Genomic surveillance of SARS-CoV-2 during the first year of the pandemic in the Bronx enabled clinical and epidemiological inference The Bronx was an early epicenter of the COVID-19 pandemic in the USA. We conducted temporal genomic surveillance of SARS-CoV-2 genomes across the Bronx from March-October 2020. Although the local structure of SARS-CoV-2 lineages mirrored those of New York City and New York State, temporal sampling revealed a dynamic and changing landscape of SARS-CoV-2 genomic diversity. Mapping the trajectories of variants, we found that while some became  endemic to the Bronx, other, novel variants rose in prevalence in the late summer/early fall. Geographically resolved genomes enabled us to distinguish between cases of reinfection and persistent infection in two pediatric patients. We propose that limited, targeted, temporal genomic surveillance has clinical and epidemiological utility in managing the ongoing COVID pandemic.

One sentence summaryTemporally and geographically resolved sequencing of SARS-CoV-2 genotypes enabled surveillance of novel genotypes, identification of endemic viral variants, and clinical inferences, in the first wave of the COVID-19 pandemic in the Bronx.
Optimal Prevalence Threshold To Guide The Implementation Of Mass Drug Administration In Countries Endemic For Schistosomiasis: Comprehensive Synthesis Of Evidence For Developing The Tool BackgroundThe WHO-recommended prevalence thresholds for deciding schistosomiasis mass drug administration (MDA) are based on anecdotal evidence and may mislead. This study systematically synthesized evidence to generate a single optimal  global prevalence threshold that should guide schistosomiasis MDA programmes worldwide.

MethodsWe searched several databases from 1978 to 31st October 2021 without language restriction. Two reviewers selected studies, extracted data, and assessed risk of bias using relevant risk of bias tools, and resolved disagreements through discussion. The review followed best practices protocols and guidelines. Data were analysed and presented as prevalence reduction (PR) and relative risk (RR) for dichotomous outcomes or mean difference for continuous outcomes, each presented with their 95% confidence intervals (CI). Meta-regression of observations on prevalence rates and intensity of infection were performed to assess the effect of repeat MDA over time. Sensitivity analysis was performed to test the robustness of the results to the risk of bias components. The overall level of evidence was graded using GRADE.

FindingsOf the 1,232 studies retrieved, 38 met our inclusion criteria and 34 were included in the meta-analysis. No direct relation was observed between prevalence and intensity of infection. Praziquantel reduced prevalence of S. mansoni in school age children (SAC) at 12 months (RR 0.56, 95% CI 0.46 to 0.69; 14 studies, n=86,073); 24 months (RR 0.46; 95% CI 0.32 to 0.66; 14 studies; n=83,721); 36 months (RR 0.44, 95% CI 0.33 to 0.58; 7 studies, n=70,933) and 48 months (RR 0.25, 95% CI 0.11 to 0.59; 5 studies; n=27,483). Similarly for S. haematobium, there were reductions in prevalence in school age children (SAC) at 12 months (RR 0.38, 95% CI 0.28 to 0.52; 8 studies, n=37,868); at 24 months (RR 0.30; 95% CI 0.30[boxh]0.52; 7 studies; n=37,107); and 36 months (RR 0.39, 95% CI 0.21 to 0.71; 5 studies, n=28,146). There was no significant reduction in prevalence at 48 months (2 studies, n=10,954). Further analyses were performed from a series of prevalence thresholds created from the data at 5%, 10%, 15%, 20%, 30% and [&ge;]40% and the results showed differences in the effect of MDA when each threshold was applied in the regression model. For annual MDA involving SAC, school-based treatment (SBT) appeared to perform better than community-wide treatment (CWT) in terms of prevalence reduction; but this could be subject to the frequency of treatment and retreatment applied in SAC compared to CWT. Using the optimal prevalence threshold of 10%, the model suggested it will take over 10 years to bring the prevalence of schistosomiasis to 1% for S. haematobium and up to 15 years for S. mansoni with repeated annual MDA.

InterpretationThis systematic review and meta-analysis provides evidence that 10% prevalence is the optimum that should be used as the  standard global threshold for implementing MDA in endemic countries.

