Infectious SARS-CoV-2 Virus in Symptomatic COVID-19 Outpatients: Host, Disease, and Viral Correlates BackgroundWhile SARS-CoV-2 infectious virus isolation in outpatients with COVID-19 has been associated with viral RNA levels and symptom duration, little is known about the host, disease and viral determinants of infectious virus detection.

MethodsCOVID-19 adult outpatients were enrolled within 7 days of symptom onset. Clinical symptoms were recorded via patient diary. Nasopharyngeal swabs were collected to quantitate SARS-CoV-2 RNA by reverse transcriptase polymerase chain reaction and for infectious virus isolation in Vero E6-cells. SARS-CoV-2 antibodies were measured in serum using a validated ELISA assay.

ResultsAmong 204 participants with mild-to-moderate symptomatic COVID19, the median nasopharyngeal viral RNA was 6.5 (IQR 4.7-7.6 log10 copies/mL), and 26% had detectable SARS-CoV-2 antibodies (IgA, IgM, IgG, and/or total Ig) at baseline. Infectious virus was recovered in 7% of participants with SARS-CoV-2 antibodies compared to 58% of participants without antibodies (probability ratio (PR)=0.12, 95% CI: 0.04, 0.36; p=0.00016). Infectious virus isolation was also associated with higher levels of viral RNA (mean RNA difference +2.6 log10, 95% CI: 2.2, 3.0; p<0.0001) and fewer days since symptom onset (PR=0.79, 95% CI: 0.71, 0.88 per day; p<0.0001).

ConclusionsThe presence of SARS-CoV-2 antibodies is strongly associated with clearance of infectious virus isolation. Seropositivity and viral RNA levels are likely more reliable markers of infectious virus clearance than subjective measure of COVID-19 symptom duration. Virus-targeted treatment and prevention strategies should be administered as early as possible and ideally before seroconversion.

