title: Accurate Covid-19 prevalence measurement in the field

abstract: Timely, accurate epidemic figures are necessary for informed policy. In the Covid-19 pandemic, mismeasurement can lead to tremendous waste, in health or economic output. "Random" testing is commonly used to estimate virus prevalence, reporting daily positivity rates. However, since testing is necessarily voluntary, all "random" tests done in the field suffer from selection bias. This bias, unlike standard polling biases, goes beyond demographical representativeness and cannot be corrected by oversampling (i.e. selecting people without symptoms to test). Using controlled, incentivized experiments on a sample of all ages, we show that people who feel symptoms are up to 33 times more likely to seek testing. The bias in testing propensities leads to sizable prevalence bias: test positivity is inflated by up to five times, even if testing is costless. This effect varies greatly across time and age groups, making comparisons over time and across countries misleading. We validate our results using the REACT study in the UK and find that positivity figures have indeed a very large and time varying bias. We present calculations to debias positivity rates, but importantly, suggest a parsimonious way to sample the population bypassing the bias altogether. Our estimation is both real-time and consistently close to true values. These results are relevant for all epidemics, besides covid-19, when carriers have informative beliefs about their own status.


title: Debiasing Covid-19 prevalence estimates

category: public and global health


title: Association of Chronic Acid Suppression and Social Determinants of Health with COVID-19 Infection

abstract: Acid suppressants are a widely-used class of medications previously linked to an increased risk of aerodigestive infections. However, prior studies of these medications as potentially reversible risk factors for COVID-19 have been conflicting. We performed a case-control study involving clinician-abstracted data from 900 health records across 3 US medical centers. We incorporated sociobehavioral predictors of infectious exposure using geomapping to publicly-available data. We found no evidence for an association between chronic acid suppression and incident COVID-19 (adjusted odds ratio 1.04, 95% CI: 0.92-1.17, P=0.515). However, we identified several medical and social features as positive (Latinx ethnicity, BMI [≥] 30, dementia, public transportation use, month of the pandemic) and negative (female sex, concurrent solid tumor, alcohol use disorder) predictors of new-onset infection. These results place both medical and social factors on the same scale within the context of the COVID-19 pandemic, and underscore the importance of comprehensive models of disease.


title: Vulnerabilities in child wellbeing among primary school children: a cross-sectional study in Bradford, UK

abstract:
ObjectiveTo describe the prevalence of factors related to wellbeing among primary school children in a deprived multi-ethnic community.

Design and participantsCross-sectional survey of 15,641 children aged 7-10 years in Born in Bradfords Primary School Years study: whole-classroom samples in 89 Bradford primary schools between 2016 and 2019.

Main outcome measuresPrevalence estimates by ethnicity (%, 95% CI) of single and multiple vulnerabilities in child wellbeing within and across four domains (home, family, relationships; material resources; friends and school; subjective wellbeing).

ResultsOnly 10% of children have no vulnerabilities in any domain of wellbeing; 10% have one or more vulnerabilities in all four domains. The highest prevalence estimates were for being bullied some or all of the time (52.7%, 51.9 to 53.4%), keeping worries to oneself (31.2%, 30.5 to 31.9%), having no park near home (30.8%, 30.1 to 31.5%) and worrying all the time about how much money their family has (26.3%, 25.6 to 27%).

Boys were consistently significantly more likely than girls to report all of the vulnerabilities in the Home, Family and Family Relationships domain, and the majority of indicators in the other domains, and in all domains except Friends and School, boys were significantly more likely to have at least one vulnerability. Girls were significantly more likely to report not having many friends (16.7%, 95% CI: 15.9 to 17.6% vs. 12.5%, 95% CI: 11.8 to 13.2%), being bullied some or all of the time (55.8%, 95% CI: 54.7 to 56.9% vs. 49.7%, 95% CI: 48.6 to 50.8%) and feeling left out all the time (12.1%, 95% CI: 11.4 to 12.8%) vs. 10.3%, 95% CI: 9.7 to 11.0%).

Variations in vulnerabilities by ethnicity were complex, with children in Black, Asian and Minority Ethnic groups sometimes reporting more vulnerabilities and sometimes fewer than White British children. For example, compared to children of Pakistani heritage, White British children were more likely to say that their family never gets along well (6.3%,5.6 to 7.1% vs. 4.1%,3.6 to 4.6%) and to have no access to the internet at home (22.3%,21 to 23.6% vs. 18%,17 to 18.9%). Children with Pakistani heritage were more likely than White British children to say they had no park near their home where they can play with friends (32.7%,31.6 to 33.9% vs. 29.9%,28.6 to 31.3%), to report not having three meals a day (17.9%,16.9 to 18.8% vs. 11.9%,10.9 to 12.9%) and to worry all the time about how much money their families have (29.3%,28.2 to 30.3%) vs. 21.6%,20.4 to 22.9%). Gypsy/Irish Traveller children were less likely than White British children to say they were bullied some or all of the time (42.2%,35.4 to 49.4% vs. 53.8%,52.3 to 55.3%), but more likely to say they were mean to others all the time (9.9%,6.3 to 15.2% vs. 4%,3.5 to 4.7%) and can never work out what to do when things are hard (15.2%,10.6 to 21.2% vs. 9%, 8.2 to 9.9%).

We considered six vulnerabilities to be of particular concern during the current Covid-19 pandemic and associated national and local lockdowns: family never gets along well together; no garden where child can play; no nearby park where they can play; not having 3 meals a day; no internet at home; worried about money all the time. Pre-pandemic, 37.4% (36.6 to 38.3%) of Bradford children had one of these vulnerabilities and a further 29.6% (28.9 to 30.4%) had more than one.

ConclusionsAlthough most primary school children aged 7-10 in our study have good levels of wellbeing on most indicators across multiple domains, fewer than 10% have no vulnerabilities at all, a worrying 10% have at least one vulnerability in all the four domains we studied and two thirds have vulnerabilities of concern during the Covid-19 lockdowns.


title: Effectiveness of regional restrictions in reducing SARS-CoV-2 transmission during the second wave of COVID-19, Italy.

abstract: To counter the second COVID-19 wave in autumn 2020, the Italian government introduced a system of physical distancing measures organized in progressively restrictive tiers (coded as yellow, orange, and red) and imposed on a regional basis according to epidemiological risk assessments. The individuals attendance to locations outside the residential settings was progressively reduced with tiers, but less than during the national lockdown against the first COVID-19 wave in the spring. The reproduction number Rt decreased below the epidemic threshold in 85 out of 107 provinces after the introduction of the tier system, reaching average values of about 0.99, 0.89 and 0.77 in the yellow, orange and red tier, respectively. We estimate that the reduced transmissibility resulted in averting about 37% of the hospitalizations between November 5 and November 25, 2020. These results are instrumental to inform public health efforts aimed at preventing future resurgence of cases.


title: Impact of tiered restrictions on human activities and the epidemiology of the second wave of COVID-19 in Italy


title: Evaluation of Ultrafast Wave-CAIPI 3D FLAIR in the Visualization and Volumetric Estimation of Cerebral White Matter Lesions

abstract:
BACKGROUND AND PURPOSETo evaluate an ultrafast 3D-FLAIR sequence using Wave-CAIPI encoding (Wave-FLAIR) compared to standard 3D-FLAIR in the visualization and volumetric estimation of cerebral white matter lesions in a clinical setting.

MATERIALS AND METHODS42 consecutive patients underwent 3T brain MRI including standard 3D-FLAIR (acceleration factor R=2, scan time TA=7:15 minutes) and resolution-matched ultrafast Wave-FLAIR sequences (R=6, TA=2:45 minutes for the 20-ch coil; R=9, TA=1:50 minutes for the 32-ch coil) as part of clinical evaluation for demyelinating disease. Automated segmentation of cerebral white matter lesions was performed using the Lesion Segmentation Tool in SPM. Students t-test, intra-class correlation coefficient (ICC), relative lesion volume difference (LVD) and Dice similarity coefficients (DSC) were used to compare volumetric measurements between sequences. Two blinded neuroradiologists evaluated the visualization of white matter lesions, artifact and overall diagnostic quality using a predefined 5-point scale.

RESULTSStandard and Wave-FLAIR sequences showed excellent agreement of lesion volumes with an ICC of 0.99 and DSC of 0.97{+/-}0.05 (range 0.84 to 0.99). Wave-FLAIR was non-inferior to standard-FLAIR for visualization of lesions and motion. The diagnostic quality for Wave-FLAIR was slightly greater than standard-FLAIR for infratentorial lesions (p<0.001), and there was less pulsation artifact on Wave-FLAIR compared to standard FLAIR (p<0.001).

CONCLUSIONSUltrafast Wave-FLAIR provides superior visualization of infratentorial lesions while preserving overall diagnostic quality and yields comparable white matter lesion volumes to those estimated using standard-FLAIR. The availability of ultrafast Wave-FLAIR may facilitate the greater use of 3D-FLAIR sequences in the evaluation of patients with suspected demyelinating disease.

category: radiology and imaging


title: Proteomic and Metabolomic Investigation of COVID-19 Patients with Elevated Serum Lactate Dehydrogenase

abstract: Serum lactate dehydrogenase (LDH) has been established as a prognostic indicator given its differential expression in COVID-19 patients. However, the molecular mechanisms underneath remain poorly understood. In this study, 144 COVID-19 patients were enrolled to monitor the clinical and laboratory parameters over three weeks. Serum lactate dehydrogenase (LDH) was shown elevated in the COVID-19 patients on admission and declined throughout disease course, and its ability to classify patient severity outperformed other biochemical indicators. A threshold of 247 U/L serum LDH on admission was determined for severity prognosis. Next, we classified a subset of 14 patients into high- and low-risk groups based on serum LDH expression and compared their quantitative serum proteomic and metabolomic differences. The results found COVID-19 patients with high serum LDH exhibited differentially expressed blood coagulation and immune responses including acute inflammatory responses, platelet degranulation, complement cascade, as well as multiple different metabolic responses including lipid metabolism, protein ubiquitination and pyruvate fermentation. Specifically, activation of hypoxia responses was highlighted in patients with high LDH expressions. Taken together, our data showed that serum LDH levels are associated COVID-19 severity, and that elevated serum LDH might be consequences of hypoxia and tissue injuries induced by inflammation.

