title: UV-A and UV-B Can Neutralize SARS-CoV-2 Infectivity

abstract:
We performed an in-depth analysis of the virucidal effect of discrete wavelengths: UV-C (278 nm), UV-B (308 nm), UV-A (366 nm) and violet (405 nm) on SARS-CoV-2. By using a highly infectious titer of SARS-CoV-2 we observed that the violet light-dose resulting in a 2-log viral inactivation is only 10-4 times less efficient than UV-C light. Moreover, by qPCR and fluorescence in situ hybridization (FISH) approach we verified that the viral titer typically found in the sputum of COVID-19 patients can be completely inactivated by the long UV-wavelengths corresponding to UV-A and UV-B solar irradiation. The comparison of the UV action spectrum on SARS-CoV-2 to previous results obtained on other pathogens suggests that RNA viruses might be particularly sensitive to long UV wavelengths. Our data extend previous results showing that SARS-CoV-2 is highly susceptible to UV light and offer an explanation to the reduced incidence of SARS-CoV-2 infection seen in the summer season.

SYNOPSISUV-A, UV-B and violet wavelengths kill SARS-CoV-2, supporting the sterilizing effects of the solar pump on human pathogens and the explanation of the seasonality of the COVID-19 pandemic.


title: Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic

abstract:
IntroductionThis observational study looked at 255 COVID19 patients who required invasive mechanical ventilation (IMV) during the first two months of the US pandemic. Through comprehensive, longitudinal evaluation and new consideration of all the data, we were able to better describe and understand factors affecting outcome after intubation.

MethodsAll vital signs, laboratory values, and medication administrations (time, date, dose, and route) were collected and organized. Further, each patients prior medical records, including PBM data and available ECG, were reviewed by a physician. These data were incorporated into time-series database for statistical analysis.

ResultsBy discharge or Day 90, 78.2% of the cohort expired. The most common pre-existing conditions were hypertension, (63.5%), diabetes (59.2%) and obesity (50.4%). Age correlated with death. Comorbidities and clinical status on presentation were not predictive of outcome. Admission markers of inflammation were universally elevated (>96%). The cohorts weight range was nearly 7-fold. Causal modeling establishes that weight-adjusted HCQ and AZM therapy improves survival by over 100%. QTc prolongation did not correlate with cumulative HCQ dose or HCQ serum levels.

DiscussionThis detailed approach gives us better understanding of risk factors, prognostic indicators, and outcomes of Covid patients needing IMV. Few variables were related to outcome. By considering more factors and using new methods, we found that when increased doses of co-administered HCQ and AZM were associated with >100% increase in survival. Comparison of absolute with weight-adjusted cumulative doses proves administration [≥]80 mg/kg of HCQ with > 1 gm AZM increases survival in IMV-requiring Covid patients by over 100%. According to our data, HCQ is not associated with prolongation. Studies, which reported QTc prolongation secondary to HCQ, need to be re-evaluated more stringently and with controls.

The weight ranges of Covid patient cohorts are substantially greater than those of most antibiotic RCTs. Future clinical trials need to consider the weight variance of hospitalized Covid patients and need to study therapeutics more thoughtfully.

category: pharmacology and therapeutics


title: Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation

abstract:
BackgroundSchizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients.

MethodsWe tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n=1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n=1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers.

ResultsWe report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA) as well as increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol species and the expression of inflammasome system elements in SMI.

ConclusionsBased on these results, we suggest a link between systemic inflammasome activation/dysregulation and cholesterol load in SMI. Our findings further the understanding of possible underlying inflammatory and metabolic mechanisms and may expose important therapeutic targets in SMI.

category: psychiatry and clinical psychology


title: Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

abstract: The prevalence of Alzheimers disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) is higher among patients with somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie these observed comorbidities. We investigated genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise genetic correlations using the summary statistics of the largest available genome-wide association studies for these diseases. Stratified covariance analyses were performed to investigate the contribution of insulin-related gene-sets. Having tested these hypotheses, novel brain "insulinopathies" were explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Significant genetic correlations were found between OCD and MetS (rg=-0.315, p=3.9e-8), OCD and obesity (rg=-0.379, p=3.4e-5), and OCD and T2DM (rg=-0.172, p=3e-4). Stratified analyses showed negative genetic covariances between ASD and MetS/T2DM through gene-sets comprising insulin signalling and/or insulin processing genes, and between AD/OCD and MetS/T2DM through an insulin receptor recycling gene-set (p<6.17e-4). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa, attention-deficit/hyperactivity disorder, major depression, and schizophrenia (p<6.17e-4). Our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases and traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on "insulinopathies" of the brain, which may support the development of more effective/tolerated treatment strategies for neuropsychiatric disorders.

category: genetic and genomic medicine


title: The UGT2A1/UGT2A2 locus is associated with COVID-19-related anosmia

abstract: Loss of sense of smell is a characteristic symptom of infection with SARS-CoV-2. However, specific mechanisms linking infection with loss of smell are poorly understood. Using self-reported symptom data from the 23andMe COVID-19 study, we describe the demographic patterns associated with COVID-19 related anosmia, and find the symptom is more often reported in women and younger respondents, and less often by those of East Asian and African American ancestry compared to those of European ancestry. We ran a trans-ethnic genome-wide association study (GWAS) comparing loss of smell or taste (n=47,298) with no loss of smell or taste (n=22,543) among those with a positive SARS-CoV-2 test result. We identified an association (rs7688383) in the vicinity of the UGT2A1 and UGT2A2 genes (OR=1.115, p-value=4x10-15), which have been linked to olfactory function. These results may shed light on the biological mechanisms underlying COVID-19 related anosmia.


title: Temporal stability and detection sensitivity of the dry swab-based diagnosis of SARS-CoV-2

abstract: The rapid spread and evolution of various strains of SARS-CoV-2, the virus responsible for COVID-19, continues to challenge the disease controlling measures globally. Alarming concern is, the number of second wave infections surpassed the first wave and the onset of severe symptoms manifesting rapidly. In this scenario, testing of maximum population in less time and minimum cost with existing diagnostic amenities is the only possible way to control the spread of the virus. The previously described RNA extraction-free methods using dry swab have been shown to be advantageous in these critical times by different studies. In this work, we show the temporal stability and performance of the dry swab viral detection method at two different temperatures. Contrived dry swabs holding serially diluted SARS-CoV-2 strains A2a and A3i at 25{degrees}C (room temperature; RT) and 4{degrees}C were subjected to direct RT-PCR and compared with standard VTM-RNA based method. The results clearly indicate that dry swab method of RNA detection is as efficient as VTM-RNA-based method in both strains, when checked for up to 72 hours. The lesser CT values of dry swab samples in comparison to that of the VTM-RNA samples suggest better sensitivity of the method within 48 hours of time. The results collectively suggest that dry swab samples are stable at RT for 24 hours and the detection of SARS-CoV-2 RNA by RT-PCR do not show variance from VTM-RNA. This extraction free, direct RT-PCR method holds phenomenal standing in the present life-threatening circumstances due to SARS-CoV-2.

category: infectious diseases


title: Mendelian randomization analyses show that higher acetyl-carnitine and carnitine levels in blood protect against severe Covid19

abstract:
BackgroundSevere Covid19 is characterised by a hyperactive immune response. Carnitine, an essential nutrient, and its derivative acetyl-carnitine can downregulate proinflammatory cytokines and has been suggested as a potential treatment for the disease.

MethodsWe carried out Mendelian randomization analyses using publicly available data from a large genome wide association study (GWAS) of metabolites and a collaborative genome wide study of Covid19 to investigate the nature of the relationship between carnitine and acetyl-carnitine and Covid19 infection, hospitalisation with Covid19 and very severe Covid19. We used the same methodology to determine whether carnitine was associated with co-morbidities commonly found among those with severe Covid19.

ResultsWe found evidence of a protective effect against very severe Covid19 for both carnitine and acetyl-carnitine, with around a 40% reduction in risk associated with a doubling of carnitine or acetyl-carnitine (carnitine odds ratio (OR) = 0.56, 95% confidence intervals (CI) 0.33 to 0.95, p=0.03 and acetyl-carnitine OR=0.60, 95% CI 0.35 to 1.02, p=0.06), and evidence of protective effects on hopitalisation with Covid19. For acetyl-carnitine the largest protective effect was seen in the comparison between those hospitalised with Covid19 and those infected but not hospitalised (OR=0.34, 95%CI 0.18 to 0.62, p=0.0005).

ConclusionCarnitine and acetyl-carnitine merit further investigation in respect to the prevention of severe Covid19.

category: epidemiology


title: Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19, A double-blind, randomized placebo-controlled trial.

abstract:
BackgroundIvermectin, an anti-parasitic agent, also has anti-viral properties. Our aim was to assess whether ivermectin can shorten the viral shedding in patients at an early-stage of COVID-19 infection.

MethodsThe double-blinded trial compared patients receiving ivermectin 0{middle dot}2 mg/kg for 3 days vs. placebo in non-hospitalized COVID-19 patients. RT-PCR from a nasopharyngeal swab was obtained at recruitment and then every two days. Primary endpoint was reduction of viral-load on the 6th day (third day after termination of treatment) as reflected by Ct level>30 (non-infectious level). The primary outcome was supported by determination of viral culture viability.

ResultsEighty-nine patients were eligible (47 in ivermectin and 42 in placebo arm). Their median age was 35 years. Females accounted for 21{middle dot}6%, and 16{middle dot}8% were asymptomatic at recruitment. Median time from symptom onset was 4 days. There were no statistical differences in these parameters between the two groups.

On day 6, 34 out of 47 (72%) patients in the ivermectin arm reached the endpoint, compared to 21/ 42 (50%) in the placebo arm (OR 2{middle dot}62; 95% CI: 1{middle dot}09-6{middle dot}31). In a multivariable logistic-regression model, the odds of a negative test at day 6 was 2.62 time higher in the ivermectin group (95% CI: 1{middle dot}06-6{middle dot}45). Cultures at days 2 to 6 were positive in 3/23 (13{middle dot}0%) of ivermectin samples vs. 14/29 (48{middle dot}2%) in the placebo group (p=0{middle dot}008).