ClinicalTrials.gov IdentifierNCT04405570

Key Points (Summary)Among COVID-19 outpatients within 7 days of symptom onset, the presence of SARS-CoV-2-specific antibodies was strongly associated with clearance of infectious virus. Seropositivity appears to be more reliable marker of infectious virus clearance than subjective measure of COVID-19 symptoms.
Standard and anomalous waves of COVID-19: A multiple-wave growth model for epidemics We apply a generalised logistic growth model, with time dependent parameters, to describe the fatality curves of the COVID-19 disease for several countries that exhibit a second wave of infections. The model parameters vary as a function of time according to a logistic function, whose two extreme values, i.e., for early and late times, characterise the first and second waves, respectively. We show that the theoretical curves are in excellent agreement with the empirical data for all cases considered. The model also allows for predictions about the time of occurrence and relative severity of the second wave, in comparison to the first wave. It is shown furthermore that the COVID-19 second waves can be generically classified in two main types, namely, standard and anomalous second waves, according as to whether the second wave starts well after or still during the first wave, respectively. We have also observed that the standard second waves tend, in their majority, to be more severe than the corresponding first wave, whereas for anomalous second waves the opposite occurs.
Covid-19 Associated Hepatitis in children (CAH-C) during the second wave of SARS-CoV-2 infections in Central India: Is it a complication or transient phenomenon. Objective: While pediatric population has largely remained free of severe COVID-19, in some cases SARS-CoV-2 infection has been associated with complications like Multiple Inflammatory Syndrome in children (MIS-C). We mention another unique presentation subsequent to asymptomatic infection of SARS-CoV-2, a unique form of hepatitis designated by us as COVID-19 Associated Hepatitis in Children (CAH-C). The contrasting clinical presentations, temporal association and viral parameters of CAH-C cases, to the MIS-C cases are presented here. Methods: As a retrospective and follow-up observational study we reviewed all children testing positive for SARS-CoV-2 during study period. Children presenting with sudden onset of hepatitis, elevated transaminases, non-obstructive jaundice, lacking marked inflammatory responses and without evidence of (a) other known causes of acute hepatitis or previous underlying liver disease (b) multi-system involvement were classified as CAH-C, are described here. Results: Among 475 children who tested positive, 47 patients presented with hepatitis, 37 patients who had features of CAH-C, having symptoms of hepatitis only, with un-elevated inflammatory markers and uneventful recovery following supportive treatment. Whereas remaining 10 MIS-C hepatitis had protracted illness, multiple system involvement, required admission to critical care, and had mortality of 30%. Conclusion: With the emergence of newer variants of concern (VOC) including the Delta variant which predominated the second wave of infections in India and has now spread to more than 142 countries with changing presentations, CAH-C might be one of them. Cases of such new entities need to be identified early and differentiated from other emerging syndromes in children during the ongoing pandemic for preventing adversities by timely intervention. Associations between COVID-19 transmission rates, park use, and landscape structure The COVID-19 pandemic has had severe impacts on global public health. In England, social distancing measures and a nationwide lockdown were introduced to reduce the spread of the virus. Green space accessibility may have been particularly important during this lockdown, as it could have provided benefits for physical and mental wellbeing. However, the associations between public green space use and the rate of COVID-19 transmission are yet to be quantified, and as the size and accessibility of green spaces vary within Englands local authorities, the risks and benefits to the public of using green space may be context-dependent. To evaluate how green space affected COVID-19 transmission across 299 local authorities (small regions) in England, we calculated a daily case rate metric, based upon a seven-day moving average, for each day within the period June 1st - November 30th 2020 and assessed how baseline health and mobility variables influenced these rates. Next, looking at the residual case rates, we investigated how landscape structure (e.g. area and patchiness of green space) and park use influenced transmission. We first show that reducing mobility is associated with a decline in case rates, especially in areas with high population clustering. After accounting for known mechanisms behind transmission rates, we found that park use (showing a preference for park mobility) was associated with decreased residual case rates, especially when green space was low and contiguous (not patchy). Our results support that a reduction in overall mobility may be a good strategy for reducing case rates, endorsing the success of lockdown measures. However, if mobility is necessary, outdoor park use may be safer than other forms of mobility and associated activities (e.g. shopping or office-based working). Increase in SARS-CoV-2 RBD-specific IgA and IgG Antibodies in Human Milk from Lactating Women Following the COVID-19 Booster Vaccination The CDC recommended a booster dose of the Pfizer-BioNTech Comirnaty (BNT162b2) COVID-19 mRNA vaccine in September 2021 for high-risk individuals. Pregnant and high-risk lactating women were encouraged to receive the booster to obtain potential prolonged protection for themselves and their infants. This study investigated the ability of the booster vaccine to increase IgA and IgG antibodies specific to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein in breast milk compared to levels pre-booster. We found a significant increase in both anti-RBD-specific IgA and IgG antibodies in breast milk following the Pfizer-BioNTech booster and this increase was present in the majority of participants at the study endpoint (60 days post-booster). These results suggest the booster enhances SARS-CoV-2 specific immunity in human breast milk, which may be protective for infants. The effects of modifiable maternal pregnancy exposures on offspring 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. What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. 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. Virtual reality intervention alleviates dyspnea in patients recovering from COVID pneumonia BackgroundImmersive virtual reality (iVR)-based digital therapeutics (DTx) are gaining clinical attention in the field of pain management. Based on known analogies between pain and dyspnea, we investigated the effects of visual-respiratory feedback, on persistent dyspnea in patients recovering from COVID-19 pneumonia.

MethodsWe performed a controlled, randomized, single-blind, cross-over clinical study to evaluate an iVR-based intervention to alleviate dyspnea in patients recovering from COVID-19 pneumonia. Included patients reported persistent dyspnea ([&ge;]5 on a 10-point scale) and preserved cognitive function (MoCA>24). Assignment was random and concealed. Patients received synchronous (intervention) or asynchronous (control) feedback of their breathing, embodied via a gender-matched virtual body. Outcomes were assessed using questionnaires and breathing recordings. COVVR is registered with ClinicalTrials.gov (NCT04844567).

FindingsStudy enrollment was open between November 2020 and April 2021. Twenty-six patients were enrolled (27% women; age: median=55, interquartile range (IQR)=18). Data were available for 24 of 26 patients. The median (IQR) rating on a 7-point Likert-scale of breathing comfort improved from 1(2) at baseline, to 2(1) for synchronous feedback, but remained unchanged at 1(1.5) for asynchronous feedback (p<0.05) between iVR conditions). Moreover, 91.2% of all patients were satisfied with the intervention (p<0.0001) and 66.7% perceived it as beneficial for their breathing (p<0.05). No adverse events were reported.