category: respiratory medicine


title: Impaired sensory evidence accumulation and network function in Lewy body dementia

abstract: Deficits in attention underpin many of the cognitive and neuropsychiatric features of Lewy body dementia. These attention-related symptoms remain difficult to treat and there are many gaps in our understanding of their neurobiology. An improved understanding of attention-related impairments can be achieved via mathematical modelling approaches, which identify cognitive parameters to provide an intermediate level between observed behavioural data and its underlying neural correlate. Here, we apply this approach to identify the role of impaired sensory evidence accumulation in the attention deficits that characterise Lewy body dementia. In 31 people with Lewy body dementia (including 13 Parkinsons disease dementia and 18 dementia with Lewy bodies cases), 16 people with Alzheimers disease, and 23 healthy controls, we administered an attention task whilst they underwent functional 3T MRI. Using hierarchical Bayesian estimation of a drift diffusion model, we decomposed task performance into drift rate and decision boundary parameters. We tested the hypothesis that the drift rate - a measure of the quality of sensory evidence accumulation - is specifically impaired in Lewy body dementia, compared to Alzheimers disease. We further explored whether trial-by-trial variations in the drift rate related to activity within the default and dorsal attention networks, to determine whether altered activity in these networks was associated with slowed drift rates in Lewy body dementia. Our results revealed slower drift rates in the Lewy body dementia compared to the Alzheimers disease group, whereas the patient groups were equivalent for their decision boundaries. The patient groups were reduced relative to controls for both parameters. This highlights sensory evidence accumulation deficits as a key feature that distinguishes attention impairments in Lewy body dementia, consistent with impaired ability to efficiently process information from the environment to guide behaviour. We also found that the drift rate was strongly related to activity in the dorsal attention network across all three groups, whereas the Lewy body dementia group showed a divergent relationship relative to the Alzheimers disease and control groups for the default network, consistent with altered default network modulation being associated with impaired evidence accumulation. Together, our findings reveal impaired sensory evidence accumulation as a specific marker of attention problems in Lewy body dementia, which may relate to large-scale network abnormalities. By identifying impairments in a specific sub-process of attention, these findings will inform future exploratory and intervention studies that aim to understand and treat attention-related symptoms that are a key feature of Lewy body dementia.

category: neurology


title: Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: A modelling study based on longitudinal tumor measurements

abstract: Recurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. In contrast to prescribing high dose hypofractionated stereotactic radiotherapy (HFSRT, [≥] 6 Gyx5 in daily fractions) with debulking intent, we suggest a personalized treatment strategy to improve tumor control by delivering intermittent high dose treatment (iRT, [≥] 6 Gyx1 every six weeks). We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost ([≥] 6 Gyx3 in daily fractions at time of progression) based on a mathematical model of tumour growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Model parameters were fitted from tumour growth curves of 16 patients enrolled in the phase 1 NCT02313272 trial that combined HFSRT with bevacizumab and pembrolizumab. Then, iRT +/-boost treatments were simulated and compared to HFSRT based on time to tumor regrowth. The modelling results demonstrated that iRT+boost(-boost) treatment was equal or superior to HFSRT in 15(11) out of 16 cases and that patients that remained responsive to pembrolizumab and bevacizumab would benefit most from iRT. Time to progression could be prolonged through the application of additional, intermittently delivered fractions. iRT hence provides a promising treatment option for recurrent high grade glioma patients.

category: oncology


title: Association of Visual Impairment with Brain Structure

abstract:
ObjectiveTo investigate the association of visual impairment (VI) with brain structures in the UK Biobank Study.

MethodsThe UK Biobank Study is a large prospective study that recruited more than 500,000 participants aged 40-69 from 2006 to 2010 across the UK. Visual acuity (VA) of worse than 0.3 LogMAR units (Snellen 20/40) was defined as VI. Structural magnetic resonance imaging (MRI) data were obtained using a 3.0-T MRI imager. Volumetric measures of five global brain volumes (total brain volume, total grey matter, total white matter, cerebrospinal fluid (CSF), brain stem) and the volumes of seven specific brain region (thalamus, caudate nucleus, basal ganglia, pallidum, hippocampus, amygdala and nucleus accumbens) were included in the present analysis. Multivariable linear regression was used to investigate the association of VI with global and specific brain volumes.

ResultsA total of 8976 participants free of neurological disorders at baseline assessment were included for the present analysis. The prevalence of VI was 0.02% (n=181). After adjusting for a range of cofounding factors, VI was significantly associated with decreased volumes of the total brain ({beta} = -0.12, 95% confidence interval (CI) -0.23 to 0.00, P = 0.049), thalamus ({beta} = -0.16, 95% CI -0.18 to -0.04, P = 0.010), caudatenucleus ({beta} = -0.14, 95% CI -0.27 to 0.00, P = 0.046), pallidum ({beta} = -0.15, 95% CI-0.27 to -0.02, P = 0.028) and amygdala ({beta} = -0.18, 95% CI -0.31 to -0.04, P = 0.012).

InterpretationWe found that VI is associated with a decrease in total brain volumes and the volumes of specific brain regions implicated in neurodegenerative diseases.

category: ophthalmology


title: Atmospheric PM2.5 before and after Lockdown in relation to COVID-19 Evolution and daily Viral Counts: Could Viral Natural Selection have occurred due to changes in the Airborne Pollutant PM2.5 acting as a Vector for SARS-CoV-2?

abstract:
BackgroundGenes coding for SARS-CoV-2 have been detected on the microscopic airborne pollutant particulate matter, which has been suggested as a vector for COVID-19 transmission. Lockdown in China has been shown to be associated with significant reduction in pollution including the particulate matter component which coincided with the appearance of a viral mutant (Clade G) which steadily displaced the original Clade D after lockdown. The reason why Clade G developed a fitness advantage is as yet unknown. This paper examines the possible role of airborne particulate matter PM2.5 as selective pressure determining viral Clade predominance and further shedding light on the mode of SARS-CoV-2 transmission.

MethodsThe average levels of PM2.5 of a number of cities were obtained from the Air Quality Index (AQI), a real-time assessment of atmospheric pollution. The daily average PM2.5 levels were assessed between January 23rd and April 29th 2020 determined by the timeline when viral counts in Beijing and other cities were available. Daily viral counts of Clades D and G were available starting from the 12th February as determined by the scientific literature published in August 2020. The cities chosen were Beijing, Sheffield, Nottingham, Sydney and Cambridge because of their substantially elevated viral counts compared to other cities. Cities as opposed to vaster areas/nations were chosen as PM2.5 levels vary across regions and countries.

ResultsFor the time period assessed, the Beijing PM2.5 pattern initiated with highly elevated mean PM2.5 levels of 155.8{micro}g/m3 (SD+/-73.6) during high viral counts, followed by 82.1{micro}g/m3 (SD+/-44.9) (p<0.04) when the viral counts decreased. In all the other cities assessed, the pattern differed whereby the PM2.5 levels increased significantly over the preceding baseline contemporaneously with the viral count rise. The changes in these cities PM2.5 levels were on average 31.5{micro}g/m3 before viral counts rose and 56.35{micro}g/m3 contemporaneous with viral count rise. The average levels of PM2.5 in these cities started to decrease one week after lockdown to 46{micro}g/m3 when measured over 2 weeks post-lockdown.

As regards the viral counts from data retrieved from Beijing, the latter part of the bell-shaped curve and a subsequent smaller curve of the viral count was available for evaluation. The average viral count for Clade D in Beijing was 11.1(SD+/-13.5) followed by a mean viral count for Clade G was 13.8(SD+/-9.2). Conversely in all the other cities besides Beijing, the viral counts averaged 45.8 for Clade D and 161 for Clade G. The variation in viral counts between cities suggests the strong possibility of variation in the availability of sampling between cities.

The newer variant, Clade G demonstrated viral counts initially appearing in mid-February in Beijing to later displace Clade D as the dominant viral Clade. The appearance of Clade G coincided with the decreasing gradient of PM2.5 levels. A number of significant correlations were obtained between PM2.5 levels and the viral count in all the cities reviewed.

ConclusionCOVID-19 viral counts appear to increase concomitant with increasing PM2.5 levels. Viral counts of both Clades correlated differentially with PM2.5 levels in all the cities assessed. The significantly highly elevated PM2.5 levels in Beijing resulted in correlating mainly with Clade D, however Clade G began to appear with decreasing PM2.5 levels, suggesting the beginnings for the initial SARS-CoV-2 Clade evolution. Clade G, the newer variant was able to flourish at lower levels of PM2.5 than Clade D. Clade G may possibly have utilized other sources of particulate matter as a viral vector, such as that derived from tobacco smoking, whereby 66% of Chinese males are smokers and 70% of the Chinese non-smoking population are exposed to 2nd hand smoking.

category: infectious diseases


title: Robotic RNA extraction for SARS-CoV-2 surveillance using saliva samples

abstract: Saliva is an attractive specimen type for asymptomatic surveillance of COVID-19 in large populations due to its ease of collection and its demonstrated utility for detecting RNA from SARS-CoV-2. Multiple saliva-based viral detection protocols use a direct-to-RT-qPCR approach that eliminates nucleic acid extraction but can reduce viral RNA detection sensitivity. To improve test sensitivity while maintaining speed, we developed a robotic nucleic acid extraction method for detecting SARS-CoV-2 RNA in saliva samples with high throughput. Using this assay, the Free Asymptomatic Saliva Testing (IGI-FAST) research study on the UC Berkeley campus conducted 11,971 tests on supervised self-collected saliva samples and identified rare positive specimens containing SARS-CoV-2 RNA during a time of low infection prevalence. In an attempt to increase testing capacity, we further adapted our robotic extraction assay to process pooled saliva samples. We also benchmarked our assay against the gold standard, nasopharyngeal swab specimens. Finally, we designed and validated a RT-qPCR test suitable for saliva self-collection. These results establish a robotic extraction-based procedure for rapid PCR-based saliva testing that is suitable for samples from both symptomatic and asymptomatic individuals.


title: Characteristics of changes in circulating markers of alveolar epithelial and endothelial injury in acute respiratory distress syndrome with COVID-19

abstract: The time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of acute respiratory distress syndrome (ARDS) with coronavirus disease (COVID-19) remain unclear. Here, we evaluated the characteristics of circulating markers of alveolar epithelial and endothelial injury in serum samples from eleven ARDS patients and ten non-ARDS patients, all with COVID-19. Our results indicates that the alveolar epithelial injury at the very early disease stage and the endothelial injury which continues to exacerbate during the later disease stage seem to be the hallmarks of ARDS with COVID-19.

category: intensive care and critical care medicine


title: Distinct time courses and pathogenic contributions of alveolar epithelial and endothelial injury in acute respiratory distress syndrome with COVID-19: evidence from circulating biomarkers


title: Distinct temporal characteristics of circulating alveolar epithelial and endothelial injury markers in ARDS with COVID-19: a preliminary retrospective report


title: Convergence of Comorbidity and COVID-19 Infection to Fatality: An Investigation Based on Concurrent Health Status Evaluation among the Elderly Population in Kerala

abstract:
ObjectiveTo investigate the impact of age, comorbidity, and vaccination in the fatality of older COVID-19 patients in the state of Kerala, India, based on their comorbidity and vaccination status.

