A SARS-CoV-2 Label-Free Surrogate Virus Neutralization Test and a Longitudinal Study of Antibody Characteristics in COVID-19 Patients Background. The laboratory-based methods to measure the SARS-CoV-2 humoral response include virus neutralization tests (VNTs) to determine antibody neutralization potency. For ease of use and universal applicability, surrogate virus neutralization tests (sVNTs) based on antibody-mediated blockage of molecular interactions have been proposed. Methods. A surrogate virus neutralization test established on a label-free immunoassay platform (LF-sVNT). The LF-sVNT analyzes the binding ability of RBD to ACE2 after neutralizing RBD with antibodies in serum. Results. The LF-sVNT neutralizing antibody titers (IC50) were determined from serum samples (n=246) from COVID-19 patients (n=113), as well as the IgG concentrations and the IgG avidity indices. Although there is variability in the kinetics of the IgG concentrations and neutralizing antibody titers between individuals, there is an initial rise, plateau and then in some cases a gradual decline at later timepoints after 40 days post-symptom onset. The IgG avidity indices, in the same cases, plateau after the initial rise and did not show a decline. Conclusions. The LF-sVNT can be a valuable tool in clinical laboratories for the assessment of the presence of neutralizing antibodies to COVID-19. This study is the first to provide longitudinal neutralizing antibody titers beyond 200 days post-symptom onset. Despite the decline of IgG concentration and neutralizing antibody titer, IgG avidity index increases, reaches a plateau and then remains constant up to 8 months post-infection. The decline of antibody neutralization potency can be attributed to the reduction in antibody quantity rather than the deterioration of antibody avidity, a measure of antibody quality.
Estimating the Failure Risk of Quarantine Systems for Preventing COVID-19 Outbreaks in Australia and New Zealand ObjectivesTo identify COVID-19 outbreaks and border control failures associated with quarantine systems in Australia and New Zealand and to estimate the failure risks.

Design, setting, participantsObservational epidemiological study of travellers transiting quarantine in Australia and New Zealand up to 15 June 2021.

Main outcome measuresThe incidence of COVID-19 related failures arising from quarantine, and the failure risk for those transiting quarantine, estimated both per 100,000 travellers and per 1000 SARS-CoV-2 positive cases.

ResultsAustralia and New Zealand had 32 COVID-19 related failures arising from quarantine systems up to 15 June 2021 (22 and 10, respectively). One resultant outbreak involved an estimated 800 deaths and quarantine failures instigated nine lockdowns. The failure risk for those transiting quarantine was estimated at 5.0 failures per 100,000 travellers and 6.1 failures (95%CI: 4.0 to 8.3) per 1000 SARS-CoV-2 positive cases. The latter risk was two-fold higher in New Zealand compared with Australia. The full vaccination of frontline border workers could likely have prevented a number of quarantine system failures.

ConclusionsQuarantine system failures can be costly in terms of lives and economic impacts such as lockdowns. Ongoing improvements or alternatives to hotel-based quarantine are required.
Meta-analytic findings on reading in children with cochlear implants This meta-analysis study aims to quantify the group differences in reading skills between children with cochlear implants and their hearing peers and between children with cochlear implants and children with hearing aids (aged between 3 to 18 years old). Of the 5,642 articles screened, 47 articles met predetermined inclusion criteria (published between 2002 and 2019). The robust variance estimation based meta-analysis models were used to synthesize all the effect sizes. Children with cochlear implants scored significantly lower than their hearing peers in phonological awareness (g = - 1.62, p < .001), vocabulary (g = -1.50, p < .001), decoding (g = -1.24, p < .001), and reading comprehension (g = -1.39, p < .001), but not for fluency (g = -.67, p = .054). Compared to children with hearing aids, children with cochlear implants scored significantly lower in phonological awareness (g = -.30, p = .028). The percentage of unilateral cochlear implant negatively impacts the group difference between children with cochlear implants and their hearing peers. Findings from this study confirm a positive shift in reading outcomes for profoundly deaf children due to cochlear implantation. Some children with cochlear implants may need additional supports in educational settings. Using controlled interrupted time series to estimate the population-level effects of Ontario's recently implemented overdose prevention sites and consumption and treatment services BackgroundOntario recently implemented overdose prevention sites and consumption and treatment services (OPS/CTS) to stem the harms of the opioid epidemic. We tested whether operating any site improved local opioid-related health service use and mortality rates.