FundingThis work was commissioned and supported by the World Health Organization, Geneva, Switzerland as part of evidence-based schistosomiasis guideline development.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCurrently, the prevalence thresholds used in implementing mass drug administration within the preventive chemotherapy strategy for schistosomiasis control are based on anecdotal evidence and unreliable. We identified relevant studies regardless of language or publication status (published, unpublished, in press, and ongoing). We searched PubMed, CINAHL and LILACS from 1978 to 31st October 2021 without language restriction. We also searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2021), mRCT, Hinari, the WHO Library Database, Africa Journals Online and Google Scholar. Experts in the field of schistosomiasis were contacted, preprint repositories were searched and the reference lists of articles were reviewed for additional or unpublished data. This study was commissioned by the WHO to provide systematically synthesized evidence to inform on a single global prevalence threshold that should be applied by endemic countries when deciding MDA campaigns for the prevention and control of schistosomiasis.

Added value of this studyThis is the first systematic review and meta-analysis commissioned by the WHO to determine a single prevalence threshold that should be employed by endemic countries for the implementation of global schistosomiasis mass drug administration. This study pooled data involving thousands of participants across thousands of villages from all endemic settings, making it unique in terms of statistical power and generalizability of the main findings and conclusions. The study used PICOS (P-population, I-intervention, C-comparator, O-outcomes and S-study) to formulate an appropriate review question, clear objectives, stringent inclusion and exclusion criteria as well as rigorous quality assessment and data synthesis, following strictly best practices for preparing and reporting systematic reviews. The search has been very comprehensive including all relevant electronic databases and non-electronic sources, done in close collaboration with experienced information specialist. The review process ensured meticulous attention to details, making the necessary effort to minimize bias, carrying out aspects of the review independently by the reviewers and addressing disagreements through discussions between the reviewers. Given the geographical variations, and differences in the levels of baseline endemicities, diagnostic criteria, age groups treated and follow-up times across studies, this necessitated robust sub-group analyses to detect any sub-group effects. We ran meta-regression analyses to identify any potentially useful trends, and tested the robustness of effect estimates from sensitivity analyses. We have assembled world-class experts from diverse backgrounds and geographical locations, including epidemiologists, evidence synthesis specialists, economists, allied health professionals, statisticians, biomedical scientists, clinicians and non-medical experts to produce this innovative, demand-driven, policy- and context-relevant systematic review and meta-analysis that will help guide policy and practice in the global control of schistosomiasis.

Implications of all the available evidenceOur review provides evidence that 10% baseline prevalence is the minimum optimal threshold that should be used to decide the implementation of MDA programmes in schistosomiasis endemic countries. Praziquantel is effective in reducing the prevalence of schistosomiasis at 12 months, but incremental benefit of repeated annual treatment appears to be minimal after 12 months. Effectiveness depends on several factors, which are difficult to disentangle, however, the rate at which prevalence decreases does not appear to be influenced by baseline intensity of infection and treatment approach (whether whole community or school-based). From exploratory analysis, intensity of infection appears to be more stable than prevalence for assessing outcome of MDA. Therefore, further research is needed to determine an optimal intensity threshold and compare it with prevalence threshold. In terms of policy, the difficulty in achieving elimination with mass drug administration alone means that integration of non-pharmacological interventions such access to clean water, improved sanitation, hygiene education (WASH) and snail control to complement MDA if elimination is to be achieved.