MethodsIt is a cross sectional study adopting a mixed method approach conducted among the older population in Kerala. To study the health profile, 405 older people were surveyed, and 102 people were interviewed in-depth at their households, between June to November 2020. The results of the study were triangulated with elderly COVID-19 fatality data, available from the citizen-science dashboards of the research team and Department of Health, Kerala. Vaccination data was retrieved from cowin.gov.in to study its impact. The data was analysed using the IBM SPSS version 22.0.

ResultsAge is a predictor of COVID-19 fatality. Diabetes, hypertension, heart diseases, CKD and COPD are the significant predictors of elderly COVID-19 fatality. The current comorbidity profile of the total older population matches with the comorbidities of the COVID-19 elderly death cases. Vaccination has impacted COVID-19 mortality after vaccinating 65 percent (first dose) of the elderly.

ConclusionsAge and comorbidities can predict potential fatality among older COVID-19 patients. Timely and accurate health data and better knowledge of high-risk factors such as comorbidity can easily guide the healthcare system and authorities to efficient prevention and treatment methodologies. Knowledge on prevailing NCDs can drive early preparedness before it converges with an epidemic like the present zoonotic disease. Priority must be given for elderly vaccination to bring down the mortality rates.


title: Convergence of Comorbidity and COVID-19 Infection to Fatality: An Investigation Based on Concurrent Health Status Evaluation among Older Adults


title: Convergence of Comorbidity and COVID-19 Infection to Fatality: An Investigation Based on Health Assessment and Vaccination among Older Adults in Kerala


title: Altered kidney function and acute kidney damage markers predict survival outcomes of COVID-19 patients: A prospective pilot study.

abstract:
BackgroundThe central role in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), called as coronavirus disease 2019 (COVID-19), infection is attributed to angiotensin-converting enzyme 2 (ACE-2). ACE-2 expressing respiratory system involvement is the main clinical manifestation of the infection. However, literature about the association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and higher ACE-2 expressing kidney is very limited. In this study, we primarily aimed to investigate whether there is a kidney injury during the course of SARS-CoV-2 infection. The predictive value of kidney injury for survival was also determined.

MethodsA total of 47 participants who met the inclusion criteria were included in the study. The participants were classified as   COVID-19 patients before treatment   COVID-19 patients after treatment,   COVID-19 patients under treatment in ICU and   controls. The parameters comorbidity, serum creatinine and cystatin C levels, CKD-EPI eGFR levels, KIM-1 and NGAL levels, urine KIM-1/creatinine and NGAL/creatinine ratios were statistically compared between the groups. The associations between covariates including kidney disease indicators and death from COVID-19 were examined using Cox proportional hazard regression analysis.

ResultsSerum creatinine and cystatin C levels, urine KIM-1/creatinine levels, and CKD-EPI, CKD-EPI cystatin C and CKD-EPI creatinine-cystatin C eGFR levels exhibited significant difference in the groups. The causes of the difference were more altered kidney function and increased acute kidney damage in COVID-19 patients before treatment and under treatment in ICU. Additionally, incidences of comorbidity and proteinuria in the urine analysis were higher in the COVID-19 patients under treatment in ICU group. Urine KIM-1/creatinine ratio and proteinuria were associated with COVID-19 specific death.

ConclusionsWe found that COVID-19 patients under treatment in ICU exhibited extremely higher levels of serum cystatin C, and urine KIM-1/creatinine and urine NGAL/creatinine ratios. These results clearly described the acute kidney damage by COVID-19 using molecular kidney damage markers for the first time in the literature. Lowered CKD-EPI, CKD-EPI cystatin C and CKD-EPI creatinine-cystatin C eGFR levels were determined in them, as well. Urine KIM-1/creatinine ratio and proteinuria were associated with COVID-19 specific death. In this regard, considering kidney function and kidney damage markers must not be ignored in the COVID-19 patients, and serial monitoring of them should be considered.


title: Pragmatic, open-label, single-center, randomized, phase II clinical trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus in patients with severe pneumonia secondary to COVID-19: the TACROVID trial protocol

abstract:
IntroductionSome COVID-19 patients evolve to severe lung injury and systemic hyperinflammatory syndrome triggered by both the coronavirus infection and the subsequent host-immune response. Accordingly, the use of immunomodulatory agents has been suggested but still remains controversial. Our working hypothesis is that methylprednisolone pulses and tacrolimus may be an effective and safety drug combination for treating severe COVID-19 patients.

Methods and analysisTACROVID is a randomized, open-label, single-center, phase II trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) versus SoC alone, in patients at advanced stage of COVID-19 disease with lung injury and systemic hyperinflammatory response. Patients are randomly assigned (1:1) to one of two arms (42 patients in each group). The primary aim is to assess the time to clinical stability after initiating randomization. Clinical stability is defined as body temperature [≤] 37.5{degrees}C, and PaO2/FiO2 > 400 and/or SatO2/FiO2 > 300, and respiratory rate [≤]24 rpm; for 48 consecutive hours.

DiscussionMethylprednisolone and tacrolimus might be beneficial to treat those COVID-19 patients progressing into severe pulmonary failure and systemic hyperinflammatory syndrome. The rationale for its use is the fast effect of methylprednisolone pulses and the ability of tacrolimus to inhibit both the CoV-2 replication and the secondary cytokine storm. Interestingly, both drugs are low-cost and can be manufactured on a large scale; thus, if effective and safe, a large number of patients could be treated in developed and developing countries.

Trial registration numberNCT04341038 / EudraCT: 2020-001445-39


title: Assessments of heavy lift UAV quadcopter drone to support COVID 19 vaccine cold chain delivery for indigenous people in remote areasin South East Asia

abstract: Vaccine delivery is one important aspect need to be strengthened within health systems. One of the main challenges in COVID 19 vaccine delivery is how to cover indigenous population in remote and isolated forests in South East Asia. Another issue in COVID 19 cold chain delivery is requirement for a carrier that can maintain the suitable storage temperature. Related to this condition, COVID 19 vaccine should be delivered using heavy vaccine cooler box and this demand delivery system equipped with heavy lift capacity. In here, this study proposes and assess the potential used of heavy lift UAV quadcopter to expand the COVID 19 vaccine delivery to indigenous people living in village that impeded by rugged terrain. The landscape and terrain analysis show that access to the villages was dominated by 15%-45% slopes and the available access is only 1.5 m width trail. To transport 500 vials with 10 kg carrier along 2 km trail, it requires 2 persons to walk for 1 hour. By using drone, a straight line route with a length of 1.5 km can be developed. There were at least 3 drone types were available commercially to lift 10 kg load and several drones with payload capacity below 10 kg. For carrying 100 vials to village using drones, it is estimated the required delivery time was 1.23-1.38 minutes. Around 1.57-1.66 minute delivery times were required to transport 250 vials. For carrying the maximum and full loads of 500 vials or equals to 10 kg load, a drone requires in average of 3.13 minute delivery times. This required drone delivery time is significantly below the required time by walking that almost 1 hour. Drones were limited by flight operational times. Whereas all required delivery times for each drone assessed in this study were still below the drone operational time. The lowest drone operational time was 16 minutes and this is still higher than the time required for a drone to deliver the vaccine. Considering the effectiveness and anticipating vaccine vaccination, UAV quadcopter drone is a feasible option to support COVID 19 vaccine delivery to reach indigenous people in isolated areas.

category: health systems and quality improvement


title: Risk factors for bacterial infections in patients with moderate to severe COVID-19: A case control study

abstract:
ObjectiveBacterial infections are known to complicate respiratory viral infections and are associated with adverse outcomes in COVID-19 patients. A case control study was conducted to determine risk factors for bacterial infections where cases were defined as moderate to severe/critical COVID-19 patients with bacterial infection and those without were included as controls. Logistic regression analysis was performed.

ResultsOut of a total of 50 cases and 50 controls, greater proportion of cases had severe or critical disease at presentation as compared to control i.e 80% vs 30% (p<0.001). Hospital acquired pneumonia (72%) and Gram negative organisms (82%) were predominant. Overall antibiotic utilization was 82% and was 64% in patients who had no evidence of bacterial infection. The median length of stay was significantly longer among cases compared to controls (12.5 versus 7.5 days) (p=0.001). The overall mortality was 30%, with comparatively higher proportion of deaths among cases (42% versus 18%) (p=0.009). Severe or critical COVID-19 at presentation (AOR: 4.42 times; 95% CI; 1.63-11.9) and use of steroids (AOR: 4.60; 95% CI 1.24-17.05) were independently associated with risk of bacterial infections. These findings have implications for antibiotic stewardship as antibiotics can be reserved for those at higher risk for bacterial superinfections.


title: Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial

abstract:
Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously. Enisamium (laboratory code FAV00A, trade name Amizon(R)) is an orally active inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. Here we show that enisamium can inhibit SARS-CoV-2 infections in NHBE and Caco-2 cells. In vitro, the previously identified enisamium metabolite VR17-04 directly inhibits the activity of the SARS-CoV-2 RNA polymerase. Docking and molecular dynamics simulations suggest that VR17-04 prevents GTP and UTP incorporation. To confirm enisamiums antiviral properties, we conducted a double-blind, randomized, placebo-controlled trial in adult, hospitalized COVID-19 patients, which needed medical care either with or without supplementary oxygen. Patients received either enisamium (500 mg per dose) or placebo for 7 days. A pre-planned interim analysis showed in the subgroup of patients needing supplementary oxygen (n = 77) in the enisamium group a mean recovery time of 11.1 days, compared to 13.9 days for the placebo group (log-rank test; p=0.0259). No significant difference was found for all patients (n = 373) or those only needing medical care (n = 296). These results thus suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis and that enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen.

