free RNA Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an unprecedented opportunity to noninvasively study the development of pregnancy-related complications and to bridge gaps in clinical care. Here, we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia (PE), a multi-organ syndrome which is the second largest cause of maternal death globally. We find that changes in cfRNA gene expression between normotensive (NT) and preeclamptic mothers are striking and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial, and immune cell types and tissues that reflect important aspects of PE physiology and suggest new hypotheses for disease progression. This enabled identification and independent validation of a panel of 18 genes whose measurement between 5-16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of PE well before the clinical symptoms manifest themselves. Finally, we demonstrate that cfRNA changes reflect the multifactorial nature of PE and provide a means to non-invasively monitor maternal organ health. Tests based on these observations could help predict and manage who is at risk for PE, an important and until now unachieved objective for obstetric care. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimers Disease The genetic component of Alzheimers disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals --16,036 AD cases and 16,522 controls-- in a two-stage analysis. Next to known genes TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, A{beta}-aggregation, lipid metabolism and microglial function in AD. Colorectal Cancer Disparities Across the Continuum of Cancer Care: A Systematic Review and Meta-Analysis ImportanceDespite increases in screening among vulnerable populations, colorectal cancer disparities persist.

ObjectiveTo direct future efforts towards high impact opportunities in addressing these disparities, we performed a systematic review and meta-analysis of the colorectal cancer disparities literature with a focus on the utilization of Surgery, the primary treatment for colorectal cancer.

Data SourcesTwo electronic databases (PubMed and SCOPUS) were searched for prospective and retrospective studies reporting on colorectal cancer disparities between 2011 and March 29, 2021.

Study SelectionStudies for the systematic review were selected if: (1) reported on disparities within colorectal, colon, or rectal cancer (2) articles were published in the English language (3) articles used only United States-sourced data.

Studies for the meta-analysis were selected if: (1) reported on at least one of three utilization of surgery outcomes: receipt of colorectal, colon, or rectal surgery, refusal of surgery, or receipt of laparoscopic versus open surgery (2) Outcomes were reported as Odds ratio according to multivariate analysis.

Data Extraction and SynthesisQuality appraisal and data extraction were performed independently by 2 reviewers using the Newcastle-Ottawa Scale for quality assessment. For the meta-analysis, pooled multivariate odds ratios for the three outcomes regarding utilization of surgery were separately calculated according to fixed or random-effects models. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines.

Main Outcomes and MeasuresSystematic Review: The volume of publications attributed to the following sectors of the colorectal cancer care continuum: (1) Prevention, Screening, or Diagnosis (2) Treatment (3) Survivorship (4) End-of-life Care. Meta-analysis: Receipt of Colorectal, Colon, or Rectal Surgery and Black Race, Refusal of Surgery and Black Race, or Receipt of Laparoscopic versus Open Surgery and Black Race.

ResultsThe systematic review included 1,199 relevant publications. Among them, 60% were focused on Prevention, Screening, or Diagnosis, followed by Survivorship (20%), Treatment (15%), and End-of-Life Care (1%). Within the studies reporting on treatment disparities, 46% were focused on Race/Ethnicity, followed by Socioeconomic Status (28%), Age (17%), Gender (6%), Disabilities/Comorbidities (3%), and LGBTQI+ (0%). A total of 16 studies, including 1,110,674 patients, were applied to three separate meta-analyses regarding utilization of Surgery. Patients of black race were less likely to receive colorectal, or colon, or rectal surgery (OR 0.75, 95% CI 0.67-0.83), less likely to receive laparoscopic versus open colorectal cancer surgery (OR 0.91, 95% CI 0.88-0.94), and twice as likely to refuse colon surgery (OR 2.41, 95% CI 1.91-3.06).