This systematic review was registered in PROSPERO CRD422020221548.
Children develop strong and sustained cross-reactive immune responses against Spike protein following SARS-CoV-2 infection, with enhanced recognition of variants of concern SARS-CoV-2 infection is generally mild or asymptomatic in children but the biological basis for this is unclear. We studied the profile of antibody and cellular immunity in children aged 3-11 years in comparison with adults. Antibody responses against spike and receptor binding domain (RBD) were high in children and seroconversion boosted antibody responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Seroneutralisation assays against alpha, beta and delta SARS-CoV-2 variants demonstrated comparable neutralising activity between children and adults. T cell responses against spike were >2-fold higher in children compared to adults and displayed a TH1 cytokine profile. SARS-CoV-2 spike-specific T cells were also detected in many seronegative children, revealing pre-existing responses that were cross-reactive with seasonal Alpha and Beta-coronaviruses. Importantly, all children retained high antibody titres and cellular responses at 6 months after infection whilst relative antibody waning was seen in adults. Spike-specific responses in children also remained broadly stable beyond 12 months. Children thus distinctly generate robust, cross-reactive and sustained immune responses after SARS-CoV-2 infection with focussed specificity against spike protein. These observations demonstrate novel features of SARS-CoV-2-specific immune responses in children and may provide insight into their relative clinical protection. Furthermore, this information will help to guide the introduction of vaccination regimens in the paediatric population. Simple risk scores to predict hospitalization or death in outpatients with COVID-19 including the Omicron variant ImportanceOutpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, in particular whether to hospitalize a patient and if managed as an outpatient, how closely to follow them.

ObjectiveTo develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging.

DesignDerivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules.

SettingPrimary and Express care clinics in a Pennsylvania health system.

ParticipantsPatients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19.

Main outcomes and measuresClassification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC).

ResultsOverall, 7.4% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21) and 5.5% in the late validation cohort (3806 patients presenting 3/1/21 or later) were ultimately hospitalized. We developed and temporally validated three risk scores that all included age, dyspnea, and the presence of comorbidities, adding respiratory rate for the second score and oxygen saturation for the third. All had very good overall accuracy (AUC 0.77 to 0.78) and classified over half of patients in the validation cohort as very low risk with a 1.7% or lower likelihood of hospitalization. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization (2.8%).

Conclusions and relevanceSimple risk scores applicable to outpatient and telehealth settings can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/. Problems with Evidence Assessment in COVID-19 Health Policy Impact Evaluation (PEACHPIE): A systematic review of study design and evidence strength IntroductionAssessing the impact of COVID-19 policy is critical for informing future policies. However, there are concerns about the overall strength of COVID-19 impact evaluation studies given the circumstances for evaluation and concerns about the publication environment. This study systematically reviewed the strength of evidence in the published COVID-19 policy impact evaluation literature.

MethodsWe included studies that were primarily designed to estimate the quantitative impact of one or more implemented COVID-19 policies on direct SARS-CoV-2 and COVID-19 outcomes. After searching PubMed for peer-reviewed articles published on November 26, 2020 or earlier and screening, all studies were reviewed by three reviewers first independently and then to consensus. The review tool was based on previously developed and released review guidance for COVID-19 policy impact evaluation, assessing what impact evaluation method was used, graphical display of outcomes data, functional form for the outcomes, timing between policy and impact, concurrent changes to the outcomes, and an overall rating.

ResultsAfter 102 articles were identified as potentially meeting inclusion criteria, we identified 36 published articles that evaluated the quantitative impact of COVID-19 policies on direct COVID-19 outcomes. The majority (n=23/36) of studies in our sample examined the impact of stay-at-home requirements. Nine studies were set aside because the study design was considered inappropriate for COVID-19 policy impact evaluation (n=8 pre/post; n=1 cross-section), and 27 articles were given a full consensus assessment. 20/27 met criteria for graphical display of data, 5/27 for functional form, 19/27 for timing between policy implementation and impact, and only 3/27 for concurrent changes to the outcomes. Only 1/27 studies passed all of the above checks, and 4/27 were rated as overall appropriate. Including the 9 studies set aside, reviewers found that only four of the 36 identified published and peer-reviewed health policy impact evaluation studies passed a set of key design checks for identifying the causal impact of policies on COVID-19 outcomes.

DiscussionThe reviewed literature directly evaluating the impact of COVID-19 policies largely failed to meet key design criteria for inference of sufficient rigor to be actionable by policy-makers. This was largely driven by the circumstances under which policies were passed making it difficult to attribute changes in COVID-19 outcomes to particular policies. More reliable evidence review is needed to both identify and produce policy-actionable evidence, alongside the recognition that actionable evidence is often unlikely to be feasible. GARD is a pan-cancer predictor of radiation therapy benefit BackgroundDespite advances in cancer genomics, radiation therapy (RT) is still prescribed based on an empiric one-size-fits-all paradigm. Previously, we proposed a novel algorithm using the genomic adjusted radiation dose (GARD) to personalize RT prescription dose based on the biological effect of a given physical RT dose, calculated using individual tumor genomics. We hypothesize that GARD will reveal interpatient heterogeneity associated with opportunities to improve outcomes compared to physical RT dose alone. To test this hypothesis, and the GARD-based RT dosing paradigm, we performed a pooled pan-cancer analysis in 11 separate clinical cohorts of 1,615 unique patients with 7 different cancer types that represent all available cohorts with the data required to calculate GARD, together with clinical outcome.