ConclusionsThere were significantly lower viral loads and viable cultures in the ivermectin group, which could lead to shortening isolation time in these patients.

The study is registered at ClinicalTrials.gov NCT 044297411.


title: Antigenic minimalism of SARS-CoV-2 is linked to surges in COVID-19 community transmission and vaccine breakthrough infections

abstract: The raging COVID-19 pandemic in India and reports of "vaccine breakthrough infections" globally have raised alarm mandating the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed 1.57 million SARS-CoV-2 genomes from 187 countries/territories and performed whole-genome viral sequencing from 53 COVID-19 patients, including 20 vaccine breakthrough infections. We identified 89 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a three-month window. Deletions in the Spike protein N-terminal domain (NTD) are highly enriched for these  surge-associated mutations (Odds Ratio = 41.8, 95% CI: 6.36-1758, p-value = 7.7e-05). In the recent COVID-19 surge in India, an NTD deletion ({Delta}F157/R158) increased over 10-fold in prevalence from February 2021 (1.1%) to April 2021 (15%). During the recent surge in Chile, an NTD deletion ({Delta}246-253) increased rapidly over 30-fold in prevalence from January 2021 (0.86%) to April 2021 (33%). Strikingly, these simultaneously emerging deletions associated with surges in different parts of the world both occur at an antigenic supersite that is targeted by neutralizing antibodies. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences and identified deletions within this NTD antigenic supersite in a patient with vaccine breakthrough infection ({Delta}156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of Spike protein deletions throughout the pandemic and their association with case surges and vaccine breakthrough infections point to antigenic minimalism as an emerging evolutionary strategy for SARS-CoV-2 to evade immune responses. This study highlights the urgent need to sequence SARS-CoV-2 genomes at a larger scale globally and to mandate a public health policy for transparent reporting of relevant clinical annotations (e.g. vaccination status) in order to aid the development of comprehensive therapeutic strategies.


title: Policy and Effectiveness of Covid-19 Response

abstract: A comparative analysis of selected national jurisdictions with respect to Covid-19 policy response indicated that factors such as effective communications and effective targeted intervention in the environments of higher epidemiological risk can be the key factors in the overall effectiveness of the epidemiological response minimizing both the impact of the epidemics and disruptions in the life of the society.


title: Post-COVID assessment in a specialist clinical service: a 12-month, single-centre analysis of symptoms and healthcare needs in 1325 individuals.

abstract:
BackgroundComplications following SARS-CoV-2 infection require simultaneous characterisation and management to plan policy and health system responses. We describe the 12-month experience of the first UK dedicated Post-COVID clinical service to include both hospitalised and non-hospitalised patients.

MethodsIn a single-centre, observational analysis, we report outcomes for 1325 individuals assessed in the University College London Hospitals NHS Foundation Trust Post-COVID service between April 2020 and April 2021. Demography, symptoms, comorbidities, investigations, treatments, functional recovery, specialist referral and rehabilitation were compared by referral route ("post hospitalisation", PH; "non-hospitalised", NH; and "post emergency department", PED). Symptoms associated with poor recovery or inability to return to work full-time were assessed using multivariable logistic regression.

Findings1325 individuals were assessed (PH 547 [41.3%], PED 212 [16%], NH 566 [42.7%]. Compared with PH and PED groups, NH were younger (median 44.6 [35.6-52.8] vs 58.3 [47.0-67.7] and 48.5 [39.4-55.7] years), more likely to be female (68.2%, 43.0% and 59.9%), less likely to be from an ethnic minority (30.9%, 52.7% and 41.0%) and seen later after symptom onset (median [IQR]:194 [118-298], 69 [51-111] and 76 [55-128] days) (all p<0.0001). NH patients had similar rates of onward specialist referral as PH and PED groups (18.7%, 16.1% and 18.9%, p=0.452), and were more likely to require support for breathlessness (23.7%, 5.5% and 15.1%, p<0.001) and fatigue (17.8%, 4.8%, 8.0%, p<0.001). Hospitalised patients had higher rates of pulmonary emboli, persistent lung interstitial abnormalities, and other organ impairment. 716 (54.0%) individuals reported <75% of optimal health (median [IQR] 70% [55%-85%]). Overall, less than half of employed individuals felt able to return to work full-time at first assessment.

InterpretationSymptoms following SARS-CoV-2 infection were significant in both post- and non-hospitalised patients, with significant ongoing healthcare needs and utilisation. Trials of interventions and patient-centred pathways for diagnostic and treatment approaches are urgently required.

FundingUCLH/UCL BRC

Research in contextO_ST_ABSPrevious evidenceC_ST_ABSLong COVID and post-COVID syndrome were first identified in April 2020. We searched PubMed and medrxiv for articles published up to April 30th, 2021, using the keywords "long COVID", "post-COVID syndrome", "persistent symptoms", "hospitalised", "community" and "non-hospitalised". We identified 17 articles and 7 systematic reviews. Fifteen studies have considered symptoms, multi-organ or functional impairment but only one study to-date has considered all these variables in non-hospitalised COVID patients. No studies have compared symptom burden and management between non-hospitalised and hospitalised individuals as systematically assessed and managed in a dedicated post-COVID service.

Added value of this studyFor the first time, we report the baseline characteristics, investigation and outcomes of initial assessment of all eligible patients in a dedicated multi-professional post-COVID service, including 547 post-hospitalisation, 566 non-hospitalised and 212 patients discharged from emergency department. Despite relatively low comorbidity and risk factor burden in non-hospitalised patients, we show that both non-hospitalised and hospitalised patients presenting with persistent symptoms after SARS-CoV2 infection have high rates of functional impairment, specialist referral and rehabilitation, even 6-12 months after the acute infection. These real-world data will inform models of care during and beyond the pandemic.

Implications of all the available evidenceThe significant, long-lasting health and social consequences of SARS-CoV-2 infection are not confined to those who required hospitalisation. As with other long-term conditions, care of patients experiencing Long COVID or specific end-organ effects require consistent, integrated, patient-centred approaches to investigation and management. At public health and policy level, burden of post-COVID morbidity demands renewed focus on effective infection suppression for all age groups.


title: Forecasting COVID-19 Number of Cases by Implementing ARIMA and SARIMA with Grid Search in the United States

abstract: COVID-19 has surged in the United States since January 2020. Since then, social distancing and lockdown have helped many people to avoid infectious diseases. However, this did not help the upswing of the number of cases after the lockdown was finished. Modeling the infectious disease can help the health care providers and governors to plan ahead for obtain the needed resources. In this manner, precise short-term determining of the number of cases can be imperative to the healthcare system. Many models have been used since the pandemic has started. In this paper we will compare couple of time series models like Simple Moving Average, Exponentially Weighted Moving Average, Holt-Winters Double Exponential Smoothing Additive, ARIMA, and SARIMA. Two models that have been used to predict the number of cases are ARIMA and SARIMA. A grid search has been implemented to select the best combination of the parameters for both models. Results show that in the case of modeling, the Holt-Winters Double Exponential model outperforms Exponentially Weighted Moving Average and Simple Moving Average while forecasting ARIMA outperforms SARIMA.


title: Social support, social strain and declines in verbal memory: 16-year follow-up of the English Longitudinal Study of Ageing cohort

abstract:
ObjectiveEstimate differences in the rate of decline in verbal memory by levels of perceived relationship quality among community-dwelling adults.

ParticipantsIn the English Longitudinal Study of Ageing (ELSA), n = 10,109 participants aged 50-89 years were assessed at wave 1 (baseline: 2002-03) and followed-up over 16 years to wave 9 (2017-18).

MethodsVerbal memory was assessed biennially by tests of immediate and delayed word-recall. Positive and negative aspects of perceived relationship quality (social support and strain, respectively) were measured by relationship type (spouse; children; extended family members; friends). Random effects within-between (REWB) modelling was used to separate between- and within-person effects. Associations were estimated between levels of social support/strain and (i) baseline levels of memory (main effects), and (ii) the 2-year decline in memory (interaction with time).

ResultsLongitudinal associations were most prominent for men, specific to relationship type, and showed between-rather than within-person effects. Among men, higher spousal strain was associated with faster decline in memory ({beta}between-effectxtime = -0.043; 95% CI: -0.084, -0.002; p = 0.039), whilst greater support from children was associated with slower decline ({beta}between-effectxtime = 0.020; 95% CI: 0.002, 0.039; p = 0.033). Men with higher levels of strain from friends had lower baseline memory ({beta}between-effect = -0.382; 95% CI: -0.627, -0.137; p = 0.002) and showed faster decline ({beta}between-effectxtime = -0.047; 95% CI: -0.095, 0.000; p = 0.051).

ConclusionsDifferences between persons in levels of social support and social strain were modestly associated with the rate of memory decline, especially among men. Our findings can inform future research studies and intervention strategies designed to maximise the potential of social relations to promote healthy cognitive ageing.


title: Impact of vaccination and undetected cases on the COVID-19 pandemic dynamics in Qatar in 2021

abstract: The third COVID-19 pandemic wave in Qatar was simulated with the use of the generalized SIR-model and the accumulated number of cases reported by Johns Hopkins University for the period: April 25 - May 8, 2021. Comparison with the SIR-curves calculated before for the second wave showed that the effect of mass vaccination is not evident during 4 months after its onset in December 2020. Additional simulations have demonstrated that many COVID-19 cases are not detected. The real accumulated number of cases can exceed the laboratory-confirmed one more than 5 times. This fact drastically increases the probability of meeting an infectious person and the epidemic duration.


title: Effect of hypersensitivity pneumonitis guideline on pathologic diagnosis of interstitial pneumonia

abstract:
Hypersensitivity pneumonitis (HP) and interstitial pneumonia (IP) have several overlapping characteristics, and a high diagnostic concordance rate of HP is rarely obtained. New guideline, highly influenced by pathology, were devised for its diagnosis. We recently reported that the 2020 HP guideline may result in a possible overdiagnosis of fibrotic HP (fHP) through multidisciplinary discussion. Here, we attempted to investigate the impact of the 2020 HP guideline on the pathological diagnosis of cases previously diagnosed as IP. We classified 247 cases with fibrotic IP diagnoses sourced from 2014-2019 into three categories according to the 2020 HP guideline: typical, probable, and indeterminate HP. The original pathological diagnosis and categorization based on the 2020 HP guideline were compared. The clinical data including serum data and pulmonary function tests were compared among groups. The number of cases that changed to HP from an original diagnosis other than HP based on the guideline was 56 (23%). The clinical data of these cases bore a greater resemblance to cases diagnosed as indeterminate for HP than those diagnosed as typical or probable. The ratio of typical and probable HP to the total cases was significantly lower when using a transbronchial lung cryobiopsy (TBLC). Based on the new guideline, the pathological diagnosis of HP efficiently excluded HP cases but increased the rate of HP diagnosis for cases with fibrotic IP that may not suit an HP diagnosis. Thus, a TBLC may not be useful when imparting findings for fibrotic HP diagnosis using the new criteria.

