Trajectory of Growth of SARS-CoV-2 Variants in Houston, Texas, January through May 2021 Based on 12,476 Genome Sequences Genetic variants of the SARS-CoV-2 virus are of substantial concern because they can detrimentally alter the pandemic course and disease features in individual patients. Here we report SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist healthcare system diagnosed from January 1, 2021 through May 31, 2021. The SARS-CoV-2 variant designated U.K. B.1.1.7 increased rapidly and caused 63%-90% of all new cases in the Houston area in the latter half of May. Eleven of the 3,276 B.1.1.7 genomes had an E484K change in spike protein. Compared with non-B.1.1.7 patients, individuals with B.1.1.7 had a significantly lower cycle threshold value (a proxy for higher virus load) and significantly higher rate of hospitalization. Other variants (e.g., B.1.429, B.1.427, P.1, P.2, and R.1) also increased rapidly, although the magnitude was less than for B.1.1.7. We identified 22 patients infected with B.1.617 "India" variants; these patients had a high rate of hospitalization. Vaccine breakthrough cases (n=207) were caused by a heterogeneous array of virus genotypes, including many that are not variants of interest or concern. In the aggregate, our study delineates the trajectory of concerning SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, and heralds the arrival and spread of B.1.617 variants in the metroplex.
Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders.
Disparate Impacts on Online Information Access during the COVID-19 Pandemic The COVID-19 pandemic has stimulated a staggering increase in online information access (1, 2), but the extent to which different communities of internet users enlist digital resources to meet everyday needs varies (2-4). We analyze 55 billion everyday web search interactions across 25,150 US ZIP codes and demonstrate that there were disparate impacts of the pandemic on online information access across several information domains, including health and pandemic-relevant online resources (e.g., online learning, online food delivery). Among many findings, we show that ZIP codes associated with higher proportions of Black residents intensified their access to unemployment resources, and ZIP codes associated with lower income reduced their access to health information resources relative to their counterpart ZIP codes. Because these disparate impacts on the access to online information may result in downstream offline gaps in health, education, employment, and well-being (3), public health interventions should target potential barriers to accessing the necessary digital resources and provide adequate support to meet the intensified digital resource needs.

One Sentence SummaryLarge-scale web search logs reveal disparate impacts on online health, education, unemployment, and food information access. Diagnostic Model of in-Hospital Mortality in Patients with Acute ST-Segment Elevation Myocardial Infarction Used Artificial Intelligence Methods BackgroundPreventing in-hospital mortality in Patients with ST-segment elevation myocardial infarction (STEMI) is a crucial step.

ObjectivesThe objective of our research was to to develop and externally validate the diagnostic model of in-hospital mortality in acute STEMI patients used artificial intelligence methods.

MethodsWe divide non-randomly the American population with acute STEMI into a training set, a test set,and a validation set. We converted the unbalanced data into balanc ed data. We used artificial intelligence methods to develop and externally validate the dia gnostic model of in-hospital mortality in acute STEMI patients. We used confusion matrix combined with the area under the receiver operating characteristic curve (AUC) to evaluat e the pros and cons of the above models.

ResultsThe strongest predictors of in-hospital mortality were age, gender, cardiogenic shock, atrial fibrillation(AF), ventricular fibrillation(VF),third degree atrioventricular block,in-hospital bleeding, underwent percutaneous coronary intervention(PCI) during hospitalization, underwent coronary artery bypass grafting (CABG) during hospitalization, hypertension history, diabetes history, and myocardial infarction history.The F2 score of logistic regression in the training set, the test set, and the validation data set were 0.81, 0.6, and 0.59 respectively.The AUC of logistic regression in the training set, the test set, and the validation data set were 0.77, 0.78, and 0.8 respectively. The diagnostic model built by logistic regression was the best.

ConclusionWe had used artificial intelligence methods developed and externally validated the diagnostic model of in-hospital mortality in acute STEMI patients.