MethodsUsing 11 previously-published datasets of cancers including breast, head and neck, non-small cell lung, pancreas, endometrium, melanoma and glioma, we defined two clinical endpoints: (i) time to first recurrence and (ii) overall survival, comprising 1,298 (982 +RT, 316 -RT) and 677 patients (424 +RT, 253 -RT), respectively. We used Cox regression stratified by cohort to test association between GARD and outcome with separate models using RT dose and sham-GARD for comparison. Interaction tests between GARD and treatment (+/- RT) were performed using the Wald statistic.

ResultsPooled analysis of all available data reveal that GARD as a continuous variable is associated with recurrence (HR = 0.982, CI [0.970, 0.994], p = 0.002) and survival (HR = 0.970, CI [0.953, 0.988], p = 0.001). The interaction test revealed the effect of GARD on survival depends on whether or not that patient received RT (Wald statistic: p=0.011). Physical RT dose and sham-GARD were not significantly associated with either outcome.

ConclusionsThe biologic effect of radiation therapy, as quantified by GARD, is significantly associated with recurrence and survival for those patients treated with radiation: it is predictive of RT benefit; and physical RT dose is not. We propose integration of genomics into radiation dosing decisions, using a GARD-based framework, as the new paradigm for personalizing RT prescription dose. The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. Adjunctive Ketamine for Sedation in Critically Ill Mechanically Ventilated Patients: An Active-Controlled, Pilot, Feasibility Clinical Trial ObjectiveKetamine has been shown to decrease sedative requirements in intensive care unit (ICU). Randomized trials are limited on patient-centered outcomes. We designed this pilot clinical trial to evaluate the feasibility of using ketamine as an adjunct analgosedative compared with standard of care (SOC) alone and determine preliminary effect size on 28-day mechanical ventilation (MV) duration and ventilator-free days (VFDs).

DesignPilot, single-center, active-controlled, open-label, randomized clinical trial.

SettingMedical, surgical, and transplant ICUs at King Faisal Specialist Hospital and Research Center, Saudi Arabia.

Patients and MethodsAdult patients who were intubated within 24 hours, expected to require MV for the next calendar day, and had institutional pain and sedation protocol initiated.

InterventionAdjunct ketamine infusion 1-2 g/kg/min for 48 hours versus SOC.

Measurements and Main ResultsTotal of 83 patients (43 in SOC and 40 in ketamine) were included. Demographics were balanced between groups. Median MV duration was 7 (interquartile range [IQR] 3-9.25 days) in ketamine and 5 (IQR 2-8 days) in SOC, p= 0.15. Median VFDs was 19 (IQR 0-24.75 days) in ketamine and 19 (IQR 0-24 days) in the SOC (p=0.70). More patients attained goal RASS score at 24 and 48 hours in ketamine (67.5% and 73.5%, respectively) compared with SOC (52.4% and 66.7%, respectively). Sedatives and vasopressors cumulative doses, and hemodynamic changes were similar. ICU length-of-stay was 12.5 (IQR 6-21.2 days) in ketamine, compared with 12 (IQR 5.5-23 days) in SOC, p=0.89. Consent and protocol adherence rate were adequate. No serious adverse events were observed in either group.

ConclusionsUse of ketamine as an adjunct analgosedative agent appeared to be feasible and safe with no negative impact on outcomes, including hemodynamics. The protocol of this pilot trial could be improved by modifying ketamine dosing regimen. These findings provide a basis for future, adequately powered, multicenter trial to investigate its association with patient-centered outcomes further. Preventable deaths from SARS-CoV-2 in England and Wales: a systematic case series of coroners reports during the COVID-19 pandemic ObjectivesTo examine coroners Prevention of Future Deaths reports (PFDs) to identify deaths involving SARS-CoV-2 that coroners deemed preventable.