Significance statementSARS-CoV-2 is the causative agent of COVID-19. Although vaccines are now becoming available to prevent SARS-CoV-2 spread, the development of antivirals remains necessary for treating current COVID-19 patients and combating future coronavirus outbreaks. Here, we report that enisamium, which can be administered orally, can prevent SARS-CoV-2 replication and that its metabolite VR17-04 can inhibit the SARS-CoV-2 RNA polymerase in vitro. Moreover, we find that COVID-19 patients requiring supplementary oxygen, recover more quickly than patients treated with a placebo. Enisamium may therefore be an accessible treatment for COVID-19 patients.


title: Geographical and temporal variation in reduction of malaria infection among children under five years of age throughout Nigeria

abstract:
BackgroundGlobal progress in reducing malaria has stalled since 2015. Analysis of the situation is particularly needed in Nigeria, the country with by far the largest share of the burden, where approximately a quarter of all cases in the world are estimated to occur.

MethodsWe analysed data from three nationwide surveys (Malaria Indicator Surveys in 2010 and 2015, and a National Demographic and Health Survey in 2018), with malaria parasite prevalence in children under five years of age determined by sampling from all 36 states of Nigeria, and blood slide microscopy performed in the same accredited laboratory for all samples. Changes over time were evaluated by calculating prevalence ratio (PR) values with 95% confidence intervals (CI) for each state, together with Mantel-Haenszel adjusted prevalence ratios (PRadj) for each of the six major geopolitical zones of the country.

ResultsBetween 2010 and 2018 there were significant reductions in parasite prevalence in 25 states, but not in the remaining 11 states. Prevalence decreased most in southern zones of the country (South West PRadj = 0.53; South East PRadj = 0.59; South South PRadj = 0.51) and the North Central zone (PRadj = 0.36). Changes in the north were less marked, but were significant and indicated overall reductions by more than 20% (North West PRadj = 0.74; North East PRadj = 0.76). Changes in the south occurred mostly between 2010 and 2015, whereas those in the north were more gradual and most continued after 2015. Recent changes were not correlated with survey-reported variation in use of preventive measures.

ConclusionReductions in malaria infection in children under five have occurred in most individual states in Nigeria since 2010, but substantial geographical variation in the timing and extent indicate challenges to be overcome to enable global malaria reduction.


title: Role of pollution and weather indicators in the COVID-19 outbreak: A brief study on Delhi, India

abstract: The present study examines the impact of environment pollution indicators and weather indicators on the COVID-19 outbreak in the capital city of India. In this study, we hypothesize that certain weather conditions with an atmosphere having high content of air pollutants, might impact the transmission of COVID-19, in addition to the direct human to human diffusion. The Kendall and Spearman rank correlation tests were chosen as an empirical methodology to conduct the statistical analysis. In this regard, we compiled a daily dataset of COVID-19 cases (Confirmed, Recovered, Deceased), Weather indicators (Temperature and relative humidity) and pollution indicators (PM 2.5, PM 10, NO2, CO, and SO2) in Delhi state of India. The effects of each parameter within three time frames of same day, 7 days ago, and 14 days ago are evaluated. This study reveal a significant correlation between the transmission of COVID-19 outbreaks and the atmospheric pollutants with a combination of specific climatic conditions. The findings of this research will help the policymakers to identify risky geographic areas and enforce timely preventive measures.


title: Association of homelessness with COVID-19 positivity among individuals visiting a testing center

abstract: We conducted a chart audit of all patients attending an inner-city COVID-19 testing centre in Toronto, Canada between March and April 2020. Of the 2050 unique individuals tested, 214 (10.4%) were homeless. People experiencing homelessness were more likely to test positive for COVID-19 compared to those not experiencing homelessness even after adjustment for age, sex, and the presence of any medical co-morbidity (15.4% vs. 6.7%, p<0.001; OR 2.41, 95% CI 1.51 to 3.76, p<0.001).


title: Reverse causal effect of atrial fibrillation on 17 site-specific cancer risk: A Mendelian randomization study

abstract:
BackgroundBidirectional association between atrial fibrillation (AF) and cancer was reported by observational investigations. Additional study is warranted to investigate the causal effects of AF on risk of cancer.

MethodsThis study was a summary-level Mendelian randomization (MR) analysis. Genetic instrument for AF was developed from a genome-wide association study (GWAS) meta-analysis for AF including 537,409 European ancestry individuals including 55,144 AF cases. The outcome data for risk of 17 site-specific cancer from a previous GWAS meta-analysis of the UK Biobank (48,961/359,825 case/controls) and Genetic Epidemiology Research on Adult Health and Aging (16,001/50,525 case/controls) cohorts including European ancestry individuals was investigated. Inverse variance weighted method was the main MR method, supported by pleiotropy-robust sensitivity analysis including MR-Egger regression and penalized weighted median method.

ResultsThe causal estimates indicated that AF was causally linked to higher risk of cancers of lung, breast, cervix, endometrium, and melanoma. MR-Egger test for directional pleiotropy indicated absence of a pleiotropy in the identified causal estimates and MR-Egger regression and median-based methods provided similarly significant findings. On the other hand, the genetic predisposition of AF was significantly associated with lower risk of esophagus/gastric cancer, but possibility of a directional pleiotropy remained in the association.

ConclusionsAF is a causal factor for certain types of cancer. Appropriate cancer screening should be suggested in clinical guidelines for AF patients. Future trial is necessary to confirm whether appropriate management of AF may reduce the risk of cancer which is a major cause of deaths in AF patients.

category: cardiovascular medicine


title: Nutritional Status in Patients with Acute heart failure: A systematic review and meta-analysis with trial sequential analysis.

abstract:
A critical review of the prognosis impact of malnutrition in patients admitted with acute heart failure (AHF) has never been performed. We systematically reviewed the observational epidemiology literature to determine the all-cause mortality (ACM) in undernourished patients with acute heart failure or at risk of malnutrition through a meta-analysis of observational studies.

A systemic search using PubMed, Scopus, and Web of Science was done for articles reporting an association between malnutrition and mortality in patient with acute heart failure published before December 2019. Original data from observational cohort studies in patients with acute heart failure at baseline, and with nutritional state evaluation at admission using screening, or assessment tools. The outcome of interest was mortality independent of the timeframe for follow up. The characteristics of the included study were collected. Data quality assessment using the Newcastle Ottawa Quality Assessment Scale. The hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were extracted. For the meta-analysis, a random-effects model was considered.

Heterogeneity between studies was assessed using Cochran Q statistics and I2 statistics. Subgroup analyses were used to identify the source of heterogeneity. A sensitive analysis was performed to reflect the influence of the individual data set on the pooled HR. Publication bias was detected using the Doi plot and Luis Furuya-Kanamori asymmetry index (LFK index). The influence of potential publication bias on results was explored by using the trim-and-fill procedure. To assess the risks of random errors, trial sequential analysis (TSA) was performed.

Seven studies were eligible for review and meta-analysis. There were 9053 participants and over 1536 events occurred. The prevalence of malnutrition varied from 33% to 78.8%. Mean follow-up varied between 189 and 951 days. ACM rates varied between 7% and 42.6%. Nutritional status is significantly associated with mortality in patients with AHF (Pooled HR=1.15;95%CI[1.08-1.23]). Considerable between-study heterogeneity was observed (I2=83%, P=0.001). Heterogeneity was partially explained by the different tools used to screen malnutrition risk, and follow-up durations used by the included studies. There was evidence of major publication bias regarding the risk of malnutrition-related to ACM. The obtained LFK index was 6.12 and suggests major asymmetry. The recalculated pooled HR that incorporates the hypothetical missing studies is 1.15; 95%CI (1.08-1.22). However, the accumulating number of participants and the required information size has not yet been achieved. Then, the trial sequential monitoring boundary is inconclusive.

This first meta-analysis of the association between nutritional status in patients with acute heart failure and all-cause mortality indicated that malnutrition risk in a patient with acute heart failure was associated with increased all-cause mortality. The prognosis impact of malnutrition is real despite heterogeneity in tools and cut off for defining malnutrition and mean follow up duration. This review underlines the peremptory need for multicenter studies, for uniform guidelines for assessing nutritional status, and for reporting guidelines for prognostic studies in an acute cardiovascular setting. Better nutritional practice to improve patient care is emphasized in international and national health care guidelines.


title: The Ecological Structure of Mosquito Population Dynamics: Insights from India

abstract: Understanding the temporal dynamics of mosquito populations underlying malaria transmission is key to optimising control strategies. We collate mosquito time-series catch data spanning 40 years and 117 locations across India to understand the factors driving these dynamics. Our analyses reveal pronounced variation in dynamics across locations and between species. Many mosquito populations lacked the often-assumed positive relationship with rainfall, instead displaying patterns of abundance that were only weakly or even negatively correlated with precipitation and highlighting the role of temperature, proximity to perennial bodies of water and patterns of land use in shaping the dynamics and seasonality of mosquito populations. We show that these diverse dynamics can be clustered into "dynamical archetypes", each characterised by distinct temporal properties and driven by a largely unique set of environmental factors. These results highlight that a complex interplay of factors, rather than rainfall alone, shape the timing and extent of mosquito population seasonality.

category: epidemiology


title: The Ecological Structure of Mosquito Population Seasonal Dynamics


title: Impact of COVID-19 pandemic on use of Pediatric Emergency Health Services in a Tertiary Care Pediatric Hospital in North India

abstract:
ObjectiveTo compare Pediatric Emergency attendance pre-COVID 19 to that during COVID 19 pandemic and to study changes in patient profiles attending Pediatric Emergency Department during COVID 19 pandemic.

MethodsWe conducted a retrospective cross-sectional observational study and collected data from Medical Record Section during the COVID-19 pandemic from January to June 2020 and compared it with data from 2019 in similar months. Data collected was analyzed to find out the impact of COVID - 19 on use of pediatric emergency health services with respect to patient attendance, age and clinical profile before and during COVID-19 in a tertiary care hospital in New Delhi.

ResultsWe observed a 43% decline in PED visits which increased to 75% during the period of lock-down (p value = 0.005). There was a significant decrease in children of age group 1-5 years attending PED. Mortality rate during lockdown had gone up by nearly 3times than the average monthly mortality.