Key messagesO_LIWhat is the key question? >
Does the 2020 HP Guideline improve pathological diagnosis?
C_LIO_LIWhat is the bottom line? >
By applying the new guideline, about 1/4 of the pathological diagnoses were changed from not chronic HP to probable or typical fHP, but most of the changed cases showed a clinical picture closer to not chronic HP.
C_LIO_LIWhy read on? >
To understand that simple application of the pathological criteria of the HP guideline may cause a misleading diagnosis.
C_LI

category: pathology


title: The effect of hypersensitivity pneumonitis guideline on pathologic diagnosis of interstitial pneumonia


title: Parental plans to vaccinate children for COVID-19 in New York City

abstract: Once COVID-19 vaccines are approved for children <12 years of age, high pediatric vaccination coverage will be needed to help minimize the public health threat from the SARS-CoV-2 epidemic. We conducted an online survey of 1,119 parents and caregivers of children [≤]12 years in New York City from March 9 to April 11, 2021. Among parents surveyed, 61.9% reported plans to vaccinate their youngest child for COVID-19, 14.8% said they do not plan to vaccinate their child and 23.3% were unsure. Female and non-Hispanic Black parents were least likely to report plans to vaccinate their children. Safety, effectiveness and perceptions that children do not need vaccination were the primary reasons for vaccine hesitancy/resistance. Parents who have or will vaccinate themselves were significantly more likely to report they would vaccinate their children. Efforts to increase awareness about vaccine safety and education about the importance of vaccinating children are needed.

category: pediatrics


title: Reward Processing in Children with Psychotic-like Experiences

abstract: Alterations to striatal reward pathways have been identified in individuals with psychosis. They are hypothesised to be a key mechanism that generate psychotic symptoms through the production of aberrant attribution of motivational salience and are proposed to result from accumulated childhood adversity and genetic risk, making the striatal system hyper-responsive to stress. However, few studies have examined whether children with psychotic-like experiences (PLEs) also exhibit these alterations, limiting our understanding of how differences in reward processing relate to hallucinations and delusional ideation in childhood. Consequently, we examined whether PLEs and PLE-related distress were associated with reward-related activation in the nucleus accumbens (NAcc). The sample consisted of children (N = 6,718) from the Adolescent Brain Cognitive Development (ABCD) study aged 9-10 years who had participated in the Monetary Incentive Delay (MID) task in functional MRI. We used robust mixed-effects linear regression models to investigate the relationship between PLEs and NAcc activation during the reward anticipation and reward outcome stages of the MID task. Analyses were adjusted for gender, household income, ethnicity, depressive symptoms, movement in the scanner, pubertal development, scanner ID, subject and family ID. There was no reliable association between PLEs and alterations to anticipation-related or outcome-related striatal reward processing. We discuss the implications for developmental models of psychosis and suggest a developmental delay model of how PLEs may arise at this stage of development.


title: Development of a Deep Learning Model for Early Alzheime's Disease Detection from Structural MRIs and External Validation on an Independent Cohort

abstract: Early diagnosis of Alzheimers disease plays a pivotal role in patient care and clinical trials. In this study, we have developed a new approach based on 3D deep convolutional neural networks to accurately differentiate mild Alzheimers disease dementia from mild cognitive impairment and cognitively normal individuals using structural MRIs. For comparison, we have built a reference model based on the volumes and thickness of previously reported brain regions that are known to be implicated in disease progression. We validate both models on an internal held-out cohort from The Alzheimers Disease Neuroimaging Initiative (ADNI) and on an external independent cohort from The National Alzheimers Coordinating Center (NACC). The deep-learning model is more accurate and significantly faster than the volume/thickness model. The model can also be used to forecast progression: subjects with mild cognitive impairment misclassified as having mild Alzheimers disease dementia by the model were faster to progress to dementia over time. An analysis of the features learned by the proposed model shows that it relies on a wide range of regions associated with Alzheimers disease. These findings suggest that deep neural networks can automatically learn to identify imaging biomarkers that are predictive of Alzheimers disease, and leverage them to achieve accurate early detection of the disease.

category: radiology and imaging


title: Replication of an open-access deep learning system for screening mammography: Reduced performance mitigated by retraining on local data

abstract:
AimTo assess the generalisability of a deep learning (DL) system for screening mammography developed at New York University (NYU), USA (1, 2) in a South Australian (SA) dataset.

Methods and MaterialsClients with pathology-proven lesions (n=3,160) and age-matched controls (n=3,240) were selected from women screened at BreastScreen SA from January 2010 to December 2016 (n clients=207,691) and split into training, validation and test subsets (70%, 15%, 15% respectively). The primary outcome was area under the curve (AUC), in the SA Test Set 1 (SATS1), differentiating invasive breast cancer or ductal carcinoma in situ (n=469) from age-matched controls (n=490) and benign lesions (n=44). The NYU system was tested statically, after training without transfer learning (TL), after retraining with TL and without (NYU1) and with (NYU2) heatmaps.

ResultsThe static NYU1 model AUCs in the NYU test set (NYTS) and SATS1 were 83.0%(95%CI=82.4%-83.6%)(2) and 75.8%(95%CI=72.6%-78.8%), respectively. Static NYU2 AUCs in the NYTS and SATS1 were 88.6%(95%CI=88.3%-88.9%)(2) and 84.5%(95%CI=81.9%-86.8%), respectively. Training of NYU1 and NYU2 without TL achieved AUCs in the SATS1 of 65.8% (95%CI=62.2%-69.1%) and 85.9%(95%CI=83.5%-88.2%), respectively. Retraining of NYU1 and NYU2 with TL resulted in AUCs of 82.4%(95%CI=79.7-84.9%) and 86.3%(95%CI=84.0-88.5%) respectively.

ConclusionWe did not fully reproduce the reported performance of NYU on a local dataset; local retraining with TL approximated this level of performance. Optimising models for local clinical environments may improve performance. The generalisation of DL systems to new environments may be challenging.

Key ContributionsIn this study, the original performance of deep learning models for screening mammography was reduced in an independent clinical population.

Deep learning (DL) systems for mammography require local testing and may benefit from local retraining.

An openly available DL system approximates human performance in an independent dataset.

There are multiple potential sources of reduced deep learning system performance when deployed to a new dataset and population.


title: Remote exposure to secondhand tobacco smoke is associated with lower exercise capacity through effects on oxygen pulse- a proxy of cardiac stroke volume

abstract:
BackgroundPast exposure to secondhand tobacco smoke (SHS) is associated with exercise limitation. Pulmonary factors including air trapping contribute to this limitation but the contribution of cardiovascular factors is unclear.

ObjectiveTo determine contribution of cardiovascular mechanisms to SHS-associated exercise limitation.

MethodsWe examined the cardiovascular responses to maximum effort exercise in 245 never-smokers with remote, prolonged occupational exposure to SHS and no known history of cardiovascular disease. We estimated the contribution of oxygen-pulse (proxy for cardiac stroke volume) and changes in systolic (SBP) and diastolic blood pressures (DBP) and heart rate (HR) towards exercise capacity, and examined whether the association of SHS with exercise capacity was mediated through these variables.

ResultsAt peak exercise (highest workload completed [WattsPeak]=156{+/-}46 watts [135{+/-}33 %predicted]), oxygen consumption (VO2Peak) and oxygen-pulse (O2-PulsePeak) were 1,557{+/-}476 mL/min (100{+/-}24 %predicted) and 11.0{+/-}3.0 mL/beat (116{+/-}25 %predicted), respectively, with 29% and 3% participants not achieving their predicted normal range. Oxygen saturation at peak exercise was 98{+/-}1% and remained >93% in all participants. Sixty-six percent showed hypertensive response to exercise. In models adjusted for covariates, WattsPeak was associated directly with O2-PulsePeak, HRPeak, and SBPPeak and inversely with SHS, air trapping (RV/TLC), and rise of SBP over workload (all P<0.01). Moreover, SHS exposure association with WattsPeak was substantially (41%) mediated through its effect on O2-PulsePeak (P<0.038). Although not statistically significant, a considerable proportion (36%) of air trapping effect on WattsPeak seemed to be mediated through O2-PulsePeak (P=0.078). The likelihood of having baseline respiratory symptoms (modified Medical Research Council score [≥]1) was associated with steeper rise in SBP over workload (P<0.01).

ConclusionIn a never-smoker population with remote exposure to SHS, abnormal escalation of afterload and an SHS-associated reduction in cardiac output contributed to lower exercise capacity.

Key messagesO_ST_ABSWhat is the key question?C_ST_ABSWhat are the cardiovascular health effects of past exposure to secondhand tobacco smoke in never-smokers? How do pulmonary and cardiovascular systems interact in this setting?

What is the bottom line?Healthy never-smokers with history of remote past exposure to secondhand tobacco smoke have an abnormal cardiovascular response to exercise, which is characterized by a stroke volume and thus an exercise capacity that are reduced proportional to their years of exposure to secondhand tobacco smoke.