InterpretationBased on these findings, our iVR-based DTx presents a feasible and safe respiratory rehabilitation tool that improves breathing comfort in patients recovering from COVID-19 infection presenting with persistent dyspnea. Future research should investigate the DTxs generalizability to persistent dyspnea with other etiologies and its potential for preventing chronification.

FundingMarie Sklodowska-Curie Individual Fellowship (H2020-MSCA-IF-2019 894111/ RESPVR), Bertarelli Foundation Neutrophils and triglycerides predict critical illness in COVID-19 and reveal CDK6 inhibitors as potential preventive treatment Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing - the use of an already existing drug for a new indication - could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to lack of clinical evidence. We report here on a methodology to find and test drug target candidates for drug repurposing. Using UK Biobank data, we screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index between an infectious disease phenotype and healthy controls. We then matched critically ill COVID-19 cases with controls that exhibited mild or no symptoms after SARS-CoV-2 infection. Using data from the UK Biobank, we describe a workflow to find evidence for high neutrophil cell count and high concentrations of blood triglycerides as predictors of the immune overreaction in critical illness due to COVID-19. Based on these findings, we identified the enzyme CDK6 as a potential drug target to prevent in high risk individuals with high neutrophil cell count the immune overreaction in critical illness due to COVID-19. Three existing CDK4/6 inhibitors -- abemaciclib, ribociclib, and palbociclib -- have been approved for the treatment of breast cancer. Clinical evidence for CDK4/6 inhibitors in treating critically ill COVID-19 patients has been reported. Further clinical investigations are ongoing. Survival and outcomes of tocilizumab use in severe and critically ill COVID-19 patients not responding to steroids BackgroundMortality and morbidity are highest in severe and critically ill patients with COVID -19 pneumonia. Recently corticosteroids have shown a definite mortality benefit in these patients. In this study we used interleukin -6 inhibitor, tocilizumab in patients who failed to show any clinical improvement after initial treatment with steroids.

Patients and methodsThis is a retrospective observational study conducted at a tertiary care referral hospital in India. Severe and critical COVID 19 patients, who got admitted to intensive care unit and subsequently received tocilizumab were included. Patients who worsened clinically or had no change in oxygen requirement even after 24hrs of receiving Intravenous methylprednisolone at a dose of 1-2mg/kg/day received a maximum total dose of 800mg of intravenous tocilizumab. The day 28 all cause mortality and progression to mechanical ventilation were the primary outcome measures. Clinical improvement and oxygen requirements after tocilizumab administration along with trends in inflammatory markers were secondary outcome. Secondary infections rates and other drug related side effects were also noted.

ResultsA total of 51 patients who did not show clinical improvement even after 24 hours of intravenous steroids and received tocilizumab were included. In these patients, there was a significant decrease in oxygen requirement by day 3 and clinical improvement by day 7 of tocilizumab administration. Among the inflammatory markers, we observed elevated median baseline values of CRP (114.2 mg/L), IL-6 (55.4 pg/ml) and Neutrophil to Lymphocyte Ratio (12.4). Out of these only CRP showed a significant decrease after the drug administration. 13 (26.5%) of the 49 patients who were on non-invasive or conventional oxygen support progressed to mechanical ventilation. The day 28 all-cause mortality rate was 10/51(19.6%). 10(19.6%) of the 51 patients had life threatening infections, 5/51 had thrombocytopenia, 3/51 had pneumo-mediastenum/pneumothorax, 1 patient had colonic perforation and 1 patient had transaminitis following tocilizumab administration.

ConclusionEarly and timely administration of tocilizumab only in selected severe and critical covid patients not responding to initial steroids appears to increase the survival. Further randomized controlled trials are required to confirm this finding. 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.) Hemodynamic Differences Between Women and Men with Elevated Blood Pressure in China: A Non-Invasive Assessment of 45,082 Adults Using Impedance Cardiography BackgroundWhether there are sex differences in hemodynamic profiles among people with elevated blood pressure is not well understood and could guide personalization of treatment.