Conclusions and RelevanceThe majority of research, to date, related to colorectal cancer disparities is focused on prevention, screening, or diagnosis and a minimal amount is dedicated to treatment. Additionally, all of the limited publications related to colorectal cancer surgery, as a treatment modality, are observational in nature. The application of this knowledge of past efforts and current continuing adverse outcomes is required in order to shift the focus of the research community towards treatment. In particular, research addressing surgical disparities is necessary, as surgery remains the primary treatment for colorectal cancer. Impact of HIV Infection on COVID-19 Outcomes Among Hospitalized Adults in the U.S. BackgroundWhether HIV infection is associated with differences in clinical outcomes among people hospitalized with COVID-19 is uncertain.

ObjectiveTo evaluate the impact of HIV infection on COVID-19 outcomes among hospitalized patients.

MethodsUsing the American Heart Associations COVID-19 Cardiovascular Disease registry, we used hierarchical mixed effects models to assess the association of HIV with in-hospital mortality accounting for patient demographics and comorbidities and clustering by hospital. Secondary outcomes included major adverse cardiac events (MACE), severity of illness, and length of stay (LOS).

ResultsThe registry included 21,528 hospitalization records of people with confirmed COVID-19 from 107 hospitals in 2020, including 220 people living with HIV (PLWH). PLWH were younger (56.0+/-13.0 versus 61.3+/-17.9 years old) and more likely to be male (72.3% vs 52.7%), Non-Hispanic Black (51.4% vs 25.4%), on Medicaid (44.5% vs 24.5), and active tobacco users (12.7% versus 6.5%).

Of the study population, 36 PLWH (16.4%) had in-hospital mortality compared with 3,290 (15.4%) without HIV (Risk ratio 1.06, 95%CI 0.79-1.43; risk difference 0.9%, 95%CI -4.2 to 6.1%; p=0.71). After adjustment for age, sex, race, and insurance, HIV was not associated with in-hospital mortality (aOR 1.13; 95%CI 0.77-1.6; p 0.54) even after adding body mass index and comorbidities (aOR 1.15; 95%CI 0.78-1.70; p=0.48). HIV was not associated with MACE (aOR 0.99, 95%CI 0.69-1.44, p=0.91), severity of illness (aOR 0.96, 95%CI 0.62-1.50, p=0.86), or LOS (aOR 1.03; 95% CI 0.76-1.66, p=0.21).

ConclusionHIV was not associated with adverse outcomes of COVID-19 including in-hospital mortality, MACE, or severity of illness.

Condensed AbstractWe studied 21,528 patients hospitalized with COVID-19 at 107 hospitals in AHAs COVID-19 registry to examine the association between HIV and COVID-19 outcomes. More patients with HIV were younger, male, non-Hispanic Black, on Medicaid and current smokers. HIV was not associated with worse COVID-19 in-hospital mortality (Risk ratio 1.06, 95%CI 0.79-1.43; p=0.71) even after adjustment (aOR 1.15; 95%CI 0.78-1.70; p=0.48). HIV was also not associated with MACE (aOR 0.99, 95%CI 0.69-1.44, p=0.91) or severity of illness (aOR 0.96, 95%CI 0.62-1.50, p=0.86. Our findings do not support that HIV is a major risk factor for adverse COVID-19 outcomes. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times. Simple risk scores to predict hospitalization or death in outpatients with COVID-19 including the Omicron variant ImportanceOutpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, in particular whether to hospitalize a patient and if managed as an outpatient, how closely to follow them.

ObjectiveTo develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging.

DesignDerivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules.

SettingPrimary and Express care clinics in a Pennsylvania health system.

ParticipantsPatients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19.

Main outcomes and measuresClassification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC).

ResultsOverall, 7.4% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21) and 5.5% in the late validation cohort (3806 patients presenting 3/1/21 or later) were ultimately hospitalized. We developed and temporally validated three risk scores that all included age, dyspnea, and the presence of comorbidities, adding respiratory rate for the second score and oxygen saturation for the third. All had very good overall accuracy (AUC 0.77 to 0.78) and classified over half of patients in the validation cohort as very low risk with a 1.7% or lower likelihood of hospitalization. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization (2.8%).