Why read on?The abnormal cardiovascular response to exercise in this population reveals the presence of an occult or subclinical pathology that impairs the cardiopulmonary functional reserve and reduces the efficiency of bodys oxygen delivery machinery, which could be disadvantageous during the times of increased cardiopulmonary output demands as in physiological distress or disease.

category: respiratory medicine


title: Remote exposure to secondhand tobacco smoke is associated with lower exercise capacity through effects on oxygen pulse, a proxy of cardiac stroke volume


title: Association between individual and country-level socioeconomic factors and work participation in spondyloarthritis including psoriatic arthritis: analysis of the ASAS-perSpA study

abstract:
ObjectiveTo examine whether associations between socioeconomic factors and work outcomes in spondyloarthritis (SpA) differ across axial (axSpA), peripheral SpA (pSpA) and psoriatic arthritis (PsA), and whether associations for individual-level socioeconomic factors are modified by country-level factors.

MethodsPatients with a physician diagnosis of SpA within working age (18-65 years) were included. Associations between individual- (age, gender, education, marital status) and country-level factors (Human Development Index, Health Care Expenditure (HCE), Gross Domestic Product, percentage unemployed) with work outcomes (employment status, absenteeism, presenteeism) were assessed using multivariable mixed-effects models. Associations between individual factors and outcomes were compared according to SpA phenotypes and country-level factors using interaction terms.

ResultsA total of 3835 patients (mean age 42 years, 61% males) from 23 countries worldwide were included (66% axSpA, 10% pSpA, 23% PsA). Being employed was associated with gender (male vs. female OR 2.5; 95%CI 1.9-3.2), education (university vs. primary OR 3.7; 2.9-4.7), marital status (married vs. single OR 1.3; 1.04-1.6), and age in a non-linear manner. University (vs primary) education was associated with lower odds of absenteeism (OR 0.7; 0.5-0.96) and presenteeism (OR 0.5; 0.3-0.7). Associations were similar across SpA phenotypes. Higher HCE was associated with more favourable work outcomes, e.g., higher odds of employment (OR 2.5; 1.5-4.1). Gender discrepancy in odds of employment was greater in countries with lower socioeconomic development.

ConclusionHigher educational attainment and higher HCE were associated with more favourable work outcomes, independently of SpA phenotype. The disadvantageous effect of female gender on employment is particularly strong in countries with lower socioeconomic development.

category: rheumatology


title: IgG index and not serum 25-hydroxyvitamin D is associated with age at onset of multiple sclerosis.

abstract:
BackgroundVitamin D deficiency is associated with an increased risk of multiple sclerosis (MS). However, its effect on the age of disease onset remains unclear. This study examines the relationship between serum 25 hydroxyvitamin D (25(OH)D) levels and age of first symptom onset among recently diagnosed MS patients.

MethodSerum 25(OH)D was measured from forty MS patients sampled near disease onset. After correcting seasonal variability, a multivariable linear regression was used to examine associations to age at onset.

ResultsSerum 25(OH)D was not correlated with age at onset (P>0.5). However, CSF IgG index was lower among patients with later disease onset ({beta}=-5.35, P=0.028). Furthermore, we observed bias resulting from non-random distribution of sampling by season, which after correcting indicates a higher 25(OH)D level among patients sampled at relapse compared to remission, instead of lower as previously reported.

ConclusionIn summary, serum 25(OH)D was not associated with the age at onset.

category: neurology


title: A Randomised Crossover Trial: Exploring the Dose-Response effect Of Carbohydrate restriction on glycaemia in people with type 2 diabetes (D-ROC2)

abstract:
AimsThe role of carbohydrate restriction in the management of glycaemia in type 2 diabetes (T2D) has been a subject of immense debate and controversy partly due to low-carbohydrate trials being confounded by multiple factors including degree of calorie restriction, dietary protein content, and by no clear definition of a low-carbohydrate diet. The current study sought to provide insight into the relationship between carbohydrate restriction and glycaemia by testing the effect of varying doses of carbohydrate on continuous glucose concentrations within a range of intakes defined as low-carbohydrate while controlling for confounding factors.

MethodsThis was a randomised crossover trial in participants with T2D testing 5 different 6-day eucaloric, isocaloric dietary treatments with varying carbohydrate contents (10%, 15%, 20%, 25%, and 30% kcal). Diets were kept isocaloric by exchanging %kcal from carbohydrate with predominantly unsaturated fat, keeping protein constant at 15% kcal. Daily self-weighing was employed to ensure participants maintained their weight throughout each treatment arm. Between dietary treatments, participants underwent a washout period of at least 7 days and were advised to maintain their habitual diet. Glycemic control was assessed using a continuous glucose monitoring device that was placed while the participant was on their normal diet, and was worn for the 6 days of each treatment.

Results12 participants completed the study. There were no differences in 24-hour and postprandial sensor glucose concentrations between the 30%kcal and 10%kcal doses (7.4 {+/-} 1.1mmol/L vs 7.6 {+/-} 1.4mmol/L (P=0.28) and 8.0 {+/-} 1.4mmol/L vs 8.3 {+/-} 1.3mmol/L (P=0.28) respectively). In our exploratory analyses we did not find any dose-response relationship between carbohydrate intake and glycaemia. A small amount of weight loss occurred in each treatment arm (range: 0.4 to 1.1kg over the 6 days) but adjusting for these differences did not influence the primary or secondary outcomes.

ConclusionsModest changes in dietary carbohydrate content in the absence of weight loss while keeping dietary protein intake constant do not appear to influence glucose concentrations in people with T2D.

Trial RegistrationISRCTN 11067343.

category: nutrition


title: High concordance of 70-gene recurrence risk signature and 80-gene molecular subtyping signature between core needle biopsy and surgical resection specimen in early-stage breast cancer

abstract:
IntroductionWith an increase in neoadjuvant therapy recommendations for most early-stage breast cancer patients due to the COVID-19 pandemic, it has become increasingly imperative to ensure that molecular diagnostic assays provide reliable results from preoperative core needle biopsies. Therefore, the objective of this study was to determine the concordance of MammaPrint results (70-gene signature) and BluePrint results (80-gene signature) between core needle biopsies (CNB) and surgical resection (SR) specimens using prospectively collected matched tissues from patients enrolled in the FLEX trial (NCT03053193).

MethodsWe analyzed 113 matched CNB and SR tumor specimens from women with early-stage breast cancer enrolled in the FLEX trial. Each patient enrolled in the trial receives a MammaPrint recurrence risk classification test with or without BluePrint molecular subtyping. Concordance of MammaPrint is reported using overall percentage agreement, positive predictive value (PPV, High Risk), negative predictive value (NPV, Low Risk), and Cohens kappa coefficient. Additionally, correlations between sample types are reported using Pearson correlation coefficient.

ResultsWe found good concordance for MammaPrint results between CNB and SR tumor samples (90.3%, {kappa} = 0.803), with a 95.1% NPV and 84.6% PPV. There was also a strong correlation of MammaPrint indices between CNB and SR specimens (r = 0.94). In addition to our primary objective, we determined the concordance of BluePrint subtyping in the matched tumor samples, and found excellent concordance (98.2%) and strong correlation of BluePrint scores within each subtype.

ConclusionCNB samples demonstrated overall high concordance with paired SR samples for MammaPrint risk classification, ensuring that physicians are provided with accurate prognostic information for therapy decisions based on testing of core biopsy tissue. Further, BluePrint molecular subtyping also had good concordance between the sample types, outperforming concordance rates based on traditional IHC based classification. Overall, with an increase in neoadjuvant therapy, physicans and patients can be assured that MammaPrint and BluePrint provide reliable results that guide timely and appropriate therapies using preoperative CNB specimens.

category: oncology


title: High concordance of 70-gene recurrence risk signature and 80-gene molecular subtyping signature between core needle biopsy and surgical resection specimens in early-stage breast cancer


title: High Speed Photographic Detection of Particle Distribution During Aerosol and Smoke Generating Surgical Procedures: Effects of Surgical Site Evacuation

abstract:
ObjectiveDetermine the effectiveness of evacuation systems designed to clear bioaerosols and smoke from the surgical field.

Study designHigh-speed photographic evaluation of aerosol and smoke generated in simulated surgical fields.

Materials and methodsSurgical site aerosol clearance was evaluated using a model of the anterior neck and prototypes for surgical site evacuator ports created using 3D printing. A commercially available electrocautery handpiece fitted with an evacuator was tested on animal tissue for smoke clearance. Both systems were connected to a commercial vacuum powered evacuation system. High speed photography was used to record videos of the aerosols and plumes. Fields were recorded with and without evacuation.

ResultsEfficient aerosol clearance from an open surgical field using an evacuator port is dependent upon the port design, airflow velocity, and placement relative to the aerosol generating site. The size and surface geometry of the surgical field are also important.

Surgical smoke generated with electrocautery is cleared from the field by the evacuation enclosure around the handpiece, even at high electrocautery power settings. Except for device noise, there appears to be no reason for using evacuator flow rates below the maximum setting.

ConclusionsBioaerosol and smoke generated during surgery are potential sources of respiratory pathogens and pose a threat to operating room personnel. Surgical site evacuation can significantly reduce the volume of airborne particles in the field but requires careful design and deployment considerations.x

category: otolaryngology


title: Health expenditure among the outpatient of type-2 diabetes in selected hospital of Kathmandu district: A cross-sectional study

abstract:
IntroductionOut of Pocket (OOP) expenditure is the dominant financing mechanism in the low and middle-income countries. In these countries the prevalence of diabetes has been rising more rapidly which can lead to various micro-vascular complications thus increasing the risk of dying prematurely.

MethodsA cross-sectional - comparative and hospital-based study was carried out in which OOP expenditure of diabetic patient treating in public and private hospital was compared. A total of 154 diabetic patients i.e.77 in each type of hospitals were selected purposively in consultation with attending physician and staffs. Face to face interview was done to diabetic patient with a minimum of one year of illness using structured questionnaire. Lorentz curve and concentration curve were prepared using income and expenditure of the patients.

ResultAmong154 patients, 97.4% patients had paid out of pocket for the treatment of diabetes. Mean direct cost per month was NRs. 7312.17 in public and NRs. 10125.31 in private hospital. Direct medical cost had higher share in total direct cost i.e. 60.5% in public and 69.3 % in private hospital. Medicine cost had higher percentage share (50.9%) in public hospital and laboratory cost had higher percentage share (68%) in private hospital.