Methods and resultsWe described the clinical and hemodynamic characteristics of adults with elevated blood pressure in China using impedance cardiography. We included 45,082 individuals with elevated blood pressure (defined as systolic blood pressure of [&ge;]130 mmHg or a diastolic blood pressure of [&ge;]80 mmHg), of which 35.2% were women. Overall, women had a higher mean systolic blood pressure than men (139.0 [{+/-}15.7] mmHg vs 136.8 [{+/-}13.8] mmHg, P<0.001), but a lower mean diastolic blood pressure (82.6 [{+/-}9.0] mmHg vs 85.6 [{+/-}8.9] mmHg, P<0.001). After adjusting for age, region, and body mass index, women <50 years old had lower systemic vascular resistance index (beta-coefficient [{beta}] -31.7; 95% CI: -51.2, -12.2) and higher cardiac index ({beta} 0.07; 95% CI: 0.04, 0.09) than men of their same age group, whereas among those [&ge;]50 years old women had higher systemic vascular resistance index ({beta} 120.4; 95% CI: 102.4, 138.5) but lower cardiac index ({beta} -0.15; 95% CI: -0.16, -0.13). Results were consistent with a propensity score matching sensitivity analysis, although the magnitude of the SVRI difference was lower and non-significant. However, there was substantial overlap between women and men in the distribution plots of these variables, with overlapping areas ranging from 78% to 88%.

ConclusionsOur findings indicate that there are sex differences in hypertension phenotype, but that sex alone is insufficient to infer an individuals profile. 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. Spatial Allocation of Scarce COVID-19 Vaccines The COVID-19 Vaccines Global Access (COVAX) is an initiative led by the World Health Organization (WHO) and other partners that aims for an equitable access of COVID-19 vaccines. Despite a potential heterogeneous disease burden across space, countries receiving allotments of vaccines via COVAX may want to follow WHOs allocation rule and distribute vaccines to their jurisdictions based on the jurisdictions relative population size. Utilizing economic-epidemiological modeling, we benchmark the performance of this ad hoc allocation rule by comparing it to the rule that minimizes the economic damages and expenditures over time, including a penalty cost representing the social costs of deviating from the ad hoc allocation. Under different levels of vaccine scarcity and different demographic characteristics, we consider scenarios where length of immunity and compliance to travel restrictions vary, and consider the robustness of the rules when assumptions regarding these factors are incorrect. The benefits from deviating are especially high when immunity is permanent, when there is compliance to travel restrictions, when the supply of vaccine is low, and when there is heterogeneity in demographic characteristics. Interestingly, a lack of compliance to travel restrictions pushes the optimal allocations of vaccine towards the ad hoc and improves the relative robustness of the ad hoc rule, as the mixing of the populations reduces the spatial heterogeneity in disease burden.

JEL ClassificationC61, H12, H84, I18, Q54 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. A collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia BackgroundThe COVID-19 pandemic has resulted in a range of unprecedented disruptions to the delivery of maternity care globally and has been associated with regional changes in perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne endured one of the longest and most stringent lockdowns in 2020. This paper presents the protocol for a collaborative maternity dashboard project to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic.

MethodsDe-identified maternal and newborn outcomes will be collected monthly from all public maternity services in Melbourne, allowing rapid analysis of a multitude of perinatal indicators. Weekly outcomes will be displayed as run charts according to established methods for detecting non-random  signals in health care. A pre-pandemic median for all indicators will be calculated for the period of January 2018 to March 2020. A significant shift is defined as [&le;] six consecutive weeks, all above or below the pre-pandemic median. Additional statistical analyses such as regression, time-series, and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests.

Ethics and DisseminationThis study has been registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976).

Strengths and weaknesses of this study This project is the first clinician-led, multi-centre perinatal data collection system for metropolitan Melbourne.
 It complements the state government data collection, with the significant benefits of more timely and flexible reporting of outcomes, and granular detail on emerging areas of concern.
 The study relies on primary source coding of exposure and outcomes from each hospital that have not been internally validated during the study period.
 Data from private maternity hospitals, containing 25% of Melbourne births, are not available.
 This resource will support data-informed hospital pandemic responses through to the end of 2022. Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.

In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.

The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.

Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.

Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.

Ethics and DisseminationAs this study is a literature review, ethics approval is not required.

The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).

Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI 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. Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-Drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Cohort Study BackgroundAnti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease

MethodsA nationwide multicenter retrospective cohort study was conducted by evaluating patients charts from July 2018 until September 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across 7 hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Geometric means were calculated, and multiple linear regression was used to estimate the adjusted ratio of geometric means (RoGM) and their 95% confidence intervals (CI).