ConclusionsWhile children might not have been directly affected by the COVID-19 pandemic, but the fear of COVID 19 and measures taken to control the pandemic has affected the health seeking behavior of patients to an extent that indirectly caused more damage than anticipated.

category: pediatrics


title: Impact of Residential Neighborhood and Race/Ethnicity on Outcomes of Hospitalized Patients with COVID-19 in the Bronx

abstract:
The socially vulnerable have been most affected due to the COVID-19 pandemic, similar to the aftermath of any major disaster. Racial and social minorities are experiencing a disproportionate burden of morbidity and mortality.

The aim of this study was to evaluate the impact of residential location/community and race/ethnicity on outcomes of COVID-19 infection among hospitalized patients within the Bronx. This was a single center retrospective observational cohort study that included SARS-CoV2 positive adult residents of the Bronx (stratified as residents of South Bronx vs Rest of Bronx) hospitalized between March-May 2020. Data extracted from hospital electronic medical records included residential addresses, race, comorbidities, and insurance details. Comorbidity burden other clinical and laboratory details were also assessed to determine their correlation to COVID-19 severity of illness and outcomes of mortality and length of stay.

As expected, the COVID-19 pandemic differentially affected outcomes in those in the more socially disadvantaged area of the South Bronx versus the rest of the Bronx borough. Residents of the South Bronx had a significantly higher comorbidity burden and had public insurance to access medical care in comparison to the remainder of the Bronx. Interestingly, for the patient population studied there was no observed difference in 30-day mortality by race/ethnicity among those infected with COVID- 19 in spite of the increased disease burden observed.

This adds an interesting perspective to the current literature, and highlights the need to address the social/economic factors contributing to health access disparity to reduce the adverse impact of COVID-19 in these communities.


title: Wastewater Virus Detection Complements Clinical COVID-19 Testing to Limit Spread of Infection at Kenyon College

abstract: In-person college instruction during the 2020 pandemic required effective and economical monitoring of COVID-19 prevalence. Kenyon College and the Village of Gambier conducted measurement of SARS-CoV-2 RNA from the village wastewater plant and from an on-campus sewer line. Wastewater RNA detection revealed virus prevalence leading to individual testing and case identification. Wastewater surveillance also showed when case rates had subsided, thus limiting the need for individual clinical testing. Overall, wastewater virus surveillance allows more targeted use of individual testing and increases community confidence in student population management.


title: Effects of surgical masks on droplet and aerosol dispersion under various oxygen delivery modalities

abstract:
RationaleAerosol dispersion under various oxygen delivery modalities, including high flow nasal cannula, is a critical concern for healthcare workers who treat acute hypoxemic respiratory failure during the coronavirus disease 2019 pandemic. Effects of surgical masks on droplet and aerosol dispersion under oxygen delivery modalities are not yet clarified.

ObjectivesTo visualize and quantify dispersion particles under various oxygen delivery modalities and examine the protective effect of surgical masks on particle dispersion.

MethodsThree and five healthy men were enrolled for video recording and quantification of particles, respectively. Various oxygen delivery modalities including high flow nasal cannula were used in this study. Particle dispersions during rest breathing, speaking, and coughing were recorded and automatically counted in each condition and were evaluated with or without surgical masks.

Measurements and Main ResultsCoughing led to the maximum amount and distance of particle dispersion, regardless of modalities. Droplet dispersion was not visually increased by oxygen delivery modalities compared to breathing at room air. With surgical masks over the nasal cannula or high-flow nasal cannula, droplet dispersion was barely visible. Oxygen modalities did not increase the particle dispersion counts regardless of breathing pattens. Wearing surgical masks significantly decreased particle dispersion in all modalities while speaking and coughing, regardless of particle sizes, and reduction rates were approximately 95 and 80-90 % for larger (> 5 m) and smaller (> 0.5 m) particles, respectively.

ConclusionsSurgical mask over high flow nasal canula may be safely used for acute hypoxemic respiratory failure including coronavirus disease 2019 patients.

Subject Category List4.13 Ventilation: Non-Invasive/Long-Term/Weaning

*This article has an online data supplement, which is accessible from this issues table of content online at www.atsjournals.org.


title: Exploration of interethnic variation in the ibuprofen metabolizing enzyme CYP2C9: a cautionary guide for treatment of COVID-19 symptoms

abstract: Coronavirus disease 2019 (COVID-19), is a rapidly spreading infectious illness that causes a debilitating respiratory syndrome. While non-steroidal anti-inflammatory drugs (NSAIDs), may be prescribed for the management of pain and fever, there was early controversy on the use of ibuprofen for symptomatic treatment of COVID-19. P450 enzyme CYP2C9 are known to be involved in the metabolism of NSAIDs. Although no study has been conducted in the setting of population genetics in patients with COVID-19 yet, there are plausible mechanisms by which genetic determinants may play a role in adverse drug reactions (ADRs). In this work, we adjusted expected phenotype frequencies based on racial demographic models dependent on population ancestry in drug responses and toxicity events associated with ibuprofen treatment. A cohort of 101 Jordanian Arab samples retrospectively were selected and genotyped using Affymetrix DMET Plus Premier Package, within the context of over 100,000 global subjects in 417 published reports. European populations are 7.2x more likely to show impaired ibuprofen metabolism than Sub-Saharan populations, and 4.5x more likely than East Asian ancestry populations. Hence, a proactive assessment of the most likely gene-drug candidates will lead to more effective treatments and a better understanding of the role of pharmacogenetics for COVID-19.

category: genetic and genomic medicine


title: Exploration of interethnic variation in the ibuprofen metabolizing enzyme CYP2C9: a genetic-based cautionary guide for treatment of COVID-19 symptoms


title: Performance and Implementation Evaluation of the Abbott BinaxNOW Rapid Antigen Test in a High-throughput Drive-through Community Testing Site in Massachusetts

abstract:
BackgroundRapid diagnostic tests (RDTs) for SARS-CoV-2 antigens (Ag) that can be performed at point-of-care (POC) can supplement molecular testing and help mitigate the COVID-19 pandemic. Deployment of an Ag RDT requires an understanding of its operational and performance characteristics under real-world conditions and in relevant subpopulations. We evaluated the Abbott BinaxNOW COVID-19 Ag Card in a high-throughput, drive-through, free community testing site in Massachusetts (MA) using anterior nasal (AN) swab RT-PCR for clinical testing.

MethodsIndividuals presenting for molecular testing in two of seven lanes were offered the opportunity to also receive BinaxNOW testing. Dual AN swabs were collected from symptomatic and asymptomatic children ([≤] 18 years) and adults. BinaxNOW testing was performed in a testing pod with temperature/humidity monitoring. One individual performed testing and official result reporting for each test, but most tests had a second independent reading to assess inter-operator agreement. Positive BinaxNOW results were scored as faint, medium, or strong. Positive BinaxNOW results were reported to patients by phone and they were instructed to isolate pending RT-PCR results. The paired RT-PCR result was the reference for sensitivity and specificity calculations.

ResultsOf 2482 participants, 1380 adults and 928 children had paired RT-PCR/BinaxNOW results and complete symptom data. 974/1380 (71%) adults and 829/928 (89%) children were asymptomatic. BinaxNOW had 96.5% (95% confidence interval [CI] 90.0-99.3) sensitivity and 100% (98.6-100.0) specificity in adults within 7 days of symptoms, and 84.6% (65.1-95.6) sensitivity and 100% (94.5-100.0) specificity in children within 7 days of symptoms. Sensitivity and specificity in asymptomatic adults were 70.2% (56.6-81.6) and 99.6% (98.9-99.9), respectively, and in asymptomatic children were 65.4% (55.6-74.4) and 99.0% (98.0-99.6), respectively. By cycle threshold (Ct) value cutoff, sensitivity in all subgroups combined (n=292 RT-PCR-positive individuals) was 99.3% with Ct [≤]25, 95.8% with [≤]30, and 81.2% with [≤]35. Twelve false positive BinaxNOW results (out of 2308 tests) were observed; in all twelve, the test bands were faint but otherwise normal, and were noted by both readers. One invalid BinaxNOW result was identified. Inter-operator agreement (positive versus negative BinaxNOW result) was 100% (n = 2230/2230 double reads). Each operator was able to process 20 RDTs per hour. In a separate set of 30 specimens (from individuals with symptoms [≤]7 days) run at temperatures below the manufacturers recommended range (46-58.5{degrees}F), sensitivity was 66.7% and specificity 95.2%.

ConclusionsBinaxNOW had very high specificity in both adults and children and very high sensitivity in newly symptomatic adults. Overall, 95.8% sensitivity was observed with Ct [≤] 30. These data support public health recommendations for use of the BinaxNOW test in adults with symptoms for [≤]7 days without RT-PCR confirmation. Excellent inter-operator agreement indicates that an individual can perform and read the BinaxNOW test alone. A skilled laboratorian can perform and read 20 tests per hour. Careful attention to temperature is critical.


title: Serologic Surveillance and Phylogenetic Analysis of SARS-CoV-2 Infection in Hospital Health Care Workers

abstract:
BACKGROUNDIt is unclear how, when and where health care workers (HCW) working in hospitals are infected with SARS-CoV-2.

METHODSProspective cohort study comprising 4-weekly measurement of SARS-CoV-2 specific antibodies and questionnaires from March to June 2020. We compared SARS-CoV-2 incidence between HCW working in Covid-19 patient care, HCW working in non-Covid-19 patient care and HCW not in patient care. Phylogenetic analyses of SARS-CoV-2 samples from patients and HCW were performed to identify potential transmission clusters.

RESULTSWe included 801 HCW: 439 in the Covid-19 patient care group, 164 in the non-Covid-19 patient care group and 198 in the no patient care group. SARS-CoV-2 incidence was highest in HCW working in Covid-19 patient care (13.2%), as compared with HCW in non-Covid-19 patient care (6.7%, hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.2 to 4.3) and in HCW not working in patient care (3.6%, HR 3.9, 95% CI 1.8 to 8.6). Within the group of HCW caring for Covid-19 patients, SARS-CoV-2 cumulative incidence was highest in HCW working on Covid-19 wards (25.7%), as compared with HCW working on intensive care units (7.1%, HR 3.6, 95% CI 1.9 to 6.9), and HCW working in the emergency room (8.0%, HR 3.3, 95% CI 1.5 to 7.1). Phylogenetic analyses on Covid-19 wards identified multiple potential HCW-to-HCW transmission clusters while no patient-to-HCW transmission clusters were identified.

CONCLUSIONSHCW working on Covid-19 wards are at increased risk for nosocomial SARS-CoV-2 infection, with an important role for HCW-to-HCW transmission.