DesignConsecutive case series.

SettingEngland and Wales.

ParticipantsPatients reported in 510 PFDs dated between 01 January 2020 and 28 June 2021, collected from the UKs Courts and Tribunals Judiciary website using web scraping to create an openly available database, https://preventabledeathstracker.net/.

Main outcome measuresConcerns reported by coroners.

Public and Patient InvolvementPatients and members of the public were not involved in this study.

ResultsSARS-CoV-2 was involved in 23 deaths reported by coroners in PFDs. Twelve deaths were indirectly related to the COVID-19 pandemic, defined as those that were not medically caused by SARS-CoV-2, but were associated with mitigation measures. In 11 cases the coroner explicitly reported that COVID-19 had directly caused death. There was geographical variation in the reporting of PFDs; most (39%) were written by coroners in the North-West of England. The coroners raised 56 concerns, problems in communication being the most common (30%), followed by failure to follow protocols (23%). Organizations in the National Health Service (NHS) were sent the most PFDs (51%), followed by the Government (26%), but responses to PFDs by these organizations were poor.

ConclusionsPFDs contain a rich source of information on preventable deaths that has previously been difficult to examine systematically. Our openly available tool (https://preventabledeathstracker.net/) streamlines this process and has identified many concerns raised by coroners that should be addressed during the Governments inquiry into the handling of the COVID-19 pandemic, so that mistakes made are less likely to be repeated.

Study protocol pre-registrationhttps://osf.io/bfypc/

Summary boxO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIThe UK Government has stated that there will be a public inquiry into the handling of the COVID-19 pandemic, to learn lessons for future pandemics.
C_LIO_LICoroners in England and Wales have a duty to report and communicate information about the deaths they investigate when the coroner believes that action should be taken to prevent future deaths.
C_LIO_LIThese reports, called Prevention of Future Death reports (PFDs), had not yet been systematically analysed to identify deaths that occurred during the COVID-19 pandemic.
C_LI

What are the new findings?O_LIWe created the Preventable Deaths Database (https://preventabledeathstracker.net/) using web scraping to systematically assess PFDs published on the Courts and Tribunal Judiciary website.
C_LIO_LIBetween 01 January 2020 and 28 June 2021, one in 20 (4.5%, n=23) PFDs that were published by coroners involved SARS-CoV-2.
C_LIO_LICoroners raised many concerns about the care of patients in hospitals, care homes, and people in the community during the COVID-19 pandemic, which require action to prevent future deaths.
C_LI

How might it affect clinical practice in the foreseeable future?O_LIPreventable deaths that occurred during the COVID-19 pandemic should be referred to the coroner so that an inquest can be performed and a PFD issued, highlightng actions that could be avoided in improving the handling of future pandemics in both the UK and elsewhere.
C_LIO_LIOur tool, https://preventabledeathstracker.net/, can be used by others to examine preventable deaths in England and Wales, and to identify signals for quality improvement to reduce avoidable harms in clinical practice.
C_LI Sexual Orientation Experiences of Discrimination: Dimensionality, internal consistency, and nomological validity in a diverse Colombian population The study aimed to determine the dimensionality, internal consistency, and nomological validity of the Sexual Orientation Experiences of Discrimination (SOEOD-9) among lesbian, gay, bisexual, and queer people in Santa Marta, Colombia. The study included 303 individuals between 18 and 70 years old. Participants completed the SOEOD-9. Dimensionality was explored using confirmatory (CFA) factor analysis; internal consistency with Cronbachs alpha and McDonalds omega; and nomological validity with Students test. The SOEOD-9 presented two factors that explained 51.6% of the variance and high internal consistency. Nevertheless, the CFA showed poor indicators of goodness-of-fit for the two-dimensional solution. A five-item version (SOEOD-5) improved overall performance (dimensionality, internal consistency, and nomological validity). In conclusion, the SOEOD-9 shows a two-factor internal structure with poor goodness-of-fit indicators and acceptable internal consistency and nomological validity. The SOEOD-5 presents better global indicators of dimensionality, internal consistency, and nomological validity. Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-Drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Cohort Study BackgroundAnti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease

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

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

ConclusionIn patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed. Comparative Analysis of the Chemotherapy-related Cognitive Impairments in Patients with Breast Cancer: a Community-based Research PurposeWith increasing breast cancer (BC) survival rates, the survivors quality of life (QoL) has become an important issue. Chemotherapy-induced cognitive impairment, known as "chemobrain" has been addressed recently. Therefore, cognitive function as one of the determinants of QoL should be considered while prescribing chemotherapeutics. In this study, we aimed to evaluate the effects of two common chemotherapy regimens on BC survivors cognition.

MethodsThe participants comprised 35 BC patients who underwent two common chemotherapy regimens, AC-T and TAC, and 24 matched healthy volunteers. The participants were assessed regarding anxiety, depression, general health status, and cognitive function including aspects of concentration, verbal ability, reasoning, memory, and visuospatial skill through Addenbrookes Cognitive Examination (ACE-P) and Cambridge Brain Science (CBS) tests.

ResultsRegarding depression and anxiety, there were no significant differences between the three groups. However, BC patients significantly complained of chronic fatigue compared to healthy volunteers (P-value = 0.027). Besides, ACE-P revealed the language domain to be affected in the AC-T group in comparison with the TAC-treated cases (P-value = 0.036). Moreover, the patients receiving the AC-T regimen had worse performance in visuospatial working memory and attention domains compared to the TAC group considering CBS tests (P-value = 0.031 and 0.008, respectively).

ConclusionThe results represent the AC-T regimen to be more toxic than the TAC in domains of language, concentration, and visuospatial working memory.

Implications for cancer survivorsThe AC-T regimen should be prescribed with caution in BC patients suffering from baseline cognitive impairments to improve post-chemotherapy QoL.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/21262481v2_ufig1.gif" ALT="Figure 1">
View larger version (39K):
org.highwire.dtl.DTLVardef@242c7eorg.highwire.dtl.DTLVardef@e53ba9org.highwire.dtl.DTLVardef@1aff274org.highwire.dtl.DTLVardef@56adec_HPS_FORMAT_FIGEXP  M_FIG C_FIG S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: a randomized, double-blind, placebo-controlled clinical trial BACKGROUNDSpinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown.

METHODSWe randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery.

RESULTSOf the 100 patients analyzed, patients receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml-1 (74.7 mg) or 0.25 mg ml-1 (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013-0.32, P = 0.033). The occurrence of adverse events was similar among the groups.

CONCLUSIONSOxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects. The effect of stimulus duration on preferences for gain adjustments when listening to speech ObjectivesIn the personalisation of hearing aid fittings, gain is often adjusted to suit patient preferences using live speech. When using brief sentences as stimuli, the minimum gain adjustments necessary to elicit consistent preferences ( preference thresholds) were previously found to be much greater than typical adjustments in current practice. The current study examined the role of duration on preference thresholds.

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

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

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

ConclusionsProviding longer stimuli improves the likelihood of patients providing reliable judgments of hearing-aid gain adjustments, but the effect is limited, and alternative fitting methods may be more viable for effective hearing-aid personalisation. A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

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org.highwire.dtl.DTLVardef@53a9f0org.highwire.dtl.DTLVardef@b9e76dorg.highwire.dtl.DTLVardef@108bd12org.highwire.dtl.DTLVardef@b500ddorg.highwire.dtl.DTLVardef@14be1d8_HPS_FORMAT_FIGEXP  M_TBL C_TBL Funding and Support in Kind

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org.highwire.dtl.DTLVardef@d86811org.highwire.dtl.DTLVardef@1985973org.highwire.dtl.DTLVardef@118ca5corg.highwire.dtl.DTLVardef@8d7839org.highwire.dtl.DTLVardef@1cff6e1_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderThe pilot at North Bristol Trust (NBT) is overseen by Neuromusculoskeletal (NMSK) Division governance. NBT NMSK Division takes responsibility for ensuring that the design of the study meets appropriate standards and that arrangements are in place to ensure appropriate conduct and reporting. Governance oversight for Hospital at Home was registered with NBT NMSK, and for primary care with Horfield Health Centre.