Conclusions and relevanceSimple risk scores applicable to outpatient and telehealth settings can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/. Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. The effects of modifiable maternal pregnancy risk factors on molar-incisor hypomineralisation: A negative control study ObjectivesO_LITo explore the associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).
C_LIO_LITo explore for the presence of residual confounding using negative control analyses.
C_LI

MethodsThis study used data from Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective birth cohort. We defined offspring MIH using prospectively collected questionnaire data. We used logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We included negative control exposure (paternal BMI, smoking and alcohol around the time of pregnancy) and outcome (offspring dental trauma) analyses to explore for the presence of residual confounding.

Results5536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a positive association between maternal mean BMI and offspring MIH (OR per 1-kg/m2 difference in maternal BMI: 1.04, 95% CI: 1.00, 1.08). In subsequent analyses, we found evidence that this effect was non-linear and being driven by women in the highest BMI quintiles. In negative control analyses, we found no evidence of association between paternal BMI and offspring MIH (OR: 0.94, 95% CI: 0.89, 1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95% CI: 0.96, 1.02). There was no clear evidence of an association for maternal pregnancy smoking (OR: 0.76, 95%CI: 0.46, 1.22) and alcohol consumption (OR: 0.79, 95% CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

ConclusionIn summary we found evidence of a possible intrauterine effect of high maternal pre-pregnancy BMI on offspring MIH. We did not find robust evidence for an intrauterine effect of maternal pregnancy smoking or alcohol consumption on offspring MIH. Our findings provide further support for women of reproductive age to maintain a healthy weight. Future studies are warranted to explore possible mechanisms on how the pregnancy environment may relate to offspring MIH. Problems with Evidence Assessment in COVID-19 Health Policy Impact Evaluation (PEACHPIE): A systematic review of evidence strength IntroductionAssessing the impact of COVID-19 policy is critical for informing future policies. However, there are concerns about the overall strength of COVID-19 impact evaluation studies given the circumstances for evaluation and concerns about the publication environment. This study systematically reviewed the strength of evidence in the published COVID-19 policy impact evaluation literature.

MethodsWe included studies that were primarily designed to estimate the quantitative impact of one or more implemented COVID-19 policies on direct SARS-CoV-2 and COVID-19 outcomes. After searching PubMed for peer-reviewed articles published on November 26, 2020 or earlier and screening, all studies were reviewed by three reviewers first independently and then to consensus. The review tool was based on previously developed and released review guidance for COVID-19 policy impact evaluation, assessing what impact evaluation method was used, graphical display of outcomes data, functional form for the outcomes, timing between policy and impact, concurrent changes to the outcomes, and an overall rating.

ResultsAfter 102 articles were identified as potentially meeting inclusion criteria, we identified 36 published articles that evaluated the quantitative impact of COVID-19 policies on direct COVID-19 outcomes. The majority (n=23/36) of studies in our sample examined the impact of stay-at-home requirements. Nine studies were set aside because the study design was considered inappropriate for COVID-19 policy impact evaluation (n=8 pre/post; n=1 cross-section), and 27 articles were given a full consensus assessment. 20/27 met criteria for graphical display of data, 5/27 for functional form, 19/27 for timing between policy implementation and impact, and only 3/27 for concurrent changes to the outcomes. Only 1/27 studies passed all of the above checks, and 4/27 were rated as overall appropriate. Including the 9 studies set aside, reviewers found that only four of the 36 identified published and peer-reviewed health policy impact evaluation studies passed a set of key design checks for identifying the causal impact of policies on COVID-19 outcomes.

DiscussionThe reviewed literature directly evaluating the impact of COVID-19 policies largely failed to meet key design criteria for inference of sufficient rigor to be actionable by policy-makers. This was largely driven by the circumstances under which policies were passed making it difficult to attribute changes in COVID-19 outcomes to particular policies. More reliable evidence review is needed to both identify and produce policy-actionable evidence, alongside the recognition that actionable evidence is often unlikely to be feasible. Post-viral mental health sequelae in infected persons associated with COVID-19 and previous epidemics and pandemics: Systematic review and meta-analysis of prevalence estimates AimsPost-viral mental health problems (MHP) in COVID-19 patients and survivors were anticipated already during early stages of this pandemic. We aimed to synthesize the prevalence of the anxiety, depression, post-traumatic and general distress domain associated with virus epidemics since 2002.