ConclusionDirect medical cost was higher in private hospital as compared to public hospital. All the income groups have to pay similar amount of money for the treatment i.e. economic burden for the treatment of disease was found higher for the poor people as there was not any financial protection mechanism.

category: health economics


title: Progression of COVID19 Pandemic in India: A Concurrent Linear Regression Analysis Approach

abstract: This paper uses concurrent linear regression analysis approach to describe the progression of COVID 19 pandemic in India during the period 15 March 2020 through 15 May 2021. The approach provides very good fit to the daily reported new confirmed cases of the disease. The paper suggests that, based on the parameter of the model, an early warning system may be developed and institutionalised to undertaken necessary measures to control the spread of the disease, thereby controlling the pandemic.

category: health informatics


title: The Digital Analytic Patient Reviewer (DAPR) for COVID-19 Data Mart Validation

abstract:
ObjectiveTo provide high-quality data for COVID-19 research, we validated COVID-19 clinical indicators and 22 associated computed phenotypes, which were derived by machine learning algorithms, in the Mass General Brigham (MGB) COVID-19 Data Mart.

Materials and MethodsFifteen reviewers performed a manual chart review for 150 COVID-19 positive patients in the data mart. To support rapid chart review for a wide range of target data, we offered the Digital Analytic Patient Reviewer (DAPR). DAPR is a web-based chart review tool that integrates patient notes and provides note search functionalities and a patient-specific summary view linked with relevant notes. Within DAPR, we developed a COVID-19 validation task-oriented view and information extraction logic, enabled fast access to data, and considered privacy and security issues.

ResultsThe concepts for COVID-19 positive cohort, COVID-19 index date, COVID-19 related admission, and the admission date were shown to have high values in all evaluation metrics. For phenotypes, the overall specificities, PPVs, and NPVs were high. However, sensitivities were relatively low. Based on these results, we removed 3 phenotypes from our data mart. In the survey about using the tool, participants expressed positive attitudes towards using DAPR for chart review. They assessed the validation was easy and DAPR helped find relevant information. Some validation difficulties were also discussed.

Discussion and ConclusionDAPRs patient summary view accelerated the validation process. We are in the process of automating the workflow to use DAPR for chart reviews. Moreover, we will extend its use case to other domains.


title: The COVID-19 pandemic shifted the Veterans Affairs System toward being a payer and virtual care provider: is it sustainable?

abstract:
Structured AbstractO_ST_ABSObjectiveC_ST_ABSTo examine how VA shifted care delivery methods one year into the pandemic.

Study SettingAll encounters paid or provided by VA between January 1, 2019 and February 27, 2021.

Study DesignWe aggregated all VA paid or provided encounters and classified them into community (non-VA) acute and non-acute visits, VA acute and non-acute visits, and VA virtual visits. We then compared the number of encounters by week over time to pre-pandemic levels.

Data Extraction MethodsAggregation of administrative VA claims and health records.

Principal FindingsVA has experienced a dramatic and persistent shift to providing virtual care and purchasing care from non-VA providers. Before the pandemic, a majority (63%) of VA care was provided in-person at a VA facility. One year into the pandemic, in-person care at VAs constituted just 33% of all visits. Most of the difference made up by large expansions of virtual care; total VA provided visits (in person and virtual) declined (4.9 million to 4.2 million) while total visits of all types declined only 3.5%. Community provided visits exceeded prepandemic levels (2.3 million to 2.9 million, +26%).

ConclusionUnlike private health care, VA has resumed in-person care slowly at its own facilities, and more rapidly in purchased care with different financial incentives a likely driver. The very large expansion of virtual care nearly made up the difference. With a widespread physical presence across the U.S., this has important implications for access to care and future allocation of medical personnel, facilities, and resources.

category: health policy


title: Detection of Human Papillomaviruses DNA in paired peripheral blood and cervix samples patients with cervical lesions and healthy individuals

abstract: This study evaluated the presence of HPV DNA in the cervix and peripheral blood of women with cervical intraepithelial neoplasia (CIN I, II, and III) and healthy individuals. Overall, 139 paired peripheral blood and cervix samples of healthy women and women with CIN I, II, and III (n= 68) were tested for HPV DNA by using standard procedures. PCR-sequencing determined HPV types. Quantification of HPV16 E6 and E2 genes was performed to determine viral load and physical state. HPV DNA was detected in the cervix (21.1% in healthy individuals; 48.8-55.5% in CIN patients), blood (46.4% in healthy individuals; 44.1-77.7% in CIN patients), and paired peripheral blood and cervix samples (24% in healthy individuals; 32.5-44.4% in CIN patients). The most frequent types found in the cervix were HPV16, 18, 31, 33, 58, and 70, while HPV16, 18, 33, 58, and 66 were the most frequent types found in the blood. HPV DNA in the cervix was associated with previous sexually transmitted infections (STIs) (P=0.023; OR: 2.978; CI:1.34-7.821), HPV DNA in the blood (P=0.000; OR: 3.369; CI:3.700-18.540), and cervical lesions (CIN I/II or III) (P=0.001; OR: 3.369; CI:1.634-6.945). Binomial Logistic regression showed that HPV DNA in the blood (P=0.000; OR: 9.324; CI:3.612-24.072) and cervical lesions (P=0.011; OR: 3.622; CI:1.338-9.806) were associated with HPV DNA in the cervix. However, we did not find an association between HPV DNA in blood and cervical lesions (P=0.385). Our results showed that, although there is an association between HPV DNA in the cervix with HPV DNA in blood, only HPV DNA found in the cervix was associated with cervical lesions.


title: A one-step real-time RT-PCR assay for simultaneous typing of SARS-CoV-2 mutations associated with the E484K and N501Y spike protein amino-acid substitutions

abstract: The emergence of SARS-CoV-2 mutations resulting in the S protein amino-acid substitutions N501Y and E484K, which have been associated with enhanced transmissibility and immune escape, respectively, necessitates immediate actions, for which their rapid identification is crucial. For the simultaneous typing of both of these mutations of concern (MOCs), a one-step real-time RT-PCR assay employing four locked nucleic acid (LNA) modified TaqMan probes was developed. The assay is highly sensitive with a LOD of 117 copies/reaction, amplification efficiencies >94% and a linear range of over 5 log10 copies/reaction. Validation of the assay using known SARS-CoV-2-positive and negative samples from human and animals revealed its ability to correctly identify wild type strains, and strains possessing either one or both targeted amino-acid substitutions, thus comprising a useful pre-screening tool for rapid MOC identification. The basic principles of the methodology for the development of the assay are explained in order to facilitate the rapid design of similar assays able to detect emerging MOCs.


title: Aerosol SARS-CoV-2 in hospitals and long-term care homes during the COVID-19 pandemic.

abstract:
BackgroundFew studies have quantified aerosol concentrations of SARS-CoV-2 in hospitals and long-term care homes, and fewer still have examined samples for viability. This information is needed to clarify transmission risks beyond close contact.

MethodsWe deployed particulate air samplers in rooms with COVID-19 positive patients in hospital ward and ICU rooms, rooms in long-term care homes experiencing outbreaks, and a correctional facility experiencing an outbreak. Samplers were placed between 2 and 3 meters from the patient. Aerosol (small liquid particles suspended in air) samples were collected onto gelatin filters by Ultrasonic Personal Air Samplers (UPAS) fitted with <2.5{micro}m (micrometer) and <10 {micro}m size-selective inlets operated for 16 hours (total 1.92m3), and with a Coriolis Biosampler over 10 minutes (total 1.5m3). Samples were assayed for viable SARS-CoV-2 virus and for the viral genome by multiplex PCR using the E and N protein target sequences. We validated the sampling methods by inoculating gelatin filters with viable vesicular stomatitis virus (VSV), and with three concentrations of viable SARS-CoV-2, operating personal samplers for 16hrs, and quantifying viable virus recovery by TCID50 assay.

ResultsIn total, 138 samples were collected from 99 rooms. RNA samples were positive in 9.1% (6/66) of samples obtained with the UPAS 2.5{micro}m samplers, 13.5% (7/52) with the UPAS 10{micro}m samplers, and 10.0% (2/20) samples obtained with the Coriolis samplers. Culturable virus was not recovered in any samples. Viral RNA was detected in 10.9% of the rooms sampled. There was no significant difference in viral RNA recovery between the different room locations or samplers. Method development experiments indicated minimal loss of SARS-CoV-2 viability via the personal air sampler operation.

Key FindingsAlthough a subset of aerosol samples exhibited detectable SARS-CoV-2 RNA at low titres, the presence of viable SARS-CoV-2 virus in aerosols appears to be infrequent at >2m distance.


title: Emerging SARS-CoV-2 variants of concern evade humoral immune responses from infection and vaccination

abstract: Emerging SARS-CoV-2 variants pose a threat to human immunity induced by natural infection and vaccination. We assessed the recognition of three variants of concern (B.1.1.7, B.1.351 and P.1) in cohorts of COVID-19 patients ranging in disease severity (n = 69) and recipients of the Pfizer/BioNTech vaccine (n = 50). Spike binding and neutralization against all three VOC was substantially reduced in the majority of samples, with the largest 4-7-fold reduction in neutralization being observed against B.1.351. While hospitalized COVID-19 patients and vaccinees maintained sufficient neutralizing titers against all three VOC, 39% of non-hospitalized patients did not neutralize B.1.351. Moreover, monoclonal neutralizing antibodies (NAbs) show sharp reductions in their binding kinetics and neutralizing potential to B.1.351 and P.1, but not to B.1.1.7. These data have implications for the degree to which pre-existing immunity can protect against subsequent infection with VOC and informs policy makers of susceptibility to globally circulating SARS-CoV-2 VOC.


title: Safety and immunogenicity of a recombinant DNA COVID-19 vaccine containing the coding regions of the spike and nucleocapsid proteins: Preliminary results from an open-label, phase 1 trial in healthy adults aged 19-55 years

abstract:
BackgroundWe investigated the safety and immunogenicity of two recombinant COVID-19 DNA vaccine candidates in first-in-human trials. GX-19 contains plasmid DNA encoding SARS-CoV-2 spike protein, and GX-19N contains plasmid DNA encoding SARS-CoV-2 receptor binding domain (RBD) foldon and nucleocapsid protein (NP) as well as plasmid DNA encoding SARS-CoV-2 spike protein.