(Funded by the Netherlands Organization for Health Research and Development ZonMw & the Corona Research Fund Amsterdam UMC; Netherlands Trial Register number NL8645)


title: Epidemiological impact of prioritizing SARS-CoV-2 vaccination by antibody status: Mathematical modeling analyses

abstract:
BackgroundVaccines against SARS-CoV-2 have been developed, but their availability falls far short of global needs. This study aimed to investigate the impact of prioritizing available doses on the basis of recipient antibody status, that is by exposure status, using Qatar as an example.

MethodsVaccination impact was assessed under different scale-up scenarios using a deterministic meta-population mathematical model describing SARS-CoV-2 transmission and disease progression in the presence of vaccination.

ResultsFor a vaccine that protects against infection with an efficacy of 95%, half as many vaccinations were needed to avert one infection, disease outcome, or death by prioritizing antibody-negative individuals for vaccination. Prioritization by antibody status reduced incidence at a faster rate and led to faster elimination of infection and return to normalcy. Further prioritization by age group amplified the gains of prioritization by antibody status. Gains from prioritization by antibody status were largest in settings where the proportion of the population already infected at the commencement of vaccination was 30-60%, which is perhaps where most countries will be by the time vaccination programs are up and running. For a vaccine that only protects against disease and not infection, vaccine impact was reduced by half, whether this impact was measured in terms of averted infections or disease outcomes, but the relative gains from using antibody status to prioritize vaccination recipients were similar.

ConclusionsMajor health, societal, and economic gains can be achieved more quickly by prioritizing those who are antibody-negative while doses of the vaccine remain in short supply.


title: International risk of the new variant COVID-19 importations originating in the United Kingdom

abstract: A fast-spreading SARS-CoV-2 variant identified in the United Kingdom in December 2020 has raised international alarm. We estimate that, in all 15 countries analyzed, there is at least a 50% chance the variant was imported by travelers from the United Kingdom by December 7th.


title: Using excess deaths and testing statistics to improve estimates of COVID-19 mortalities

abstract: Factors such as non-uniform definitions of mortality, uncertainty in disease prevalence, and biased sampling complicate the quantification of fatality during an epidemic. Regardless of the employed fatality measure, the infected population and the number of infection-caused deaths need to be consistently estimated for comparing mortality across regions. We combine historical and current mortality data, a statistical testing model, and an SIR epidemic model, to improve estimation of mortality. We find that the average excess death across the entire US is 13% higher than the number of reported COVID-19 deaths. In some areas, such as New York City, the number of weekly deaths is about eight times higher than in previous years. Other countries such as Peru, Ecuador, Mexico, and Spain exhibit excess deaths significantly higher than their reported COVID-19 deaths. Conversely, we find negligible or negative excess deaths for part and all of 2020 for Denmark, Germany, and Norway.


title: Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation.

abstract:
BACKGROUNDNeurological complications occur in COVID-19. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 subjects with neurological complications and determine presence of neuroinflammatory changes implicated in pathogenesis.

METHODSCross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity (critical, severe, moderate, mild). COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n=82). Cytokines (IL-6, TNF, IFN{gamma}, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA.

RESULTSCSF from COVID-19 subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis or specific increases in pro-inflammatory markers or cytokines (IL-6, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines (IL-6, TNF, IL-12p70) and IL-10 in CSF of COVID-19 and non-COVID-19 stroke subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke and critical COVID-19. CSF-hsCRP was present almost exclusively in COVID-19 cases.

CONCLUSIONThe paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. Elevated CSF-NF-L indicates neuroaxonal injury in COVID-19 cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.

FUNDINGThis work was supported by NIH R01-NS110122 and The Bart McLean Fund for Neuroimmunology Research.


title: Explainable AI enables clinical trial patient selection to retrospectively improve treatment effects in schizophrenia

abstract:
BackgroundHeterogeneity among patients responses to treatment is prevalent in psychiatric disorders. Personalized medicine approaches - which involve parsing patients into subgroups better indicated for a particular treatment - could therefore improve patient outcomes and serve as a powerful tool in patient selection within clinical trials. Machine learning approaches can identify patient subgroups but are often not "explainable" due to the use of complex algorithms that do not mirror clinicians natural decision-making processes.

MethodsHere we combine two analytical approaches - Personalized Advantage Index and Bayesian Rule Lists - to identify paliperidone-indicated schizophrenia patients in a way that emphasizes model explainability. We apply these approaches retrospectively to randomized, placebo-controlled clinical trial data to identify a paliperidone-indicated subgroup of schizophrenia patients who demonstrate a larger treatment effect (outcome on treatment superior than on placebo) than that of the full randomized sample as assessed with Cohens d. For this study, the outcome corresponded to a reduction in the Positive and Negative Syndrome Scale (PANSS) total score which measures positive (e.g., hallucinations, delusions), negative (e.g., blunted affect, emotional withdrawal), and general psychopathological (e.g., disturbance of volition, uncooperativeness) symptoms in schizophrenia.

ResultsUsing our combined explainable AI approach to identify a subgroup more responsive to paliperidone than placebo, the treatment effect increased significantly over that of the full sample (p<0.0001 for a one-sample t-test comparing the full sample Cohens d=0.82 and a generated distribution of subgroup Cohens ds with mean d=1.22, std d=0.09). In addition, our modeling approach produces simple logical statements (if-then-else), termed a "rule list", to ease interpretability for clinicians. A majority of the rule lists generated from cross-validation found two general psychopathology symptoms, disturbance of volition and uncooperativeness, to predict membership in the paliperidone-indicated subgroup.

ConclusionsThese results help to technically validate our explainable AI approach to patient selection for a clinical trial by identifying a subgroup with an improved treatment effect. With these data, the explainable rule lists also suggest that paliperidone may provide an improved therapeutic benefit for the treatment of schizophrenia patients with either of the symptoms of high disturbance of volition or high uncooperativeness.

Trial Registrationclincialtrials.gov identifier: NCT 00083668; registered May 28, 2004

category: psychiatry and clinical psychology


title: Traumatic subarachnoid hemorrhage: a scoping review

abstract: Sixty-nine million people suffer from traumatic brain injury (TBI) each year, and TBI is the most common cause of subarachnoid hemorrhage (SAH). Traumatic SAH (tSAH) has been described as an adverse prognostic factor leading to progressive neurological deterioration and increased morbidity and mortality. However, a limited number of studies evaluate recent trends in the diagnostic and management of SAH in the context of trauma. The objective of this scoping review was to understand the extent and type of evidence concerning the diagnostic criteria and management of traumatic subarachnoid hemorrhage. This scoping review was conducted following the JBI methodology for scoping reviews. The review included adults who suffered SAH secondary to trauma. Data extracted from each study included study aim, country, methodology, population characteristics, outcome measures, a summary of findings, and future directives. Thirty studies met inclusion criteria. Studies were grouped into five categories by topic: tSAH associated with mild TBI (n=13), and severe TBI (n=3); clinical management and diagnosis (n=9); imaging (n=3); and 5) aneurysmal tSAH (n=1). Of the 30 studies, two came from a low-and middle-income country (LMIC); excluding China, nearly a high-income country. Patients with tSAH associated with mTBI have a very low risk of clinical deterioration and surgical intervention and should be managed conservatively when considering ICU admission. The Helsinki and Stockholm CT scoring systems, in addition to the AIS, Cr, age decision tree, may be valuable tools to use when predicting outcome and mortality.


title: Simple Linear Cancer Risk Prediction Models with Novel Features Outperform Complex Approaches

abstract: A patients risk for cancer is usually estimated through simple linear models that sum effect sizes of proven risk factors. In theory, more advanced machine learning models can be used for the same task. Using data from the UK Biobank, a large prospective health study, we have developed linear and machine learning models for the prediction of 12 different cancers diagnoses within a 10 year time span. We find that the top machine learning algorithm, XGBoost (XGB), trained on 707 features generated an average area under the receiver operator curve of 0.736 (with a range of 0.65-0.85). Linear models trained with only 10 features were found to be statistically indifferent from the machine learning performance. The linear models were significantly more accurate than the prominent QCancer models (p = 0.0019), which are trained on 45 million patient records and available to over 4,000 United Kingdom general practices. The increase in accuracy may be caused by the consideration of often omitted feature types, including survey answers, census records, and genetic information. This approach led to the discovery of significant novel risk features, including self-reported happiness with own health (relevant to 12 cancers), measured testosterone (relevant to 8 cancers), and ICD codes for rehabilitation procedures (relevant to 3 cancers). These ten feature models can be easily implemented within the clinic, allowing for personalized screening schedules that may increase the cancer survival within a population.


title: High Throughput Screening for Expanded CTG repeats in Myotonic Dystrophy Type 1 Using Melt Curve Analysis

abstract:
BackgroundMyotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often non-specific and overlapping with other disorders. Clinical genetic testing by Southern blot or triplet-primed PCR (TP-PCR) is technically challenging and cost prohibitive for population surveys.

MethodsHere, we present a high throughput, low-cost screening tool for CTG repeat expansions using TP-PCR followed by high resolution melt curve analysis with saturating concentrations of SYBR GreenER dye.

ResultsWe determined that multimodal melt profiles from the TP-PCR assay are a proxy for amplicon length stoichiometry. In a screen of 10,097 newborn blood spots, melt profile analysis accurately reflected the tri-modal distribution of common alleles from 5 to 35 CTG repeats, and identified the premutation and full expansion alleles.

ConclusionWe demonstrate that robust detection of expanded CTG repeats in a single tube can be achieved from samples derived from specimens with minimal template DNA such as dried blood spots (DBS). This technique is readily adaptable to large-scale testing programs such as population studies and newborn screening programs.


title: Labeling self-tracked menstrual health records with hidden semi-Markov models

abstract: Globally, millions of women track their menstrual cycle and fertility via smartphone-based health apps, generating multivariate time series with frequent missing data. To leverage data from self-tracking tools in epidemiological studies on fertility or the menstrual cycles effects on diseases and symptoms, it is critical to have methods for identifying reproductive events, e.g. ovulation, pregnancy losses or births. We present two coupled hidden semi-Markov models that adapt to changes in tracking behavior, explicitly capture variable- and state- dependent missingness, allow for variables of different type, and quantify uncertainty. The accuracy on synthetic data reaches 98% with no missing data, 90% with realistic missingness, and 94% accuracy on our partially labeled real-world time series. Our method also accurately predicts cycle length by learning user characteristics. It is publicly available (HiddenSemiMarkov R package) and transferable to any health time series, including self-reported symptoms and occasional tests.

category: health informatics


title: Electronic prescribing systems as tools to improve patient care: a learning health systems approach to increase guideline concordant prescribing for venous thromboembolism prevention.

abstract:
BACKGROUNDVenous thromboembolism (VTE) causes significant mortality and morbidity in hospitalised patients. In England, reporting the percentage of patients with a completed VTE risk assessment is mandated, but this does not include whether that risk assessment resulted in appropriate prescribing. Full guideline compliance (an assessment and action) is rarely reported. Education, audit and feedback enhance guideline compliance but electronic prescribing systems(EPS) can mandate guideline-compliant actions. We hypothesised that EPS-based interventions would increase full VTE guideline compliance more than other interventions.