We registered this study with WHO International Clinical Trials Registry Platform (ICTRP) (registration number: ChiCTR1900027129; registered date: 1 November 2019). USING PHYLOGENETICS TO INFER HIV-1 TRANSMISSION DIRECTION BETWEEN KNOWN TRANSMISSION PAIRS Inferring the transmission direction between linked individuals living with HIV provides unparalleled power to understand the epidemiology that determines transmission. Phylogenetic ancestral state reconstruction approaches infer the transmission direction by identifying the individual in whom the most recent common ancestor of the virus populations originated. However, these methods vary in their accuracy but it is unclear why. To evaluate the performance of phylogenetic ancestral state reconstruction, we inferred the transmission direction for 112 HIV transmission pairs where transmission direction was known and detailed additional information was available. We then fit a statistical model to evaluate the extent to which epidemiological, sampling, genetic and phylogenetic factors influenced the outcome of the inference. We repeated the analysis under real-life conditions with only routinely-collected data. We found that the inference of transmission direction depends principally on the topology class and branch length characteristics of the phylogeny. Under real-life conditions, the probability of identifying the correct transmission direction increases from 52%--when a monophyletic-monophyletic or paraphyletic-polyphyletic tree topology is observed, when the sample size in both partners is small and when the tip closest to the root does not agree with the state at the root--to 93% when a paraphyletic-monophyletic topology is observed, when the sample size is large and when the tip closest to the root agrees with root state. Our results suggest that discordance between previous studies in inferring the transmission direction can be explained by differences in key phylogenetic properties that arise due to different evolutionary, epidemiological and sampling processes.

Significance StatementIdentifying the direction of infectious disease transmission between individuals provides unparalleled power to understand infectious disease epidemiology. With epidemiological and clinical information typically unable to distinguish the direction, phylogenetic analysis of pathogen sequence data is an alternative approach. However, when these phylogenetic methods have been implemented, their accuracy is highly variable, and the reasons for this discordance is unknown. Here we analyse sequence data from over 100 pairs of individuals for whom both the direction of transmission of HIV is known and detailed epidemiological and sampling information is available. We find that easily quantifiable phylogenetic characteristics discriminate whether a phylogenetically-inferred transmission direction is correct. Our analysis highlights that phylogenetic approaches are unsuitable for individual-level analysis such as forensic investigations. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Alzheimer's Disease Assessments Optimised for Diagnostic Accuracy and Administration Time ObjectiveDespite the potential of machine learning techniques to improve dementia diagnostic processes, research outcomes are often not readily translated to or adopted in clinical practice. Importantly, the time taken to administer diagnostic assessment has yet to be taken into account in feature-selection based optimisation for dementia diagnosis. We address these issues by considering the impact of assessment time as a practical constraint for feature selection of cognitive and functional assessments in Alzheimers disease diagnosis.

MethodsWe use three different feature selection algorithms to select informative subsets of dementia assessment items from a large open-source dementia dataset. We use cost-sensitive feature selection to optimise our feature selection results for assessment time as well as diagnostic accuracy. To encourage clinical adoption and further evaluation of our proposed accuracy-vs-cost optimisation algorithms, we also implement a sandbox-like toolbox with graphical user interface to evaluate user-chosen subsets of assessment items.

ResultsWe find that there are subsets of accuracy-cost optimised assessment items that can perform better in terms of diagnostic accuracy and/or total assessment time than most other standard assessments.

DiscussionOverall, our analysis and accompanying sandbox tool can facilitate clinical users and other stakeholders to apply their own domain knowledge to analyse and decide which dementia diagnostic assessment items are useful, and aid the redesigning of dementia diagnostic assessments. Clinical Impact (Clinical Research): By optimising diagnostic accuracy and assessment time, we redesign predictive and efficient dementia diagnostic assessments and develop a sandbox interface to facilitate evaluation and testing by clinicians and non-specialists. Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases ObjectiveTo study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).

MethodsNeutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.

ResultsMTX patients showed a significantly lower median antibody response compared to AIRD patients without immunosuppressive therapy (p< 0.001). Young age (<60 years) and MTX-hold after vaccination were found to be the main factors influencing antibody response after vaccination, while BMI or MTX dose demonstrated no effect. For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001) and all patients with antibody levels (14 %) below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher median neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (68.82 %, 92.73 %, p=<0.001). This effect was particularly pronounced in patients older than 60 years (p=0.0016). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.

ConclusionMTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age. Using controlled interrupted time series to estimate the population-level effects of Ontario's recently implemented overdose prevention sites and consumption and treatment services BackgroundOntario recently implemented overdose prevention sites and consumption and treatment services (OPS/CTS) to stem the harms of the opioid epidemic. We tested whether operating any site improved local opioid-related health service use and mortality rates.

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

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

ConclusionAlthough OPS/CTS are not sufficient to stem the harms of the opioid overdose epidemic on their own, they play a critical role in local harm reduction strategies. Three-dimensional cephalometric landmarking and Frankfort horizontal plane construction: reproducibility of conventional and novel landmarks ObjectivesTo assess manual landmarking repeatability and reproducibility (R&R) of a set of three-dimensional (3D) landmarks and to evaluate R&R of vertical cephalometric measurements using two Frankfort Horizontal (FH) planes as references for horizontal 3D imaging reorientation.