MethodsTwo open-label phase 1 trials of GX-19 and GX-19N safety and immunogenicity were performed in healthy adults aged 19-55 years. GX-19 trial participants received two vaccine injections (1{middle dot}5 mg or 3{middle dot}0 mg, 1:1 ratio) four weeks apart. GX-19N trial participants received two 3{middle dot}0 mg vaccine injections four weeks apart.

FindingsBetween June 17 and July 30 and December 28 and 31, 2020, 40 and 21 participants were enrolled in the GX-19 and GX-19N trials, respectively. Thirty-two participants (52{middle dot}5%) reported 80 treatment-emergent adverse events (AE) after vaccination. All solicited AEs were mild except one case of moderate fatigue reported in the 1{middle dot}5 mg GX-19 group. Binding antibody responses increased after vaccination in all groups. The geometric mean titers (GMTs) of spike-binding antibodies on day 57 were 85{middle dot}74, 144{middle dot}20, and 201{middle dot}59 in the 1{middle dot}5 mg, 3{middle dot}0 mg GX-19 groups and the 3{middle dot}0 mg GX-19N group, respectively. In GX-19N group, neutralizing antibody response (50% neutralizing titer using FRNT) significantly increased after vaccination, but GMT of neutralizing antibody on day 57 (37.26) was lower than those from human convalescent serum (288.78). GX-19N induced stronger T cell responses than GX-19. The magnitude of GX-19N-induced T cell responses was comparable to those observed in the convalescent PBMCs. GX-19N induced both SARS-CoV-2 spike- and NP-specific T cell responses, and the amino acid sequences of 15-mer peptides containing NP-specific T cell epitopes identified in GX-19N-vaccinated participants were identical with those of diverse SARS-CoV-2 variants

InterpretationGX-19N is safe, tolerated and induces humoral and broad SARS-CoV-2-specific T cell response which may enable cross-reactivity to emerging SARS-CoV-2 variants.

FundingThis research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HQ20C0016, Republic of Korea).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo overcome the COVID-19 outbreak, the development of safe and effective vaccines is crucial. Despite the successful clinical efficacy of the approved vaccines, concerns exist regarding emerging new SARS-CoV-2 variants that have mutated receptor binding domains in the spike protein. We searched PubMed for research articles published up to May 1, 2021, using various combinations of the terms "COVID-19" or "SARS-CoV-2", "vaccine", and "clinical trial". No language or data restrictions were applied. We also searched the ClinicalTrials.gov registry and World Health Organization (WHO) draft landscape of COVID-19 candidate vaccines for ongoing trials of COVID-19 vaccines up to May 1, 2021. Ten DNA-based vaccines, including the vaccine candidate reported here, are in ongoing clinical trials. Among these, safety and immunogenicity results were reported from only one phase 1 trial of a DNA vaccine against SARS-CoV-2 (INO-4800). INO-4800 demonstrated favorable safety and tolerability and was immunogenic, eliciting humoral and/or cellular immune responses in all vaccinated subjects. There is only one ongoing clinical trial of a vaccine against SARS-CoV-2 variants (mRNA-1273.351).

Added value of this studyThis is the first-in-human phase 1 trial in healthy adults of a recombinant DNA vaccine for COVID-19 (GX-19N) containing the coding regions of both the spike and nucleocapsid proteins. This trial showed that GX-19N is safe, tolerated, and able to induce both humoral and cellular responses. A two-dose vaccination of 3{middle dot}0 mg GX-19N (on days 1 and 29) induced significant humoral and cellular responses. The neutralizing geometric mean titers in individuals vaccinated with GX-19N were lower than those of human convalescent sera. However, the GX-19N group showed increased T cell responses, which was similar to those analyzed using convalescent PBMCs. Furthermore, GX-19N induced not only SARS-CoV-2 spike-specific T cell responses but also broad nucleocapsid-specific T cell responses, which were also specific to SARS-CoV-2 variants.

Implications of all the available evidenceIt is important to note that GX-19N contains a plasmid encoding both the spike and nucleocapsid proteins, and that it showed broad SARS-CoV-2-specific T cell responses, which may allow cross-reactivity with emerging SARS-CoV-2 variants. Based on these safety and immunogenicity findings, GX-19N was selected for phase 2 immunogenicity trials.


title: Use of respirator vs. surgical masks in healthcare personnel and its impact on SARS-CoV-2 acquisition: a prospective multicentre cohort study

abstract:
BackgroundThere is insufficient evidence regarding the role of respirators in the prevention of SARS-CoV-2 infection. We analysed the impact of filtering facepiece class 2 (FFP2) vs. surgical masks on the risk of SARS-CoV-2 acquisition among Swiss healthcare workers (HCW).

MethodsOur prospective multicentre cohort enrolled patient-facing HCWs from June to August 2020. Participants were asked about COVID-19 risk exposures/behaviours, including preferred mask type when caring for COVID-19 patients outside of aerosol-generating procedures (AGP). For those performing AGPs, we asked whether they used FFP2 irrespective of the patients COVID-19 status (i.e. universal use). The impact of FFP2 on i) self-reported SARS-CoV-2-positive nasopharyngeal PCR/rapid antigen tests captured during weekly surveys, and ii) SARS-CoV-2 seroconversion between baseline and January/February 2021 was assessed.

ResultsWe enrolled 3259 participants from nine healthcare institutions, whereof 716 (22%) preferentially used FFP2 respirators. Among these, 81/716 (11%) reported a SARS-CoV-2-positive swab, compared to 352/2543 (14%) surgical mask users (median follow-up 242 days); seroconversion was documented in 85/656 (13%) FFP2 and 426/2255 (19%) surgical mask users. Adjusted for baseline characteristics, COVID-19 exposure, and risk behaviour, FFP2 use was non-significantly associated with a decreased risk for SARS-CoV-2-positive swab (adjusted hazard ratio [aHR] 0{middle dot}8, 95% CI 0{middle dot}6-1{middle dot}0, p=0{middle dot}052) and seroconversion (adjusted odds ratio [aOR] 0{middle dot}7, 95% CI 0{middle dot}5-1{middle dot}0, p=0{middle dot}053); household exposure was the strongest risk factor (aHR for positive swab 10{middle dot}1, p<0{middle dot}001; aOR for seroconversion 5{middle dot}0, p<0{middle dot}001). In subgroup analysis, FFP2 use was clearly protective among those with frequent (>20 patients) COVID-19 exposure (aHR 0{middle dot}7, p<0{middle dot}001; aOR 0{middle dot}6, p=0{middle dot}035). Universal FFP2 use during AGPs showed no protective effect (aHR 1{middle dot}1, p=0{middle dot}7; aOR 0{middle dot}9, p=0{middle dot}53).

ConclusionRespirators compared to surgical masks may convey additional protection from SARS-CoV-2 for HCW with frequent exposure to COVID-19 patients.

FundingSwiss National Sciences Foundation, Federal Office of Public Health, Cantonal Health Department St.Gallen


title: SARS-CoV-2 infectious virus, viral RNA in nasopharyngeal swabs, and serostatus of symptomatic COVID-19 outpatients in the United States

abstract:
BackgroundWhile SARS-CoV-2 infectious virus isolation in outpatients with COVID-19 has been associated with viral RNA levels and symptom duration, little is known about the host, disease and viral determinants of infectious virus detection.

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

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

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

ClinicalTrials.gov IdentifierNCT04405570

Key Points (Summary)Among COVID-19 outpatients within 7 days of symptom onset, the presence of SARS-CoV-2-specific antibodies was strongly associated with clearance of infectious virus. Seropositivity appears to be more reliable marker of infectious virus clearance than subjective measure of COVID-19 symptoms.


title: Infectious SARS-CoV-2 Virus in Symptomatic COVID-19 Outpatients: Host, Disease, and Viral Correlates


title: Admission criteria in critically ill COVID-19 patients: a physiology-based approach.

abstract:
IntroductionThe COVID-19 pandemic required a careful management of intensive care unit (ICU) admissions, to reduce ICU overload while facing resources limitations. We implemented standardized, physiology-based, ICU admission criteria and analyzed the mortality rate of patients refused from the ICU.

Materials and MethodsCOVID-19 patients proposed for ICU admission were consecutively analyzed; Do-not-resuscitate patients were excluded. Patients presenting a SpO2 lower than 85% and/or dyspnea and/or mental confusion resulted eligible for ICU admission; patients not presenting these criteria remained in the ward with an intensive monitoring protocol. Primary outcome was both groups survival rate. Secondary outcome was a sub analysis correlating SpO2 cutoff with ICU admission.

ResultsFrom March 2020 to January 2021, 1623 patients were admitted to our Center; 208 DNR patients were excluded; 97 patients underwent intensivist evaluation. The ICU-admitted group mortality rate resulted 15.9% at 28 days and 27% at 40 days; the ICU-refused group mortality rate resulted 0% at both intervals (p < 0.001). With a SpO2 cut-off of 92%, the hypoxia rate distribution did not correlate with ICU admission (p = 0.26); with a SpO2 cut-off of 85%, a correlation was found (p = 0.009). A similar correlation was also found with dyspnea (p =0.0002).

ConclusionIn COVID-19 patients, standardized ICU admission criteria appeared to reduce safely ICU overload. In the absence of dyspnea and/or confusion, a SpO2 cutoff up to 85% for ICU admission was not burdened by negative outcomes. In a pandemic context, the SpO2 cutoff of 92%, as a threshold for ICU admission, needs critical re-evaluation.

category: intensive care and critical care medicine


title: Overexpression of long non coding RNA OR3A4 is associated with altered p38 signalling, morphological and phenotypic changes, and reduced immunogenicity in Barretts Oesophagus

abstract:
BackgroundBarretts Oesophagus (BO) presents a particular pathological dilemma, in that patients who have no dysplasia within their BO experience a small but significant risk of malignant progression each year. Screening programmes have attempted to reduce the mortality from BO associated oesophageal adenocarcinoma but cannot predict which BO patients will progress to invasive malignancy. We have previously identified the long non coding RNA, OR3A4, is differentially hypomethylated in progressive BO. We aimed to understand its role in BO pathogenicity

MethodsThe stable BO cell line CP-A, as well as the oesophageal adenocarcinoma cells line OE-33 was transfected with a lentiviral OR3A4 over-expression vector, and underwent high resolution microscopy, immunofluorescence, RT-qPCR, RNA sequencing, and targeted drug screening with the p38-MAPK inhibitor domipramod to understand the effects of OR3A4 expression on progression. We then compared progressive vs. non-progressive BO samples using quantitative multi-fluorophore (Vectra) immunohistochemistry.