METHODSAll admitted patients within University Hospitals Birmingham NHS Foundation Trust were included for analysis between 2011-2020. The proportion of patients who received a fully compliant risk assessment and action was assessed over time. Interventions included face-to-face feedback based on measured performance (an individual approach) and mandatory risk assessment and prescribing rules into an EPS (a systems approach).

RESULTSData from all 235,005 admissions and all 5503 prescribers were included in the analysis. Face-to-face feedback improved full VTE guideline concordance from 70% to 77% (p=<0.001). Changes to the EPS to mandate assessment with prescribing rules increased full VTE compliance to 95% (p=<0.001). Further amendments to the EPS system to reduce erroneous VTE assessments slightly reduced full compliance to 92% (p<0.001), but this was then maintained including during changes to the low molecular weight heparin used for VTE prophylaxis.

DISCUSSION/ CONCLUSIONAn EPS-systems approach was more effective in improving sustained guideline-compliant VTE prevention. Non-compliance was still not eradicated despite this mandated system and requires further research.

FUNDINGHDR-UK Hub PIONEER

Summary BoxO_ST_ABSWhat is already known?C_ST_ABSHospitalised patients are at an increased risk of venous thromboembolism (VTE), which can lead to significant morbidity and mortality. Risk factors for VTE are well known, there are established screening criteria and there is an effective prophylactic therapy, using low molecular weight heparin where indicated. Since 2010, NHS England has mandated the reporting of the percentage of patients with a completed VTE risk assessment. However, it does not automatically follow that completing a risk assessment leads to the appropriate action (prescribing and administering VTE prophylaxis where indicated). Currently it is unclear what percentage of patients have a guideline compliant VTE risk assessment and an associated action, or how full guideline compliance can be improved.

What does this paper add?First, this paper describes that a VTE risk assessment does not always lead to full VTE guideline compliance (an appropriate prescription and administration of heparin where indicated). This is currently not part of mandated reporting but potentially could lead to patient harm. Second, that Electronic Health Systems (EHS) can capture and interrogate guideline-associated risk assessments and prescribing, and be used to improve full guideline compliance, through a combination of individual feedback to prescribing outliers and mandated prescribing rules. These EPS-assisted systems are robust, and sustain guideline compliance through personnel and formulary changes.


title: Diverse Humoral Immune Responses in Younger and Older Adult COVID-19 Patients

abstract: We sought to discover links between antibody responses to SARS-CoV-2 and patient clinical variables, cytokine profiles and antibodies to endemic coronaviruses. Serum from patients of varying ages and clinical severity were collected and used to probe a novel multi-coronavirus protein microarray containing SARS-CoV-2 proteins and overlapping protein fragments of varying length as well as SARS-CoV, MERS-CoV, HCoV-OC43 and HCoV-NL63 proteins. IgG, IgA and IgM antibody responses to specific epitopes within the spike (S), nucleocapsid (N) and membrane proteins (M) were higher in older adult patients. Moreover, the older age group displayed more consistent correlations of antibody reactivity with systemic cytokine and chemokine responses when compared to the younger adult group. A subset of patients, however, had little or no response to SARS-CoV-2 antigens and disproportionately severe clinical outcomes. Further characterization of these serosilent individuals with cytokine analysis revealed significant differences in IL-10, IL-15, IP-10, EGF and sCD40L levels when compared to seroreactive patients in the cohort.


title: Increased mortality associated with uncontrolled diabetes mellitus in patients with Pulmonary Cryptococcosis- a single U.S. cohort study

abstract:
BackgroundDiabetes mellitus is an established risk factor for bacterial infections, but its role in Cryptococcosis is unclear. The study aimed to determine whether uncontrolled diabetes (HbA1c >7%) was an independent risk factor for mortality in cryptococcosis.

MethodsA retrospective case-control study partially matched by age and gender was performed in patients tested for Cryptococcus infection at the University of Colorado Hospital from 2000-2019. A multivariable logistic regression model was used to identify mortality predictors. Cox proportional hazard model was used for survival analysis.

ResultsWe identified 96 cases of Cryptococcosis and 125 controls. Among cases, cryptococcal meningitis (49.0%) and pneumonia (36.5%) constituted most infections. Cases with pulmonary cryptococcosis had a higher mortality at 10 weeks (50% vs 7%, p=0.006) and one year (66.7% vs 13.8%, p=0.005). Unadjusted Cox proportional hazard model found an increased rate of death for uncontrolled diabetes at 10-weeks (hazard ratio 8.4, CI: 1.4-50.8, p=0.02), and 1-year (hazard ratio 7.0, CI: 1.7-28.4, p=0.007) among pulmonary cryptococcosis cases. Multivariable analysis showed a significantly increased odds of 10-weeks (OR=4.3, CI: 1.1-16.5, p=0.035) and one-year (OR=5.9, CI: 2.2-15.8, p=0.014) mortality for uncontrolled diabetes among pulmonary cryptococcosis cases. After adjustment for gender, age, and case/control, for every 1% increase in HbA1c levels, the odds of pulmonary cryptococcosis mortality at one-year increased by 11% (OR = 1.6, CI 95%: 1.1-2.3, p= 0.006).

ConclusionUncontrolled diabetes is associated with worse outcomes in pulmonary cryptococcosis, including a 4-fold and 6-fold increased odds of death at 10-weeks and 1-year, respectively. Glucose control interventions should be explored to improve clinical outcomes in patients with pulmonary cryptococcosis.


title: The Relationship between Democracy embracement and COVID-19 reported casualties worldwide

abstract:
BackgroundThe COVID-19 toll of cases and deaths followed an uneven pattern across the world. The literature has partly explained the observed discrepancy between the different countries by country-specific and systemic patterns worldwide. In this study, we propose an additional explanation that the magnitude of COVID-19 toll reported to the WHO could be influenced by the level of free speech and Democracy in the reporting countries.

MethodsWe constructed a longitudinal dataset including the daily COVID-19 count of cases and deaths worldwide and each countrys respective score on the Freedom in the World index. We applied two Generalized Estimating Equation models to investigate if a countrys reported toll count of COVID-19 cases and deaths is related to that countrys freedom level. We controlled for factors identified in the current literature to affect the pandemics spread.

ResultsA countrys score on the Freedom In the World Index was associated with its reported COVID-19 cases count (57028.43, 95% CI 985.3619 - 113071.5, P= 0.0461) and deaths count (3473.273, 95% CI1217.12-5729.42, P=.002). Also, despite having almost equal shares of the worlds population, countries at the bottom category of the Freedom index reported 21% and 11% of the COVID-19 toll cases and death counts reported by countries of highest scores on the index, respectively.

ConclusionsThe known magnitude of the COVID-19 pandemics morbidity and mortality appears to be as transparent as the reporting countries uphold free speech and Democracy. This pattern could potentially misguide international aid and global vaccine distribution plans.


title: Model-based cellular kinetic analysis of SARS-CoV-2 infection: different immune response modes and treatment strategies

abstract: Increasing number in global COVID-19 cases demands for mathematical model to analyze the interaction between the virus dynamics and the response of innate and adaptive immunity. Here, based on the assumption of a weak and delayed response of the innate and adaptive immunity in SARS-CoV-2 infection, we constructed a mathematical model to describe the dynamic processes of immune system. Integrating theoretical results with clinical COVID-19 patients data, we classified the COVID-19 development processes into three typical modes of immune responses, correlated with the clinical classification of mild & moderate, severe and critical patients. We found that the immune efficacy (the ability of host to clear virus and kill infected cells) and the lymphocyte supply (the abundance and pool of naive T and B cell) play important roles in the dynamic process and determine the clinical outcome, especially for the severe and critical patients. Furthermore, we put forward possible treatment strategies for the three typical modes of immune response. We hope our results can help to understand the dynamical mechanism of the immune response against SARS-CoV-2 infection, and to be useful for the treatment strategies and vaccine design.


title: Detection of SARS-CoV-2 nucleocapsid antigen from serum can aid in timing of COVID-19 infection

abstract:
SARS-CoV-2 RNA can be detected in respiratory samples for weeks or even months after onset of COVID-19 disease. Therefore, one of the diagnostic challenges of PCR positive cases is differentiating between acute COVID-19 disease and convalescent phase. Recently, the presence of SARS-CoV-2 nucleocapsid antigen in serum samples of COVID-19 patients was published [Le Hingrat et al. Detection of SARS-CoV-2 N-antigen in blood during acute COVID-19 provides a sensitive new marker and new testing alternatives, Clinical Microbiology and Infection, 2020].

Our study aimed to characterize the analytical specificity and sensitivity of an enzyme-linked immunosorbent assay (Salocor SARS-CoV-2 Antigen Quantitative Assay Kit(C) (Salofa Ltd, Salo, Finland)) for the detection of SARS-CoV-2 antigen in serum, and to characterize the kinetics of antigenemia. The evaluation material included a negative serum panel of 155 samples, and 126 serum samples from patients with PCR-confirmed COVID-19.

The specificity of the Salocor SARS-CoV-2 serum N antigen test was 98.0%. In comparison with simultaneous positive PCR from upper respiratory tract (URT) specimens, the test sensitivity was 91.7%. In a serum panel in which the earliest serum sample was collected two days before the collection of positive URT specimen, and the latest 48 days after (median 1 day post URT sample collection), the serum N antigen test sensitivity was 94% within 14 days post onset of symptoms. The antigenemia resolved approximately two weeks after the onset of disease and diagnostic PCR.