MethodsWe used monthly counts of all opioid-related emergency department (ED) visits, hospitalizations, and deaths between January 2014 and December 2020 for our outcomes. For each public health unit (PHU) that implemented any OPS/CTS, we created a synthetic control as a weighted combination of unexposed PHU. We estimated the population-level effects of operating any site using controlled interrupted time series with segmented regression and adjusted for time varying confounders (i.e. OPS/CTS capacity, naloxone kits distributed, and persons receiving opioid agonist treatment per 100,000 population). We repeated the analysis using a multiple baseline approach to estimate province-wide effects.

ResultsBetween 2017 and 2020, nine out of 34 PHU implemented at least one OPS/CTS. ED visit (RR=0.96, 95%CI: 0.92 - 0.99) and hospitalization (RR=0.95, 95%CI: 0.92 - 0.98) trends declined faster among treated units. Improvements in local ED visit rate trends were observed for the majority of treated units. Hospitalization rates declined faster for London (RR=0.97, 95%CI: 0.95 - 0.99) and Niagara (RR=0.95, 95%CI: 0.92 - 0.98); while mortality rates declined faster for Hamilton (RR=0.93, 95%CI: 0.90 - 0.96), Niagara (RR=0.97, 95%CI: 0.94 - 0.99) and Guelph (RR=0.94, 95%CI: 0.88 - 1.00).

ConclusionAlthough OPS/CTS are not sufficient to stem the harms of the opioid overdose epidemic on their own, they play a critical role in local harm reduction strategies. CD19+IgD+CD27- naive B Cells as predictors of humoral response to COVID 19 mRNA vaccination in immunocompromised patients Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naive B cells was strongly associated with antibody levels ({rho}=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-{micro}l increase, 95%CI 1.02-1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at [&ge;]61 naive B cells per {micro}l to discriminate between patients with and without an optimal antibody response. Consequently, measuring naive B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response. 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/. How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes. Endometriosis symptoms are heterogeneous with controversy on whether it constitutes a single disease or multiple distinct types. Our previous work found recurrent somatic cancer-driver alterations in endometriosis; however, these have not been found ubiquitously. A handful of cases spread across studies also suggest mutations might be shared (clonal) between lesions of the same type. As current classification systems correlate poorly with symptoms or outcomes, somatic genomics may improve the current system. Here, we investigate heterogeneity of somatic cancer-driver mutations within patients and across endometriosis types. We examined anatomically distinct types of endometriosis (ovarian, deep infiltrating, and superficial endometriosis) in 27 individual patients all of whom had at least two types of endometriosis. Specimens were analyzed using high-sensitivity targeted sequencing with orthogonal validation from droplet digital PCR and mutation-surrogate immunohistochemistry. Results found 13/27 patients had informative somatic driver mutation in endometriosis, 9/13 had identical mutations across distinct lesions. Endometriomas tended to have a higher mutational complexity, with functionally redundant driver mutations in same gene and within the same lesions.

Our data are consistent with clonality across endometriosis lesions regardless of subtype. Further the finding of redundancy in mutations with the same gene and lesions is also consistent with endometriosis representing an oligoclonal disease with dissemination likely to consist of multiple epithelial clones travelling together. This suggests the current anatomically defined classification of endometriosis does not fully recognize the etiology of the disease. A novel classification should take into account genomic and other molecular features. These findings could further contribute to development of a more personalized endometriosis diagnosis and care. 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. External Validation Of A Novel Signature Of Illness In Continuous Cardiorespiratory Monitoring To Detect Early Respiratory Deterioration Of ICU Patients The goal of predictive analytics monitoring is the early detection of patients at high risk of subacute potentially catastrophic illnesses. An excellent example of a targeted illness is respiratory failure leading to urgent unplanned intubation, where early detection might lead to interventions that improve patient outcomes. Previously, we identified signatures of this illness in the continuous cardiorespiratory monitoring data of Intensive Care Unit patients and devised algorithms to identify patients at rising risk. Here, we externally validated three logistic regression models to estimate the risk of emergency intubation developed in Medical and Surgical ICUs at the University of Virginia. We calculated the model outputs for more than 8000 patients in the University of California - San Francisco ICUs, 240 of whom underwent emergency intubation as determined by individual chart review. We found that the AUC of the models exceeded 0.75 in this external population, and that the risk rose appreciably over the 12 hours before the event. We conclude that there are generalizable physiological signatures of impending respiratory failure in the continuous cardiorespiratory monitoring data. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) Knowledge, attitude, and practices regarding COVID-19: A study on food handlers in a joint venture food industry in Dhaka, Bangladesh. While people around the world are terrified of the global pandemic coronavirus disease 2019 (COVID-19) and are dying for a permanent solution, undertaking preventive safety measures are said to be the most effective way to stay away from it. Peoples adherences to these measures are broadly dependent on their knowledge, attitude, and practices (KAP). People working in the food industries must be extra cautious during this time because they are in close proximity to consumable items. The present study was designed to evaluate food handlers knowledge, attitude, and practices regarding COVID-19 in different food industries in Bangladesh. A number of 400 food handlers from 15 food industries took part in this online-based study. The information was collected from the participants through a questionnaire prepared in Google form. With a correct response rate of about 90% on average (knowledge 89.7%, attitude 93%, practices 88.2%), the participants showed an acceptable of KAP regarding COVID-19. Education and working experiences had a significant association with the total KAP scores (p < 0.05). The findings may assist public health professionals and practitioners in developing targeted strategies for implementing such studies in other industrial sectors and taking appropriate measures based on the KAP studies. Population Pharmacokinetic Analysis of Dexmedetomidine in Children using Real World Data from Electronic Health Records and Remnant Specimens AimOur objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and data from electronic health records (EHRs) and explore the impact of patients characteristics and pharmacogenetics on dexmedetomidine clearance.

MethodsDexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modeling. The first stage developed a model without genotype variables; the second stage added pharmacogenetic effects.

ResultsOur final study population included 354 post-cardiac surgery patients age 0 to 22 years (median 16 months). The final two-compartment model included allometric weight scaling and age maturation. Population parameter estimates and 95% confidence intervals were 27.3 L/hr (24.0 - 31.1 L/hr) for total clearance (CL), 161 L (139 - 187 L) for central compartment volume of distribution (V1), 26.0 L/hr (22.5 - 30.0 L/hr) for intercompartmental clearance (Q), and 7903 L (5617 - 11119 L) for peripheral compartment volume of distribution (V2). The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5 - 42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99 - 7.08). Genotype was not statistically or clinically significant.

ConclusionOur study demonstrates the use of real-world EHR data and remnant specimens to perform a population PK analysis and investigate covariate effects in a large pediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.

What is already known about this subject{circ} Previous dexmedetomidine pharmacokinetic (PK) studies in pediatric populations have limited sample size.
{circ}Smaller studies present a challenge for identifying covariates that may impact individual PK profiles.


What this study adds{circ} We performed a dexmedetomidine population PK study with a large pediatric cohort using data obtained from electronic health records and remnant plasma specimens to enable increased sample size.
{circ}xsDifferences in PK due to UGT1A4 or UGT2B10 variants or CYP2A6 risk score are not clinically impactful for this population. Trajectory of Growth of SARS-CoV-2 Variants in Houston, Texas, January through May 2021 Based on 12,476 Genome Sequences Genetic variants of the SARS-CoV-2 virus are of substantial concern because they can detrimentally alter the pandemic course and disease features in individual patients. Here we report SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist healthcare system diagnosed from January 1, 2021 through May 31, 2021. The SARS-CoV-2 variant designated U.K. B.1.1.7 increased rapidly and caused 63%-90% of all new cases in the Houston area in the latter half of May. Eleven of the 3,276 B.1.1.7 genomes had an E484K change in spike protein. Compared with non-B.1.1.7 patients, individuals with B.1.1.7 had a significantly lower cycle threshold value (a proxy for higher virus load) and significantly higher rate of hospitalization. Other variants (e.g., B.1.429, B.1.427, P.1, P.2, and R.1) also increased rapidly, although the magnitude was less than for B.1.1.7. We identified 22 patients infected with B.1.617 "India" variants; these patients had a high rate of hospitalization. Vaccine breakthrough cases (n=207) were caused by a heterogeneous array of virus genotypes, including many that are not variants of interest or concern. In the aggregate, our study delineates the trajectory of concerning SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, and heralds the arrival and spread of B.1.617 variants in the metroplex. The incidence of delirium in an acute geriatric community hospital: an observational cohort feasibility study. ObjectivesDelirium in hospitalised older adults is associated with negative health outcomes. Admission to an alternative care setting may lower the incidence of delirium. The Acute Geriatric Community Hospital (AGCH) was recently opened in the Netherlands and uses a multi-component non-pharmacological intervention strategy to prevent delirium. The objective of this study was to describe the incidence of delirium at the AGCH and compare this incidence to existing rates from literature. If a possible effect on delirium is seen in this comparison this would support conducting a larger prospectively controlled study on delirium in this new care setting.