ResultsOver-expression of OR3A4 in CP-A lines resulted in a hyperproliferative, dysplastic cellular phenotype, with strong over-expression of MAPK and anti-apoptotic pathways at the RNA and protein level, which was sensitive to the p38-MAPK inhibitor domipramod. Vectra immunohistochemistry demonstrated that progressive BO had reduced visibility associated with a reduction in CD8+ T-cells and CD68+ macrophages and reduced CD4+ T-cells in the stomal compartment.

ConclusionThe overexpression of OR3A4, which we have previously shown is associated with progressive BO leads to a proliferative dysplastic cellular phenotype associated with increased, reversible MAPK signalling and loss of immune visibility.

category: gastroenterology


title: Development and operationalization of an electronic palliative care registry in a large integrated health system

abstract:
BackgroundPalliative care teams generally lack prospective tools to identify individuals who could benefit from specialty palliative care, which hinders their ability to find and treat patients early in their illness trajectories. Health systems are also limited in their ability to assess how well their palliative care services reach the population in need, which in turn makes it much more difficult to determine the quality, value, and effectiveness of those services. This study describes the creation, validation, and operationalization of an electronic registry of patients potentially eligible for palliative care at Sutter Health, a large integrated health system in northern California, US.

ResultsThe electronic palliative care eligibility algorithm performed well within the chart review validation sample, with an area under the receiver operating characteristic curve (AUROC) of 0.903 and area under the precision-recall curve (AUPRC) of 0.545. Within the 2.4 million individuals who contacted the SH electronic health record (EHR) during 2017, the final algorithm identified 1.1%-1.8% of patients (26,773-42,847) as potentially eligible for palliative care services. This included approximately 12.9%-17.7% of inpatients (16,392-22,507 out of 126,916), and 1.2%-1.9% of ambulatory care patients (20,140-32,212 out of 1.7 million).

ConclusionsA palliative care electronic patient registry was successfully created and operationalized. Performance based on an extensive chart review sample of Sutter Health patients indicated good capture of the palliative care-appropriate population, and this is further supported by successful identification of a majority of enrollees in Sutter Healths palliative care programs during 2017.

category: palliative medicine


title: A new method to measure inter-breath intervals in infants for the assessment of apnoea and respiratory dynamics

abstract:
BackgroundRespiratory disorders, including apnoea, are common in preterm infants due to their immature respiratory control and function compared with term-born infants. However, our inability to accurately measure respiratory rate in hospitalised infants results in unreported episodes of apnoea and an incomplete picture of respiratory dynamics.

MethodsWe develop, validate and use a novel algorithm to identify inter-breath intervals (IBIs) and apnoeas in infants. In 42 infants (a total of 1600 hours of recordings) we assess IBIs from the chest electrical impedance pneumograph using an adaptive amplitude threshold for the detection of individual breaths. The algorithm is refined by comparing its accuracy with clinically-observed breaths and pauses in breathing. We also develop an automated classifier to differentiate periods of true central apnoea from artefactually low amplitude signal. We use this algorithm to explore its ability to identify morphine-induced respiratory depression in 15 infants. Finally, in 22 infants we use the algorithm to investigate whether retinopathy of prematurity (ROP) screening alters the IBI distribution.

Findings88% of the central apnoeas identified using our algorithm were missed in the clinical notes. As expected, morphine caused a shift in the IBI distribution towards longer IBIs, with significant differences in all IBI metrics assessed. Following ROP screening, there was a shift in the IBI distribution with a significant increase in the proportion of pauses in breathing that lasted more than 10 seconds (t-statistic=1.82, p=0.023). This was not reflected by changes in the monitor-derived respiratory rate or episodes of apnoea recorded on clinical charts.

InterpretationBetter measurement of infant respiratory dynamics is essential to improve care for hospitalised infants. Use of the novel IBI algorithm demonstrates that following ROP screening increased instability in respiratory dynamics can be detected in the absence of clinically-significant apnoeas.

FundingWellcome Trust and Royal Society

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSRespiratory disorders are one of the most common reasons for admission to a neonatal care unit and many pathologies and clinically-required procedures affect respiration. Despite this, current methods to measure respiratory rate in infants often provide inaccurate measurements due to factors such as poor electrode placement, movement artefact and cardiac interference. Lee and colleagues previously developed an algorithm to better identify episodes of apnoea in infants from the electrical impedance pneumograph following removal of cardiac-frequency interference. This algorithm substantially improves apnoea detection and demonstrates the high number of apnoeas that are missed in medical records. However, false apnoeas can be detected during periods of low amplitude signal caused by shallow breathing or poor electrode placement, and shorter inter-breath intervals (IBIs) cannot be assessed using the method proposed by Lee et al. limiting its use in assessing more subtle changes in an infants respiratory dynamics.

Added value of this studyWe develop, test and use a new algorithm for the identification of IBIs from the electrical impedance pneumograph. We use an adaptive amplitude threshold for the identification of breaths and develop a classification model to remove periods of low amplitude signal falsely identified as episodes of apnoea. Using the algorithm, we demonstrate that retinopathy of prematurity (ROP) screening causes a significant increase in pauses in breathing that last more than 10 seconds. Our apnoea detection method was more sensitive than the current standard monitor-derived approach that is used to monitor respiratory rate in neonatal care units.

Implications of all the available evidenceTo improve understanding of infant respiratory dynamics, better methods of assessment are essential. This will create a more complete clinical understanding of infant well-being, that will lead to improved treatment options for infants with respiratory disorders.


title: Albumin-dependent and independent mechanisms in the syndrome of kwashiorkor

abstract: The syndrome of kwashiorkor is a striking phenotype of childhood severe malnutrition (SM) comprising oedema, fatty liver, and skin and hair changes. Despite high fatality, the aetiology and pathophysiology of kwashiorkor remain enigmatic, including the role of serum albumin on oedema development. Here, we demonstrate that serum albumin is associated with the presence and severity of oedema among severely malnourished children. Further, in two independent cohorts of children in Malawi and Kenya, we show albumin-independent mechanisms are associated with oedema in SM, including oxidative stress and extracellular matrix (ECM) remodelling. Plasma concentrations of ECM-related proteins: lumican, podoplanin, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) and matrix metalloproteinase (MMP)2 were associated with kwashiorkor. We therefore conclude that the pathophysiology of kwashiorkor has both albumin-dependent and independent mechanisms. We discuss the ways in which albumin-independent mechanisms may explain the clinical features observed in kwashiorkor.


title: Contributions of PTSD polygenic risk and environmental stress to suicidality in preadolescents

abstract: Suicidal ideation and attempts (i.e., suicidality) are complex behaviors driven by environmental stress, genetic susceptibility, and their interaction. Preadolescent suicidality is a major health problem with rising rates, yet its underlying biology is understudied. Here we studied effects of genetic stress susceptibility, estimated by polygenic risk score (PRS) for post-traumatic-stress-disorder (PTSD), on preadolescent suicidality in participants from the Adolescent Brain Cognitive Development (ABCD) Study(R). We further evaluated PTSD-PRS effects on suicidality in the presence of environmental stressors that are established suicide risk factors. Analyses included both European and African ancestry participants using PRS calculated based on summary statistics from ancestry-specific genome-wide association studies. In European ancestry participants (N=4,619, n=378 suicidal), PTSD-PRS was associated with preadolescent suicidality (odds ratio [OR]=1.12, 95%CI 1-1.25, p=0.038). Results in African ancestry participants (N=1,334, n=130 suicidal) showed a similar direction but were not statistically significant (OR=1.21, 95%CI 0.93-1.57, p=0.153). Sensitivity analyses using non-psychiatric polygenic score for height and using cross-ancestry PTSD-PRS did not reveal any association with suicidality, supporting the specificity of the association of ancestry-specific PTSD-PRS with suicidality. Environmental stressors were robustly associated with suicidality across ancestries with moderate effect size for negative life events and family conflict (OR 1.27-1.6); and with large effect size (OR [~] 4) for sexual-orientation discrimination. When combined with environmental factors, PTSD-PRS showed marginal additive effects in explaining variability in suicidality, with no evidence for G X E interaction. Results support use of cross-phenotype PRS, specifically stress-susceptibility, as a robust genetic marker for suicidality risk early in the lifespan.

category: psychiatry and clinical psychology


title: Mechanistic modeling of SARS-CoV-2 immune memory, variants, and vaccines

abstract: The functional relationship between neutralizing antibodies (NAbs) and protection against SARS-CoV-2 infection and disease remains unclear. We jointly estimated protection against infection and disease progression following natural infection and vaccination from meta-study data. We find that NAbs are strongly correlated with prevention of infection and that any history of NAbs will stimulate immune memory to moderate disease progression. We also find that natural infection provides stronger protection than vaccination for the same level of NAbs, noting that infection itself, unlike vaccination, carries risk of morbidity and mortality, and that our most potent vaccines induce much higher NAb levels than natural infection. These results suggest that while sterilizing immunity may decay, we expect protection against severe disease to be robust over time and in the face of immune-evading variants.

category: public and global health


title: Quantifying the role of naturally- and vaccine-derived neutralizing antibodies as a correlate of protection against COVID-19 variants


title: Quality of Cervical Cancer Screening at a Family Health Unit in Salvador-BA

abstract:
IntroductionCytopathological examination is the main method for the screening of cervical cancer, its occurrence can be prevented or minimized through screening, with good coverage, quality of collection and analysis and womens adherence to the examination.

ObjectiveTo describe the quality of cytopathological exams performed at a family health unit in Salvador - Bahia during the years 2015 and 2016.

MethodA cross-sectional study, of an exploratory descriptive character, was conducted, using a database from a previous study carried out in a health unit in Salvador / BA and approved by the Ethical Committee from State University of Feira de Santana.