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

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

ConclusionsThe "dental" and "foraminal" landmarks tended to be more reliable than the "conventional" landmarks. Despite the poor overall reliability of the landmarks orbitale and porion, the construction of the conventional FH plane using 3 landmarks provided a reliable horizontal reference for 3D craniofacial CT scan reorientation. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Safety and efficacy of Pulmonary physiotherapy in hospitalized patients with severe COVID-19 pneumonia (PPTCOVID Study): A prospective, randomised, single-blind, controlled trial BackgroundPulmonary physiotherapy (PPT) is an important treatment in the management of patients with different types of pulmonary disorders. We aimed to evaluate safety and efficacy of PPT in hospitalized patients with severe COVID-19 pneumonia.

MethodsIn this randomised, single-blind, controlled trial, we enrolled hospitalized, non-intubated patients (18 to 75 years with oxygen saturation (Spo2) in free-air breathing [&le;]90%) with COVID-19 pneumonia at a referral hospital. Participants were randomly assigned (1:1) to receive PPT (six sessions PPT with breathing exercises and airway clearance techniques) or basic care. The primary outcomes were venous blood O2 (pO2) and CO2 (pCO2) pressures, Spo2, and three-minute walking test (3MWT) that were assessed before and end of sixth session. Secondary outcomes included level of dyspnea, venous blood PH, one-month mortality, three-month mortality and short form-36 (SF-36) after one and three months. The assessor was blinded to the assignment. This trial is registered with ClinicalTrials.gov (NCT04357340).

FindingsIn April-May 2020, 40 participants were randomly assigned to PPT or basic care groups. While at the end of intervention, pO2 (adjusted mean difference to baseline measure (AMD) 6.43 mmHg [95%CI 2.8, 10.07], P<0.01), Spo2 (AMD 4.43% [95%CI 2.04, 6.83], P=0.0011), and 3MTW (AMD 91.44 m [95%CI 68.88, 113.99], P<0.01) were higher in PPT group and basic care group, pCO2 was not improved (AMD -2.1 mmHg [95%CI-6.36, 2.21], P=0.33). Mortality rate was 20% (OR adjusted to baseline Spo2 .19 [95%CI .03, 1.30], P=.09) and 25% (OR adjusted to baseline Spo2 .16 [95%CI .26, 1.05], P=.056) lower in the PPT group at three-month at one-month and three-month, respectively. There were no significant differences in most SF-36 domains scores after one and three months. No serious adverse event was observed during PPT sessions.

ConclusionEarly PPT can be considered a safe and effective therapeutic choice for patients with severe COVID-19. Surgical interventions targeting the nucleus caudalis for craniofacial pain: a systematic and historical review. IntroductionChronic facial pain is a prevalent group of conditions and when refractory to common treatments poses a social and economic burden. The last decade has seen a multitude of advancements in the multimodal management of pain. Ablative or neuromodulatory interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex is one such treatment that has remained underutilized.

MethodsHere we present a systematic review of the literature and historical perspective regarding interventions targeting the NC. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome reporting scheme was devised to allow comparison between studies using differing outcome reporting methods.

ResultsA review of the literature revealed 49 retrospective studies published over the last 80 years, reporting on 858 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy (n=515, 60.0%); however, there has been an emergence of novel approaches such as endoscopic (n=6, 0.7%) and spinal cord stimulation (n=20, 2.3%) in the last 10 years. Regardless of intervention technique or preoperative diagnosis, 90.4% of patients demonstrated some improvement from treatment.

ConclusionThis systematic review highlights recent advancements in NC intervention technique and the wide range of facial pain syndromes for which these interventions show promising efficacy. New and less invasive techniques continue to emerge, however prospective studies remain absent in the literature. Future work should address efficacy comparisons between intervention type and preoperative diagnosis. Reflex single-gene non-invasive prenatal testing significantly increases the cost-effectiveness of carrier screening ObjectiveTo evaluate the clinical and cost savings benefits of adoption of a carrier screen with reflex single-gene non-invasive prenatal test (sgNIPT) in prenatal care.

MethodA decision-analytic model was developed to compare carrier screen with reflex sgNIPT (maternal carrier status and fetal risk reported together) as first-line carrier screening to the traditional carrier screening workflow (positive maternal carrier screen followed by paternal screening to evaluate fetal risk). The model compared the clinical outcomes and cost effectiveness between the two screening methods. These results were used to simulate appropriate pricing for reflex sgNIPT.