The combination of simultaneous SARS-CoV-2 antigen and antibody testing appeared to provide useful information for the timing of COVID-19. Our results suggest that SARS-CoV-2 N-antigenemia may be used as a diagnostic marker in acute COVID-19.


title: A national retrospective cohort study of mechanical ventilator availability and its association with mortality risk in intensive care patients with COVID-19

abstract:
ObjectivesTo determine if there is an association between survival rates in intensive care units (ICU) and occupancy of the unit on the day of admission.

DesignNational retrospective observational cohort study during the COVID-19 pandemic.

Setting90 English hospital trusts (i.e. groups of hospitals functioning as single operational units).

Participants6,686 adults admitted to an ICU in England between 2nd April and 1st December, 2020 (inclusive), with presumed or confirmed COVID-19, for whom data was submitted to the national surveillance programme and met study inclusion criteria.

InterventionsN/A

Main Outcomes and MeasuresA Bayesian hierarchical approach was used to model the association between hospital trust level (mechanical ventilation compatible) bed occupancy, and in-hospital all-cause mortality. Results were adjusted for unit characteristics (pre-pandemic size), individual patient-level demographic characteristics (age, sex, ethnicity, time-to-ICU admission), and recorded chronic comorbidities (obesity, diabetes, respiratory disease, liver disease, heart disease, hypertension, immunosuppression, neurological disease, renal disease).

Results121,151 patient-days were observed, with a mortality rate of 20.8 per 1,000 patient days. Adjusting for patient-level factors, mortality was higher for admissions during periods of high occupancy (>85% occupancy versus the baseline of 45 to 85%) [OR 1.18 (95% posterior credible interval (PCI): 1.00 to 1.38)]. In contrast, mortality was decreased for admissions during periods of low occupancy (<45% relative to the baseline) [OR 0.79 (95% PCI: 0.69 to 0.90)].

Conclusion and RelevanceIncreasing occupancy of beds compatible with mechanical ventilation, a proxy for operational strain, is associated with a higher mortality risk for individuals admitted to ICU. Public health interventions (such as expeditious vaccination programmes and non-pharmaceutical interventions) to control both incidence and prevalence of COVID-19, and therefore keep ICU occupancy low in the context of the pandemic, are necessary to mitigate the impact of this type of resource saturation.

O_TEXTBOXSummary Box

What is already known on this topicPre-pandemic, higher occupancy of intensive care units was shown to be associated with increased mortality risk. However, there is limited data on the extent to which occupancy levels impacted patient outcomes during the COVID-19 pandemic, especially in light of the mobilisation of significant additional resources. A recent study from Belgium reported a 42% higher mortality during periods of ICU surge capacity deployment, although in the analysis surge capacity was evaluated only as a binary variable, and notably this contradicts earlier results from smaller studies in Australia and Wales, where no association between ICU occupancy and mortality was identified.

What this study addsThe results of this study suggest that survival rates for patients with COVID-19 in intensive care settings appears to deteriorate as the occupancy of (surge capacity) beds compatible with mechanical ventilation (a proxy for operational pressure), increases. Moreover, this risk doesnt occur above a specific threshold, but rather appears linear; whereby going from 0% occupancy to 100% occupancy increases risk of mortality by 69% (after adjusting for relevant individual-level factors). Furthermore, risk of mortality based on occupancy on the date of recorded outcome is even higher; OR 2.98 (95% posterior credible interval: 2.33 - 3.83). As such, this national-level cohort study of England provides compelling evidence for a relationship between occupancy and critical care mortality, and highlights the needs for decisive action to control the incidence and prevalence of COVID-19.

C_TEXTBOX


title: Deep RNA Sequencing of Intensive Care Unit Patients with COVID-19

abstract:
PurposeCOVID-19 has impacted millions of patients across the world. Molecular testing occurring now identifies the presence of the virus at the sampling site: nasopharynx, nares, or oral cavity. RNA sequencing has the potential to establish both the presence of the virus and define the hosts response in COVID-19.

MethodsSingle center, prospective study of patients with COVID-19 admitted to the intensive care unit where deep RNA sequencing (>100 million reads) of peripheral blood with computational biology analysis was done. All patients had positive SARS-CoV-2 PCR. Clinical data was prospectively collected.

ResultsWe enrolled fifteen patients at a single hospital. Patients were critically ill with a mortality of 47% and 67% were on a ventilator. All the patients had the SARS-CoV-2 RNA identified in the blood in addition to RNA from other viruses, bacteria, and archaea. The expression of many immune modulating genes, including PD-L1 and PD-L2, were significantly different in patients who died from COVID-19. Some proteins were influenced by alternative transcription and splicing events, as seen in HLA-C, HLA-E, NRP1 and NRP2. Entropy calculated from alternative RNA splicing and transcription start/end predicted mortality in these patients.

ConclusionsCurrent upper respiratory tract testing for COVID-19 only determines if the virus is present. Deep RNA sequencing with appropriate computational biology may provide important prognostic information and point to therapeutic foci to be precisely targeted in future studies.

Take Home MessageDeep RNA sequencing provides a novel diagnostic tool for critically ill patients. Among ICU patients with COVID-19, RNA sequencings can identify gene expression, pathogens (including SARS-CoV-2), and can predict mortality.

TweetDeep RNA sequencing is a novel technology that can assist in the care of critically ill COVID-19 patients & can be applied to other disease


title: The Effect of Short Message Service (SMS)-Reminders on Child Health in Parents of Newborns: A Pilot Randomised Controlled Trial

abstract:
BackgroundIncomplete vaccination in Australia is greatly due to vaccine hesitancy, which is driven by multiple factors. Studies analysing the effect of behavioural  nudges on vaccine uptake have shown promising results. Although there is some evidence for positively framed SMS vaccine messages, evidence is lacking for loss-based framed messages which may be highly effective but may paradoxically risk increasing vaccine hesitancy. This pilot study aimed to evaluate the effect of loss-based framed SMS messages on vaccine hesitancy.

MethodsThis single-blinded randomised controlled trial enrolled pregnant women from antenatal clinics in King Edward Memorial Hospital, Perth, WA which delivers approximately 6000 higher-risk infants per year. Participants were randomised to receive either a loss-based framed SMS message warning of the risks of failure to vaccinate, or a sham SMS message unrelated to vaccination, and were asked to complete the short-scale vaccine hesitancy questionnaire before and after the intervention.

DiscussionThe application of behavioural sciences through SMS-reminders has the potential to improve vaccination rates. There are difficulties in engaging with parents of newborns about vaccine hesitancy. Further research is warranted using other approaches to recruitment.

HighlightsO_LIPilot randomised controlled trial on the use of SMS reminders to influence vaccine hesitancy
C_LIO_LIApplication of behavioural economics, nudge techniques and mobile health
C_LIO_LIVaccine hesitancy measured using the short-scale PACV questionnaire
C_LIO_LIThere are difficulties in engaging with parents of newborns about vaccine hesitancy
C_LIO_LIFurther research needed to optimise message framing, timing and reduce vaccine hesitancy
C_LI

Trial RegistrationThe trial is registered with the Australia and New Zealand Clinical Trials Register (ACTRN12618001510235).

category: allergy and immunology


title: Factors Influencing AVF Dysfunction in Patients with Maintenance Hemodialysis: A retrospective study

abstract:
ObjectiveTo explore factors influencing primary dysfunction of autologous arteriovenous fistula (AVF) in patients with maintenance hemodialysis (MHD).

MethodsThis is a retrospectively study. One hundred and twenty-one patients who underwent anastomosis for AVF in our hospital Between 1st January 2016 and 31st December 2018 were selected. Seventy-seven patients satisfied the inclusion criteria and were included in the final analyses. Patients were divided into two groups based on the function of vascular access. The comparisons of complete blood count and other blood biochemical parameters were made between two groups. Factors influencing AVF dysfunction were analyzed by multivariate Cox proportional hazard regression model for patients with End stage renal disease (ESRD).

ResultsThere were significant differences in total cholesterol (TC), low density lipoprotein (LDL) and serum phosphorus levels between patency and dysfunction group (P<0.05) of AVFs. Further multivariate COX proportional risk regression showed that hypercholesterolemia and hyperphosphatemia were independent risk factors for AVF dysfunction.

ConclusionsHypercholesterolemia and hyperphosphatemia are independent risk factors for primary AVF dysfunction in patients with MHD.


title: Evidence for Causal Effects of Smoking Initiation and Alcohol Consumption on Substance Use Outcomes

abstract:
Background and AimsInitial use of drugs such as tobacco and alcohol may lead to subsequent more problematic drug use - the  gateway hypothesis. However, observed associations may be due to a shared underlying risk factor, such as trait impulsivity. We used bidirectional Mendelian Randomisation (MR) to test the gateway hypothesis.

DesignOur main method was inverse-variance weighted (IVW) MR, with other methods included as sensitivity analyses (where consistent results across methods would raise confidence in our primary results). MR is a genetic instrumental variable approach used to support stronger causal inference in observational studies.

SettingEuropean ancestry individuals.

ParticipantsGenome-wide association summary data for smoking initiation, alcoholic drinks per week, cannabis use and dependence, cocaine and opioid dependence (N=1,749 to 1,232,091).

MeasurementsGenetic variants for exposure.

FindingsWe found evidence of causal effects from smoking initiation to increased drinks per week (IVW: {beta}=0.06; 95% CI=0.03 to 0.09; p=9.44x10-06), cannabis use (IVW: OR=1.34; 95% CI=1.24 to 1.44; p=1.95x10-14), and cannabis dependence (IVW: OR=1.68; 95% CI=1.12 to 2.51; p=0.01). We also found evidence of an effect of cannabis use on increased likelihood of smoking initiation (IVW: OR=1.39; 95% CI=1.08 to 1.80; p=0.01). We did not find evidence of an effect of drinks per week on other substance use outcomes, except weak evidence of an effect on cannabis use. We found weak evidence of an effect of opioid dependence on increased drinks per week (IVW: {beta}=0.002; 95% CI=0.0005 to 0.003; p=8.61x10-03).

ConclusionsSmoking initiation may lead to increased alcohol consumption, cannabis use and dependence. Cannabis use may also lead to smoking initiation, and opioid dependence to alcohol consumption. However, given tobacco and alcohol use typically begin before other drug use, these results may reflect a shared risk factor, or a bidirectional effect for cannabis use. Further research should explore potentially shared risk factors.


title: Using Mendelian randomisation to explore the gateway hypothesis: Possible causal effects of smoking initiation and alcohol consumption on substance use outcomes