Roles and Responsibilities

Study Flow Chart

O_TBL View this table:
org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL Reports of myocarditis and pericarditis following mRNA COVID-19 vaccines: A systematic review of spontaneously reported data from the UK, Europe, and the US and of the literature ObjectivesTo bring together spontaneously reported data from around the world to estimate the reporting rate in different countries and better understand the risk factors for myocarditis and pericarditis following exposure to COVID-19 mRNA vaccines.

DesignSystematic review of the literature and systematic review of spontaneously reported data from the United Kingdom (UK), United States (US), and European Union/European Economic Area (EU/EEA).

Data sourcesSpontaneously reported data for COVID-19 Vaccine Pfizer/BioNTech (Comirnaty) and COVID-19 Vaccine Moderna (Spikevax) were obtained using outputs from the UKs Yellow Card scheme (covering the period 09/12/2020 - 20/10/2021), the Vaccine Adverse Event Reporting System (VAERS; US; covering the period 23/08/2021 - 21/10/2021), and EudraVigilance (EU/EEA; covering the period 21/12/2020 - 21/10/2021). Systematic searches of PubMed and Embase literature databases were performed with a datalock point of 11 October 2021.

Eligibility criteriaAll publicly available spontaneous reporting data from the three regions of interest were included. Data on events labelled "Myocarditis" and "Pericarditis" were included. No restrictions on age or gender were applied. For the systematic literature review, all pharmacoepidemiological studies of observational design investigating myocarditis and pericarditis following mRNA COVID-19 vaccines identified by our search were included. No restrictions on language or date were applied. Pre-print manuscripts were included if no peer-reviewed version was available. Studies of non-observational design, case reports, and case series were excluded. Study quality was assessed using relevant Critical Appraisal Skills Programme (CASP) tools. All studies were considered of sufficient quality for inclusion.

Data extraction and synthesisOne researcher extracted data from spontaneous reporting systems and published pharmacoepidemiological studies. Spontaneously reported events of myocarditis and pericarditis were presented for each individual data source, and stratified by vaccine, age, sex, and dose where this information was available. Vaccination data were obtained to the same date, and reporting rates were calculated for the events of myocarditis and pericarditis for each population of interest. For published pharmacoepidemiological studies, the study design, participant characteristics, and study results were tabulated.

ResultsOverall, there were 435 reports of myocarditis and 327 reports of pericarditis reported to the UKs Yellow Card scheme up to 20 October 2021. To 21 October 2021, in the US, 1936 reports of myocarditis and 1271 reports of pericarditis had been submitted to VAERS; there had been 2924 reports of myocarditis and 1855 reports of pericarditis submitted to EudraVigilance to the same date. Most reports (73.3%) had been submitted following Comirnaty (Pfizer/BioNTech). Males represented 74.9% of reports of myocarditis and 56.9% of pericarditis overall (for US and EU/EEA populations only), and the majority of reports concerned vaccinees ages under 40 years. Reports were more frequent following the second dose of mRNA COVID-19 vaccine. Reporting rates of myocarditis and pericarditis were consistent between the data sources. Seven pharmacoepidemiological studies were included; results of these studies were largely consistent with results of our spontaneous report analyses.

ConclusionsThis study provides evidence that younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines compared with older vaccinees. These events had mild clinical course followed by full recovery in most cases. Results from published literature supported the results of our analyses.