ResultsReflex sgNIPT carrier screening detected 108 of 110 affected pregnancies per 100,000 births (98.5% sensitivity), whereas traditional carrier screening detected 46 of 110 affected pregnancies (41.5% sensitivity). The cost to identify one affected pregnancy was reduced by 62% in the reflex sgNIPT scenario compared to the traditional scenario. Adding together the testing cost savings and the savings from earlier clinical intervention made possible by reflex sgNIPT, the total cost savings was $37.6 million per 100,000 pregnancies. Based on these cost savings, we simulated appropriate reflex sgNIPT pricing range: if the cost to identify one affected pregnancy is the unit cost, carrier screening with reflex sgNIPT can be priced up to $1,859 per test (or $7,233 if sgNIPT is billed separately); if the cost per 100,000 pregnancies is the unit cost, carrier screening with sgNIPT can be priced up to $1,070 per test (or $2,336 if sgNIPT is billed separately).

ConclusionUsing the carrier screen with reflex sgNIPT as first-line screening improves the detection of affected fetuses by 2.4-fold and can save costs for the healthcare system. A real-life experience will be needed to assess the clinical utility and exact cost savings of carrier screen with reflex sgNIPT. The Relative Importance of Mindfulness Facets and Their Interactions: Relations to Psychological Symptoms in Chronic Pain ObjectivesThis study had three objectives: first, to investigate the relative importance of the five mindfulness facets to negative affect (NA) among patients with chronic musculoskeletal pain; second, to test the hypothesis that observing is associated with lower NA only if occurs in an accepting manner; and third, to investigate the relation between mindfulness and obsessive-compulsive symptoms (OCS).

MethodsOne hundred and nineteen patients with chronic musculoskeletal pain filled the Five-Facets Mindfulness Questionnaire (FFMQ), the Depression, Anxiety, Stress Scale (DASS), and the Obsessive- compulsive Inventory-Revised (OCI-R). A latent variable was constructed to represent NA. Multiple regression analysis was conducted, and several indices of relative importance were calculated.

ResultsExcept for Observing, all mindfulness facets had significant bivariate and unique relation with NA. Acting with Awareness was the most important predictor, followed by Nonjudging and Describing. The contribution of Nonreactivity was small. Regarding the second objective, the Observing x Nonjudging and Observing x Nonreactivity interactions were not significant. Finally, the five facets of mindfulness explained about one-half of the variance in obsession and one-fifth of the variance in compulsion. After excluding the shared variance between obsession and compulsion, mindfulness was only related to obsession.

ConclusionsExcept for Observing, all mindfulness facets seem to have unique contributions to psychological symptoms; among them, Acting with Awareness seems most important. Current evidence is inconsistent in supporting the moderating role of acceptance in the influence of observing. Finally, in the context of OCS, it seems that mindfulness is more related to obsession than compulsion. The role of classroom volume, occupancy, voice reduction and ffp2 masks in transmission risk of SARS-CoV2 in schools Issues linked to aerosol physics within school buildings and related infection risk still lack a proper recognition in school safety regulations. In this theoretical work we try to shed more light on the critical role of air ventilation, classroom volume, occupancy, and face mask types (surgical vs ffp2) in controlling airborne transmission risk in educational settings. Limited spaces available in many schools require to precisely assess the occupancy/volume ratio in each classroom and to investigate the specific risk levels from aerosolization of viral loads from infective sources. Moreover, most schools are not provided with mechanical HVAC systems. Fundamental questions are therefore: how the specific classroom volume affects the long-range contagion risk in a given classroom? is linear social distancing the right way to assess a volumetric risk problem? How effective are other countermeasures like reduced speaking volume or equipping teachers with microphones? We present here the results of a numerical analysis based on the Gammaitoni-Nucci infection risk model and the consolidated Wells-Riley like approach, with SARS-CoV2 input data and geometric data from a typical high-school classroom in Italy. We investigated separately the case of infective asymptomatic student and infective asymptomatic teacher as source of viral quanta, taking into account thermal gradient effects on the air ventilation rates. First recommendations based on the volumetric nature of aerosol risk are suggested to extend the linear social distancing approach applied so far. Finally we discuss the concept of "cumulative infection risk" over multiple lesson+break cycles in Wells-Riley-like infection models. We believe that any attempt to proper model infection risk in closed environments with cycled changes of the source and the susceptible individuals, should carefully consider this point, particularly when modelling air ventilation breaks in classrooms. Development of machine learning models for the prediction of complications after colonic, colorectal and small intestine anastomosis in psychiatric and non-psychiatric patient collectives (PSTUDY) Psychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.

MethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).

ResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years. Oral, similar to intranasal, administration of oxytocin decreases top-down social attention The neuropeptide oxytocin (OXT) modulates social cognition by increasing attention towards social cues and may have therapeutic potential for impaired social attention in disorders such as autism. Intranasal administration of OXT is widely used to examine its functional effects in both adults and children and is assumed to enter the brain directly via this route. However, OXT can also influence brain function via increased blood concentrations and we have recently shown that orally (lingual) administered OXT also modulates neural responses to emotional faces and may be better tolerated for therapeutic use. Here, we examined if 24IU OXT administered orally can facilitate social attention. In a randomized, placebo-controlled, pharmacological study we used a validated emotional anti-saccade eye-tracking paradigm to explore effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male subjects. Our findings showed in terms of top-down attention, oral OXT increased errors for both social (angry, fearful, happy, sad and neutral emotion faces) and non-social stimuli (oval shapes) in the anti-saccade condition but only increased response latencies in the social condition. It also significantly reduced post-task state anxiety but this was not correlated with task performance. Comparison with our previous intranasal OXT study using the same task revealed both routes have a similar effect on increasing anti-saccade errors and response latencies and reducing state anxiety. Overall, findings suggest that oral administration of OXT produces similar effects on top-down social attention control and anxiety as intranasal administration and may therefore have therapeutic utility. Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (ACE2, TMPRSS2, DPP4, and LY6E). We analyzed novel data from 2,012 ethnically diverse Africans and 15,997 individuals of European and African ancestry with electronic health records, and integrated with global data from the 1000GP. At ACE2, we identified 41 non-synonymous variants that were rare in most populations, several of which impact protein function. However, three non-synonymous variants were common among Central African hunter-gatherers from Cameroon and are on haplotypes that exhibit signatures of positive selection. We identify strong signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. "What do you mean I can't have a doctor? This is Canada!" - A Qualitative Study of the Myriad Consequences for Unattached Patients Awaiting Primary Care Attachment BackgroundPatient access to primary healthcare (PHC) is the foundation of a strong healthcare system and healthy populations. Attachment to a regular PHC provider, a key to healthcare access, has seen a decline in some jurisdictions. This study explored the consequences of unattachment from a patient perspective, an under-studied phenomenon to date.

MethodsA realist-informed qualitative study was conducted with unattached patients in Nova Scotia, Canada. Semi-structured interviews with nine participants were conducted and transcribed for analysis. The framework method was used to carry out analysis, which was guided by Donabedians model of assessing healthcare access and quality.

ResultsFive key findings were noted in this study: 1) Participants experienced a range of consequences from not having a regular PHC provider. Participants used creative strategies to 2) attempt to gain attachment to a regular PHC provider, and, to 3) address their health needs in the absence of a regular PHC provider. 4) Participants experienced negative feelings about themselves and the healthcare system, and 5) stress related to the consequences and added work of being unattached and lost care.

ConclusionsUnattached patients experienced a burden of care related to lost care and managing their own health and related information, due to the download of medical record management and system navigation to them. These findings may underestimate the consequences for further at-risk populations who would not have been included in our recruitment. This may result in poorer health outcomes, which could be mitigated by interventions at the structural level, such as enhanced centralized waitlists to promote attachment. Such waitlists may benefit from a triage approach to appropriately attach patients based on need. Characteristic and Sex Differences in Auditory Function and Cochlear Pathophysiology in a Noise-exposed Cohort: A Cross-sectional Study BackgroundTo determine the characteristics and sex differences of auditory perception and cochlear function in individuals with long-term occupational noise exposure.

MethodsYoung workers with long-term occupational noise exposure from a shipyard were recruited in the current study as the hidden hearing loss (HHL) risk group. Age-matched office workers in the same shipyard who had no occupational noise-exposure history were enrolled in the control group. The auditory processing ability of speech-in-noise (SIN) score and gap detection threshold (GDT) were further examined by sex. The cochlear function of action potential (AP) and summating potential (SP)/AP values were tested and compared by sex and side. The correlation between the SIN score and cochlear function was studied by sex. The correlation between either auditory processing ability or cochlear function and occupational-noise working length (OWL) was also analysed in the HHL risk group.