DesignProspective cohort feasibility study; exploratory meta-analysis of proportions.

Setting and ParticipantsThe AGCH is an acute geriatric unit in a skilled nursing facility for patients aged >65 years with acute medical conditions.

MethodsDelirium assessment using the Confusion Assessment Method (CAM) upon admission and on day one, two and three or until delirium had resolved. Patients charts were reviewed if CAM was missing. In an linear mixed-effects model, the delirium incidence rate in AGCH was compared to pooled delirium incidence rates from six studies found in a high-quality review.

Results214 patients from the AGCH (mean age 81.9 years, 47% male, 12% with a history of dementia) were included in the analysis. Delirium developed in 8% (18/214) (95% confidence interval [CI] 5-13%) of patients during AGCH admission compared to 16% (95% CI 12-21%) in hospitals. Admission to the AGCH was associated with a decreased delirium incidence rate compared to the hospital control group (OR[odds ratio]= 0.49, 95% CI 0.24-0.98, p-value=0.044).

Conclusions and implicationsThe delirium incidence in the AGCH was low compared to those incidences found in general hospitals in literature. Based on these findings a controlled observational or randomized study measuring delirium in this care setting is recommended. Subpopulation-specific Machine Learning Prognosis for Underrepresented Patients with Double Prioritized Bias Correction Many clinical datasets are intrinsically imbalanced, dominated by overwhelming majority groups. Off-the-shelf machine learning models that optimize the prognosis of majority patient types (e.g., healthy class) may cause substantial errors on the minority prediction class (e.g., disease class) and demographic subgroups (e.g., Black or young patients). For example, our work found that missed death cases are 3.14 times higher than missed survival cases in a mortality prediction model. In the typical one-machine-learning-model-fits-all paradigm, racial and age disparities are likely to exist, but unreported. What makes it worse is the deceptive nature of widely used whole-population metrics, such as AUC-ROC. We show that some metrics fail to reflect serious prediction deficiencies. To mitigate representational biases, we design a double prioritized (DP) bias correction technique. Our method trains customized models for specific ethnicity or age groups, a substantial departure from the one-model-predicts-all convention. We report our findings on four prognosis tasks over two imbalanced clinical datasets. DP reduces relative disparities among race and age groups, 5.6% to 86.8% better than the 8 existing sampling solutions being compared, in terms of the minority class' recall. In depth analysis of patients with severe SARS-CoV-2 in sub-Saharan Africa demonstrates distinct clinical and immunological profiles Although the COVID-19 pandemic has left no country untouched there has been limited research to understand clinical and immunological responses in African populations. Here we comprehensively characterise patients hospitalised with suspected or confirmed COVID-19, and healthy community controls. PCR-confirmed COVID-19 participants were more likely to receive dexamethasone and a beta-lactam antibiotic, and survive to hospital discharge than PCR-/IgG+ and PCR-/IgG-participants. PCR-/IgG+ participants exhibited a nasal and systemic cytokine signature analogous to PCR-confirmed COVID-19 participants, but increased propensity for Staphylococcus aureus and Streptococcus pneumoniae colonisation. We did not find evidence that HIV co-infection in COVID-19 participants was associated with mortality or altered cytokine responses. The nasal immune signature in PCR-/IgG+ and PCR-confirmed COVID-19 participants was distinct and predominated by chemokines and neutrophils. In addition, PCR-/IgG+ individuals with high COVID-19 clinical suspicion had inflammatory profiles analogous to PCR-confirmed disease and potentially represent a target population for COVID-19 treatment strategies. 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. 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. Precision MRI Phenotyping Enables Detection of Small Changes in Body Composition for Longitudinal Cohorts Longitudinal studies provide unique insights into the impact of environmental factors and lifespan issues on health and disease. Here we investigate changes in body composition in 3,088 free-living participants, part of the UK Biobank in-depth imaging study. All participants underwent neck-to-knee MRI scans at the first imaging visit and after approximately two years (second imaging visit). Image-derived phenotypes for each participant were extracted using a fully-automated image processing pipeline, including volumes of several tissues and organs: liver, pancreas, spleen, kidneys, total skeletal muscle, iliopsoas muscle, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), as well as fat and iron content in liver, pancreas and spleen. Overall, no significant changes were observed in BMI, body weight, or waist circumference over the scanning interval, despite some large individual changes. A significant decrease in grip strength was observed, coupled to small, but statistically significant, decrease in all skeletal muscle measurements. Significant increases in VAT and intermuscular fat in the thighs were also detected in the absence of changes in BMI, waist circumference and ectopic-fat deposition. Adjusting for disease status at the first imaging visit did not have an additional impact on the changes observed. In summary, we show that even after a relatively short period of time significant changes in body composition can take place, probably reflecting the obesogenic environment currently inhabited by most of the general population in the United Kingdom. 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. Early management of severe COVID-19 coagulopathy should be guided by TEG, microclot and platelet mapping An important component of severe COVID-19 disease is virus-induced endothelilitis. This leads to disruption of normal endothelial function, initiating a state of failing normal clotting physiology. Massively increased levels of von Willebrand Factor (VWF) lead to overwhelming platelet activation, as well as activation of the enzymatic (intrinsic) clotting pathway. In addition, there is an impaired fibrinolysis, caused by, amongst others, increased levels of alpha-(2) antiplasmin. The end result is hypercoagulation [proven by thromboelastography(R) (TEG(R))] and reduced fibrinolysis, inevitably leading to a difficult-to-overcome hypercoagulated physiological state. Platelets in circulation also plays a significant role in clot formation, but themselves may also drive hypercoagulation when they are overactivated due to the interactions of their receptors with the endothelium, immune cells or circulating inflammatory molecules. From the literature it is clear that the role of platelets in severely ill COVID-19 patients has been markedly underestimated or even ignored. We here highlight the value of early management of severe COVID-19 coagulopathy as guided by TEG(R), microclot and platelet mapping. We also argue that the failure of clinical trials, where the efficacy of prophylactic versus therapeutic clexane (low molecular weight heparin (LMWH)) were not always successful, might be because the significant role of platelet activation was not taken into account during the planning of the trial. We conclude that, because of the overwhelming alteration of clotting, the outcome of any trial evaluating an any single anticoagulant, including thrombolytic, would be negative. Here we suggest the use of the degree of platelet dysfunction and presence of microclots in circulation, together with TEG(R), should be used as a guideline for disease severity. A multi-pronged approach, guided by TEG(R) and platelet mapping, would be required to maintain normal clotting physiology in severe COVID-19 disease. Monitoring socioeconomic inequalities across HIV knowledge, attitudes, behaviours and prevention in 18 sub-Saharan African countries ObjectivesSocioeconomic inequalities in HIV prevention services coverage constitute important barriers to global prevention targets, especially in sub-Saharan Africa (SSA). We aimed at monitoring these inequalities from population-based survey data in 18 SSA countries between 2010 and 2018.