ResultsPreventive gynecological exams of 1,350 women were analyzed, but 330 (24.4%) of them could not be evaluated due to the absence of the report in the health unit and the presence of acellular or hypocellular material that prevented the analysis. From 1020 exams, 45 (3.3%) presented an unsatisfactory sample, without conditions for analysis, while 589 (43.19%) showed only squamous cells. From 392 (29.0%) reports with an adequate study sample, 150 (%) were women with a mean age of 38.49 years. These were located and composed the final sample of the present investigation.

Final ConsiderationsWe suggest the need for investments in continuing education for professionals involved in performing cytopathological exams, in order to ensure the right of women to comprehensive and quality health care.


title: College Students' COVID-19 Vaccine Beliefs and Intentions: Implications for interventions

abstract: On college campuses, effective management of vaccine-preventable transmissible pathogens requires understanding student vaccination intentions. This is necessary for developing and tailoring health messaging to maximize uptake of health information and vaccines. The current study explored students beliefs and attitudes about vaccines in general, and the new COVID-19 vaccines specifically. This study provides insights into effective health messaging needed to rapidly increase COVID-19 vaccination on college campuses--information that will continue to be informative in future academic years across a broad scope of pathogens. Data were collected via an online cohort survey of college students aged 18 years and older residing on or near the campus of a large public university during fall 2020. Overall, we found COVID-19 vaccine hesitancy in college students correlated strongly with some concerns about vaccines in general as well as with concerns specific to COVID-19 vaccines. Taken together, these results provide further insight for message development and delivery, and can inform more effective interventions to advance critical public health outcomes on college campuses beyond the current pandemic.


title: Automated Chest Radiographs Triage Reading by a Deep Learning Referee Network

abstract: Chest radiographs are often obtained as a screening for early diagnosis tool to rule out abnormalities mainly related to different cardiovascular and respiratory diseases. Reading and reporting numerous chest radiographs is a complex and time-consuming task. This research proposes and evaluates a deep learning (DL) approach based on convolutional neural networks (CNN) combined with a referee fully connected neural network as a computer-aided diagnosis tool in chest X-ray triage and worklist prioritization. The CNN models were trained with a combination of three large scale databases: ChestX-ray14, CheXpert and PadChest. The final database contained 327,176 images labeled with findings obtained by natural language processing (NLP) techniques applied to the radiology reports. The dataset was split in 16 different balanced binary partitions, which were used to train 16 finding-specific classification CNNs. Afterwards, a normal vs abnormal partition of the dataset was created, being abnormal the presence of at least one pathologic change. This final partition was used to train a fully connected neural network as referee that was fed with all the 16 previously trained outcomes. The Area Under the Curve (AUC) analysis evaluated and compared the performance of the models. The system was successfully implemented and evaluated with a test set of 3400 images. The AUC of the normal vs abnormal classification was 0.94. The highest AUC of the finding-specific classifiers was 0.99 for hernia. The proposed system can be used to assist radiologists identifying abnormal exams, allowing a time-efficiency triage approach.


title: Acute kidney injury in hospitalized patients due to COVID-19

abstract:
The incidence of acute kidney injury (AKI) in hospitalized patients with coronavirus disease 2019 (COVID-19) is variable, being associated with worse outcomes. The objectives of the study were to evaluate the incidence, risk factors and impact of AKI in subjects hospitalized for COVID-19 in two third- level hospitals in Cordoba, Argentina.

A retrospective cohort study was conducted. 448 adults who were consecutively hospitalized for COVID-19 between March and the end of October 2020 at Hospital Privado Universitario de Cordoba and Hospital Raul Angel Ferreyra were included. The incidence of AKI was 19% (n = 85). 50.6% presented AKI stage 1 (n=43), 20% stage 2 (n=17) and 29.4% stage 3 (n=25, of which 18 required renal replacement therapy). In the multivariate analysis, the variables that were independently associated with AKI were: age (adjusted Odd ratio -aOR- =1.30, 95%CI=1.04-1.63, p=0.022), history of chronic kidney disease (aOR=9.92, 95%CI=4.52-21.77, p<0.001), blood neutrophil count at admission (aOR=1.09, 95%CI=1.01-1.18, p=0.037) and requirement for mechanical ventilation (MV) (aOR=6.69, 95%CI=2.24-19.9, p=0.001). AKI was associated with longer hospitalization, greater admission and length of stay in the intensive care unit, a positive association with bacterial superinfection, sepsis, respiratory distress syndrome, MV requirement and mortality (mortality with AKI=47.1% vs without AKI=12.4%, p<0.001). AKI was independently associated with higher mortality (aOR=3.32, 95%CI=1.6-6.9, p=0.001).

In conclusion, the incidence of AKI in adults hospitalized for COVID-19 was 19% and had a clear impact on morbidity and mortality. Local predisposing factors for AKI were identified.

category: nephrology


title: Multiomics implicate gut microbiota in altered lipid and energy metabolism in Parkinsons disease

abstract: We aimed to investigate the link between serum metabolites, gut bacterial community composition, and clinical variables in Parkinsons disease (PD) and healthy control subjects (HC). 139 metabolite features were found to be differentially abundant between the PD and Control groups. No associations were found between metabolite features and within-PD clinical variables. The results suggest alterations in serum metabolite profiles in PD, and the results of correlation analysis between metabolite features and microbiota suggest that several bacterial taxa are associated with altered lipid and energy metabolism in PD.


title: The role of obesity in female reproductive conditions: A Mendelian Randomisation Study

abstract:
BackgroundObesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear.

Methods and FindingsWe estimated observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive conditions using logistic regression, generalised additive models, and Mendelian randomisation (two-sample, non-linear, and multivariable) applied to data from UK Biobank and publicly available genome-wide association studies (GWAS).

Body mass index (BMI), waist-hip ratio (WHR), and WHR adjusted for BMI (WHRadjBMI) were observationally (odds ratios (ORs) = 1.02 - 1.87 per 1 S.D. obesity trait) and causally (ORs = 1.06 - 2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Causal effect estimates of WHR and WHRadjBMI, but not BMI, were attenuated compared to their observational counterparts. Genetically predicted visceral adipose tissue mass was causal for the development of HMB, PCOS, and pre-eclampsia (ORs = 1.01 - 3.38). Increased waist circumference also posed a higher causal risk (ORs = 1.16 - 1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06 - 1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% -50% of the total causal effect of obesity on pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity.

ConclusionsIn this first systematic, large-scale, genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions, we found that common indices of overall and central obesity increased risk of reproductive disorders to heterogenous extents, mediated by metabolic hormones. Our results suggest exploring the mechanisms mediating the causal effects of overweight and obesity on gynaecological health to identify targets for disease prevention and treatment.

category: genetic and genomic medicine


title: Variation in the reporting of elective surgeries and its influence on patient safety indicators

abstract:
BackgroundUS hospital safety is routinely measured via patient safety indicators (PSIs). Receiving a score for most PSIs requires a minimum number of qualifying cases, which are partly determined by whether the associated diagnosis-related group (DRG) was surgical and whether the surgery was elective. While these criteria can exempt hospitals from PSIs, it remains to be seen whether exemption is driven by low volume, small numbers of DRGs, or perhaps, policies that determine how procedures are classified as elective.

MethodsUsing Medicare inpatient claims data from 4,069 hospitals between 2015 and 2017, we examined how percentages of elective procedures relate to numbers of surgical claims and surgical DRGs. We used a combination of quantile regression and machine learning based anomaly detection to characterize these relationships and identify outliers. We then used a set of machine learning algorithms to test whether outliers were explained by the DRGs they reported.

ResultsAverage percentages of elective procedures generally decreased from 100% to 60% in relation to the number of surgical claims and the number of DRGs among them. Some providers with high volumes of claims had anomalously low percentages of elective procedures (5% - 40%). These low elective outliers were not explained by the particular surgical DRGs among their claims. However, among hospitals exempted from PSIs, those with the greatest volume of claims were always low elective outliers.

ConclusionSome hospitals with relatively high numbers of surgical claims may have classified procedures as non-elective in a way that ultimately exempted them from certain PSIs.

category: health systems and quality improvement


title: Evaluation of a clinical decision support tool for matching cancer patients to clinical trials using simulation-based research

abstract: Simulation-based research (SBR) methods have been proposed as an alternative methodology for evaluating digital health solutions; however, applicability remains to be established. This study used SBR to evaluate a clinical decision support (CDS) tool used for matching cancer patients to clinical trials. 25 clinicians and research staff were recruited to match 10 synthetic patient cases to clinical trials using both the CDS tool and publicly available online trial databases. Participants were significantly more likely to report having sufficient time (p = 0.020) and to require less mental effort (p = 0.001) to complete trial matching with the CDS tool. Participants required less time for trial matching using the CDS tool, but the difference was not significant (p = 0.093). Most participants reported that they had sufficient guidance to participate in the simulations (96%). This study demonstrates the use of SBR methods is a feasible approach to evaluating digital health solutions.


title: Clarity Plus™ digital PCR: A novel platform for absolute quantification of SARS-CoV-2

abstract: In recent years, the usage of digital polymerase chain reaction (dPCR) for various clinical applications has increased exponentially. Considering the growing demand for improved dPCR technology, the Clarity Plus dPCR system which features enhanced multiplexing capability and a wider dynamic range for nucleic acid analysis was recently launched. In this study, a dPCR assay optimized for use on Clarity Plus was evaluated for the absolute quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent responsible for the global coronavirus disease 2019 (COVID-19) outbreak. The assay demonstrated good inter- and intra-assay precision, accuracy, as well as excellent linearity across a range of over 6 orders of magnitude for target gene quantification. In addition, comparison of the assay on both dPCR and qPCR platforms revealed that dPCR exhibited a slightly higher sensitivity compared to its qPCR counterpart when quantifying SARS-CoV-2 at a lower concentration. Overall, the results showed that the dPCR assay is a reliable and effective approach for the absolute quantification of SARS-CoV-2 and can potentially be adopted as a molecular tool for detecting low viral load in patients and wastewater surveillance of COVID-19.

category: infectious diseases