MethodsIn this systematic review and meta-analysis, we searched PubMed, PsycINFO, and Embase from 2002 until April 14, 2021 for peer-reviewed studies reporting prevalence of MHP in adults with laboratory-confirmed or suspected SARS-CoV-1, H1N1, MERS-CoV, H7N9, Ebolavirus, or SARS-CoV-2 infection. We included studies that assessed post-viral MHP with validated and frequently used scales. A three-level random-effects meta-analysis for dependent sizes was conducted to account for multiple outcome reporting. We pooled MHP across all domains and separately by severity (above mild or moderate-to-severe) and by acute (one month), ongoing (one to three months), and post-illness stages (longer than three months). A meta-regression was conducted to test for moderating effects, particularly for exploring estimate differences between SARS-Cov-2 and previous pandemics and epidemics. PROSPERO registration: CRD42020194535.

ResultsWe identified 59 studies including between 14 to 1002 participants and providing 187 prevalence estimates. MHP, in general, decreased from acute to post-illness from 46{square}3% to 38{square}8% and for mild and moderate-to-severe from 22{square}3% to 18{square}8%, respectively. We found no evidence of moderating effects except for non-random sampling and H1N1 showing higher prevalence. Pooled MHP differed somewhat between previous pandemics/ epidemics and SARS-CoV-2 but were in a comparable range.

ConclusionsMHP prevalence estimates decreased over time but were still on a substantial level at post-illness. Post-viral mental health problems caused by SARS-CoV-2 could have been expected much earlier, given the previous post-viral sequelae. Pulsed electromagnetic fields may be effective for the management of primary osteoporosis: a systematic review and meta-analysis ObjectiveTo investigate the effectiveness of pulsed electromagnetic fields (PEMFs) for the management of primary osteoporosis in older adults.

DesignSystematic review and meta-analysis.

Data SourcesMEDLINE, EMBASE, Web of Science, CENTRAL and CCTR, Physiotherapy Evidence Database, CNKI, VIP, Wan Fang, ClinicalTrials.gov and Current controlled trials from the inception dates to April 30, 2021.

Eligibility criteria for study selectionRandomised controlled trials or quasi-randomised trials examining the effects of PEMFs compared to placebo or sham or other agents for the management of primary osteoporosis (including those with previous fractures).

Data extraction and synthesisTwo independent reviewers extracted data. Primary outcomes were bone mass and number of incident fractures. Secondary outcomes were functional assessments, quality of life, and adverse events. Risk of bias was assessed with the Cochrane Collaborations tool and certainty of evidence with the grading of recommendations assessment, development and evaluation (GRADE) framework. A random effects model was used to calculate mean differences and 95% confidence intervals.

ResultsEight trials including 396 participants met the inclusion criteria. Low certainty evidence showed that PEMFs was non-inferior to conventional pharmacological agents in preventing the decline of Bone Mineral Density (BMD) at the lumbar (MD 0.01; CI -0.04 to 0.06) and femur neck (MD 0.01; CI -0.02 to 0.04), and improving balance function measured by Berg Balance Scale (BBS) (MD 0.01; CI -0.09 to 0.11) and Timed Up and Go test (MD -0.04; CI -0.80 to 0.72), directly after intervention. The similar effects were observed in BMD and BBS at 12- and 24-weeks follow-up from baseline with moderate certainty evidence. Very low certainty evidence showed that PEMFs (versus exercise) had small but significant effect on BMD at the femur neck (MD 0.10; CI 0.01 to 0.20), and no effect on BMD at the lumbar (MD 0.15; CI -0.04 to 0.35).

ConclusionPEMFs had positive effects non-inferior to first-line treatment on BMD and balance function in older adults with primary osteoporosis, but with low to very low certainty evidence and short-term follow-ups. There is a need for high-quality randomised controlled trials evaluating PEMFs for the management of primary osteoporosis.

RegistrationPROSPERO CRD42018099518.