ResultsSignificantly decreased SIN scores and a higher GDT of the 4 kHz gap marker were only found in men in the HHL risk group. Although the hearing thresholds of the women in the HHL risk group were slightly but significantly worse than those of the women in the control group, no significant defects in auditory processing or temporal resolution were found between the two groups. Significantly decreased cochlear function and increased SP/AP values in the left ear were only found in men in the HHL risk group. Neither the AP amplitude nor the AP latency differed significantly between the two groups by sex. A correlation study indicated that only the correlation between the SIN score and the AP amplitude of the right ear in men was significant. No significant difference was found between the SIN score and cochlear function in women. The AP latency of the right ear was only significantly correlated with OWL in men.

ConclusionIn long-term occupational working exposure individuals with normal hearing, defects in auditory processing, temporal resolution and cochlear function showed sex differences, none of which were significant in women. In men, a weak correlation between the SIN score and the AP amplitude of the right ear was found. There was only a weak correlation between OWL and the AP latency of the right ear in men. Our findings indicate men are more vulnerable to occupational noise than women. Considering the noise-exposure dose differences between the control and HHL risk groups, our measures are insensitive to cochlear synaptopathy in humans. Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

MethodsIn a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.

Results175 dialysis patients (40% women, 65{+/-}15 years), 252 kidney transplant patients (33% women, 54{+/-}14 years) and 71 controls (65% women, 44{+/-}14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p<0.05). Moreover, higher antibody titers associated with fewer events, HR 0.41 for each unit increased in log10titer (p<0.05).

ConclusionsDialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.

SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease. Using Adversarial Images to Assess the Stability of Deep Learning Models Trained on Diagnostic Images in Oncology PurposeDeep learning (DL) models have rapidly become a popular and cost-effective tool for image classification within oncology. A major limitation of DL models is output instability, as small perturbations in input data can dramatically alter model output. The purpose of the study is to investigate the robustness of DL models in the oncologic image domain through the application of adversarial images: manipulated images with small pixel-level perturbations designed to assess the stability of DL models.

Experimental DesignWe examined the impact of adversarial images on the classification accuracies of DL models trained to classify cancerous lesions across three common oncologic imaging modalities (CT, mammogram, and MRI). The CT model was trained to classify malignant lung nodules using the LIDC dataset. The mammogram model was trained to classify malignant breast lesions using the DDSM dataset. The MRI model was trained to classify brain metastases using an institutional dataset. We also explored the utility of an iterative adversarial training approach to improve the stability of DL models to small pixel-level changes.

ResultsOncologic images showed instability with small pixel-level changes. A pixel-level of perturbation of .004 resulted in a majority of oncologic images to be misclassified by their respective DL models (CT 25.64%, mammogram 23.93%, MRI 6.36%). Adversarial training mitigated improved the stability and robustness of DL models trained on oncologic images compared to naive models [(CT 67.72% vs 26.92%), mammogram (63.39% vs 27.68%), MRI (87.20% vs 24.32%)].

ConclusionsDL models naively trained on oncologic images exhibited dramatic instability to small pixel-level changes resulting in substantial decreases in accuracy. Adversarial training techniques improved the stability and robustness of DL models to such pixel-level changes. Prior to clinical implementation, adversarial training should be considered to proposed DL models to improve overall performance and safety. Unraveling Attributes of COVID-19 Vaccine Hesitancy and Uptake in the U.S.: A Large Nationwide Study SARS-CoV-2 vaccines are powerful tools to combat the COVID-19 pandemic, but vaccine hesitancy threatens these vaccines effectiveness. To address COVID-19 vaccine hesitancy and ensure equitable distribution, understanding the extent of and factors associated with vaccine acceptance and uptake is critical. We report the results of a large nationwide study conducted December 2020-May 2021 of 34,470 users from COVID-19-focused smartphone-based app How We Feel on their willingness to receive a COVID-19 vaccine. Nineteen percent of respondents expressed vaccine hesitancy, the majority being undecided. Of those who were undecided or unlikely to get a COVID-19 vaccine, 86% reported they ultimately did receive a COVID-19 vaccine. We identified sociodemographic and behavioral factors that were associated with COVID-19 vaccine hesitancy and uptake, and we found several vulnerable groups at increased risk of COVID-19 burden, morbidity, and mortality were more likely to be vaccine hesitant and had lower rates of vaccination. Our findings highlight specific populations in which targeted efforts to develop education and outreach programs are needed to overcome vaccine hesitancy and improve equitable access, diversity, and inclusion in the national response to COVID-19.