ResultsIn the total study sample (n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30-2.27, p-value <0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44-0.88, p-value = 0.007). In the subgroup analysis (n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79-2.40, p-value = 0.254). There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab.

ConclusionIn patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed. The effect of stimulus duration on preferences for gain adjustments when listening to speech ObjectivesIn the personalisation of hearing aid fittings, gain is often adjusted to suit patient preferences using live speech. When using brief sentences as stimuli, the minimum gain adjustments necessary to elicit consistent preferences ( preference thresholds) were previously found to be much greater than typical adjustments in current practice. The current study examined the role of duration on preference thresholds.

DesignParticipants heard 2, 4 and 6-s segments of a continuous monologue presented successively in pairs. The first segment of each pair was presented at each individuals real-ear or prescribed gain. The second segment was presented with a {+/-}0-12 dB gain adjustment in one of three frequency bands. Participants judged whether the second was "better", "worse" or "no different" from the first.

Study SampleTwenty-nine adults, all with hearing-aid experience.

ResultsThe minimum gain adjustments needed to elicit "better" or "worse" judgments decreased with increasing duration for most adjustments. Inter-participant agreement and intra-participant reliability increased with increasing duration up to 4 s, then remained stable.

ConclusionsProviding longer stimuli improves the likelihood of patients providing reliable judgments of hearing-aid gain adjustments, but the effect is limited, and alternative fitting methods may be more viable for effective hearing-aid personalisation. Characterization of small fiber neuropathy in hypermobile Ehlers Danlos Syndrome Ehlers Danlos syndromes (EDS) are heritable connective tissue disorders. The hypermobile form (hEDS) is the most frequent, yet the only one without an identified genetic mutation. Patients suffering from symptomatic joint hypermobility, yet not fulfilling the hEDS criteria, enter the Hypermobility Spectrum Disorder (HSD) category. In addition to musculoskeletal pain affecting joints, hEDS/HSD patients often describe painful sensations, hypoesthesia, and autonomic symptoms suggesting a neuropathic component. Small fiber neuropathy (SFN) refers to the dysfunction or damage of A-{delta} and C-fibers, which relay thermal and nociceptive information as well as mediating autonomic function. SFN has been suggested by prior studies in hEDS but these early findings (case series N[&le;]20) with sole reliance on intraepidermal nerve fiber density (IENFD) called for a larger sample combined with functional testing.

In this retrospective chart extraction from 79 hEDS/HSD patients referred to a pain center due to neuropathic pain or dysautonomia, both functional (Quantitative Sensory Testing (QST), N=79) and structural (IENFD, N=69) evaluations of small nerve fibers were analyzed in combination with clinical data and standardized questionnaires.

All the patients reported moderate to severe pain interfering with daily life. A decreased thermal detection (QST) was shown in 55/79 patients (70%) and a decreased IENFD in 54/69 patients (78%). Hence a small fiber neuropathy (both abnormal IENFD and QST) was definite in 40/69 patients (58%), possible in 23/69 patients (33%) and excluded in only 6/69 patients (9%).

These results add strong evidence for a peripheral neuropathic contribution to pain symptoms in hEDS/HSD, in addition to the known nociceptive and central sensitization components. Such neuropathic contribution could raise the hypothesis of a neurological cause of hEDS, the only EDS syndrome still without a known genetic cause. Hence, our data is leading the way to a better stratification of this very heterogeneous population, which could improve symptommanagement and expand pathophysiological research. Human lipoproteins comprise at least 12 different classes that are lognormally distributed. Lipoproteins in medical samples have been measured by enzymatic methods that coincide with conventional ultracentrifugation. However, the high gravity and time required for ultracentrifugation can cause sample degradation. This study presents the results of HPLC, a gentler and rapid separation method, for 55 human serum samples. The elution patterns were analysed parametrically, and the attribute of each class was confirmed biochemically. Human samples contained 12 classes of lipoproteins, each of which may consist primarily of proteins. There are three classes of VLDLs. The level of each class was distributed lognormally, and the standard amount and the 95% range were estimated. Enzymatic methods measure the levels of several mixed classes. This lognormal character suggests that the levels are controlled by the synergy of multiple factors.