MethodsWe defined eight HIV indicators aimed at capturing uptake of HIV prevention services among adult participants. Country-specific wealth-related inequalities were measured using the Relative and Slope Index of Inequalities (RII and SII, respectively) and then pooled using random-effects meta-analyses. We compared inequalities between African regions using the Wilcoxon rank-sum test.

ResultsThe sample consisted of 358,591 participants (66% women). Despite variability between countries and indicators, the meta-analysis revealed significant levels of relative and absolute inequalities in 6 out of 8 indicators: HIV-related knowledge, positive attitudes toward people living with HIV (PLHIV), condom use at last sexual intercourse, participation to prevention of mother-to-child transmission programs, medical male circumcision and recent HIV testing. The largest inequalities were reported in condom use, with condom use reported 5 times more among the richest versus the poorest (RII=5.02, 95% Confidence interval, CI: 2.79-9.05) and in positive attitudes toward PLHIV, with a 32-percentage point difference between the richest and poorest (SII=0.32, 95% CI: 0.26-0.39). Conversely, no significant inequalities were observed in multi-partnership and HIV seropositivity among youth. Overall, inequalities tended to be larger in West and Central vs. East and Southern African countries.

ConclusionsDespite efforts to scale-up HIV-prevention programs, socioeconomic inequalities remain substantial over the continuum of HIV primary and secondary prevention in several SSA countries. Three-dimensional cephalometric landmarking and Frankfort horizontal plane construction: reproducibility of conventional and novel landmarks ObjectivesTo assess manual landmarking repeatability and reproducibility (R&R) of a set of three-dimensional (3D) landmarks and to evaluate R&R of vertical cephalometric measurements using two Frankfort Horizontal (FH) planes as references for horizontal 3D imaging reorientation.

MethodsThirty-three landmarks, divided into "conventional", "foraminal" and "dental", were manually located twice by 3 experienced operators on 20 computed tomography (CT) scans of orthognathic surgery patients. R&R of the landmark localization were computed according to the ISO 5725 standard. These landmarks were then used to construct 2 FH planes: a conventional FH plane (orbitale left, porion right and left) and a newly proposed FH plane (midinternal acoustic foramen, orbitale right and left). R&R of vertical cephalometric measurements were computed using these 2 FH planes as horizontal references for CT reorientation.

ResultsLandmarks showing a 95% confidence interval (CI) of repeatability and/or reproducibility > 2mm were found exclusively in the "conventional" landmarks group. Vertical measurements showed excellent R&R (95% CI < 1mm) with either FH plane as horizontal reference. However, the 2 FH planes were not found to be parallel (absolute angular difference of 2.41{degrees}, SD 1.27{degrees}). The average time needed to landmark one CT scan was 14 {+/-} 3 minutes.

ConclusionsThe "dental" and "foraminal" landmarks tended to be more reliable than the "conventional" landmarks. Despite the poor overall reliability of the landmarks orbitale and porion, the construction of the conventional FH plane using 3 landmarks provided a reliable horizontal reference for 3D craniofacial CT scan reorientation. Psychological factors associated with instrumental activities of daily living disability in older adults with knee osteoarthritis PurposeThe population of older adults with knee osteoarthritis (OA)-related disabilities is increasing globally. This study aimed to investigate the psychological factors associated with instrumental activities of daily living (IADL) disability in older adults with knee OA.

Materials and MethodsA cross-sectional study was conducted on 179 patients with knee OA aged [&ge;] 65 years. The six-item short form of the Pain Catastrophizing Scale (PCS-6), the four-item short form of the Pain Self-Efficacy Questionnaire (PSEQ-4), and the fifteen-item Geriatric Depression Scale (GDS-15) were used to assess psychological factors. IADL status was assessed using eight activity items. Participants were divided into IADL-disabled and non-disabled groups. Binary logistic regression analyses were performed with the IADL disability status as the dependent variable. The PCS-6, PSEQ-4, and GDS-15 tools were included as independent variables in the logistic regression model. Demographics, motor functions, and pain intensity were also included as confounders.

ResultsOf the total participants, 88 (49.1%) showed disability in conducting IADL. PSEQ-4 (odds ratio =0.90, 95%; confidence interval=0.82-0.99, p=0.02) was a significant independent variable among all psychological factors.

ConclusionOur study showed the importance of assessing self-efficacy using the PSEQ-4 in relation to IADL disability in older adults with knee OA. EDUCATIONAL NEEDS OF MEDICAL PRACTITIONERS ABOUT MEDICAL BILLING: A SCOPING REVIEW OF THE LITERATURE. IntroductionThe World Health Organization has suggested the solution to health system waste caused by incorrect billing and fraud is policing and prosecution. However, a growing body of evidence suggests leakage may not always be fraudulent or corrupt, with researchers suggesting medical practitioners may sometimes struggle to understand increasingly complex legal requirements around health financing and billing transactions, which may be improved through education. To explore this phenomenon further, we undertook a scoping review of the literature to identify the medical billing education needs of medical practitioners and whether those needs are being met.

MethodsEligible records included English language materials published between 1 January 2000 and 4 May 2020. Searches were conducted on MEDLINE, PubMed, Google Scholar, CINAHL, LexisNexis and Heinonline.

ResultsWe identified 74 records as directly relevant to the search criteria. Despite undertaking a comprehensive, English language search, with no country restrictions, studies meeting the inclusion criteria were limited to three countries (Australia, Canada, U.S), indicating a need for further work internationally. The literature suggests the education needs of medical practitioners in relation to medical billing compliance are not being met and medical practitioners desire more education on this topic. Evidence suggests education may be effective in improving medical billing compliance and reducing waste in health systems. There is broad agreement amongst medical education stakeholders in multiple jurisdictions that medical billing should be viewed as a core competency of medical education, though there is an apparent inertia to include this competency in medical education curricula. Penalties for non-compliant medical billing are serious and medical practitioners are at risk of random audits and investigations for breaches of sometimes incomprehensible, and highly interpretive regulations they may never have been taught.

ConclusionDespite acknowledged significance of waste in health systems due to poor practitioner knowledge of billing practices, there has been very little research to date on education interventions to improve health system efficiency at a practitioner level.