Strengths and Limitations of the StudyO_LIThis is the first study to bring together spontaneously reported data from the United Kingdom, United States, and Europe on myocarditis and pericarditis following mRNA COVID-19 vaccines.
C_LIO_LIResults from this study provide evidence on the frequency of reported events of myocarditis and pericarditis following mRNA vaccines in different age groups, and by sex and vaccine dose. Analyses of spontaneous reports were consolidated with results of published literature, identified by systematic review.
C_LIO_LIResults may have been influenced by biases including different vaccination policies in each region examined, and publicity on events of myocarditis and pericarditis following mRNA vaccines.
C_LIO_LIThe study relied on outputs from spontaneous reporting systems in which the level of detail differed between the systems examined; furthermore, it is not possible to estimate incidence rates using spontaneous reports due to the lack of data on the exposed population, and there is no unvaccinated comparison group.
C_LIO_LIThere is an urgent need for further pharmacoepidemiological studies to be conducted to provide more accurate estimates of the frequency, clinical course, long term outcome, effects of treatment and impact on quality of life, to address many of the limitations of spontaneous reporting.
C_LI Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19 AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSPurposeC_ST_ABSIndividuals with diabetes/stress hyperglycemia carry an increased risk for adverse clinical outcome in case of SARS-CoV-2 infection. The purpose of this study was to evaluate whether this risk is, at least in part, modulated by an increase of thromboembolic complications.

MethodsWe prospectively followed 180 hospitalized patients with confirmed COVID-19 pneumonia admitted to the Internal Medicine Units of San Raffaele Hospital. Data from 11 out of 180 patients were considered incomplete and excluded from the analysis. We analysed inflammation, tissue damage biomarkers, hemostatic parameters, thrombotic events (TEs) and clinical outcome according to the presence of diabetes/stress hyperglycemia.

ResultsAmong 169 patients, 51 (30.2%) had diabetes/stress hyperglycemia. Diabetes/stress hyperglycemia and fasting blood glucose (FBG) were associated with increased inflammation and tissue damage circulating markers, higher D-dimer levels, increased prothrombin time and lower antithrombin III activity. Forty-eight venous and 10 arterial TEs were identified in 49 (29%) patients. Diabetes/stress hyperglycemia (HR 2.71, p=0.001), fasting blood glucose (HR 4.32, p<0.001) and glucose variability (HR 1.6, p < 0.009) were all associated with an increased risk of thromboembolic complication. TEs significantly increased the risk for an adverse clinical outcome only in the presence of diabetes/stress hyperglycemia (HR 3.05, p=0.01) or fasting blood glucose [&ge;] 7 mmol/l (HR 3.07, p=0.015).

ConclusionsThromboembolism risk is higher among patients with diabetes/stress hyperglycemia and COVID-19 pneumonia and is associated to poor clinical outcome. In case of SARS-Cov-2 infection patients with diabetes/stress hyperglycemia could be considered for a more intensive prophylactic anticoagulation regimen. Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas Genetic variants of SARS-CoV-2 continue to dramatically alter the landscape of the COVID-19 pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized very recently, many knowledge gaps exist about its epidemiology and clinical severity and disease course. A comprehensive genome sequencing study of SARS-CoV-2 in the Houston Methodist healthcare system identified 862 symptomatic patients with infections caused by Omicron from late November 2021 through December 18, 2021. Omicron very rapidly increased in only three weeks to cause 90% of all new COVID-19 cases. Compared to patients infected with either Alpha or Delta variants in our healthcare system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with decreased disease severity. Although the number of Omicron patients we studied is relatively small, in the aggregate the data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, and provide information about disease character. The effects of modifiable maternal pregnancy risk factors on molar-incisor hypomineralisation: A negative control study ObjectivesO_LITo explore the associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).
C_LIO_LITo explore for the presence of residual confounding using negative control analyses.
C_LI

MethodsThis study used data from Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective birth cohort. We defined offspring MIH using prospectively collected questionnaire data. We used logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We included negative control exposure (paternal BMI, smoking and alcohol around the time of pregnancy) and outcome (offspring dental trauma) analyses to explore for the presence of residual confounding.

Results5536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a positive association between maternal mean BMI and offspring MIH (OR per 1-kg/m2 difference in maternal BMI: 1.04, 95% CI: 1.00, 1.08). In subsequent analyses, we found evidence that this effect was non-linear and being driven by women in the highest BMI quintiles. In negative control analyses, we found no evidence of association between paternal BMI and offspring MIH (OR: 0.94, 95% CI: 0.89, 1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95% CI: 0.96, 1.02). There was no clear evidence of an association for maternal pregnancy smoking (OR: 0.76, 95%CI: 0.46, 1.22) and alcohol consumption (OR: 0.79, 95% CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

ConclusionIn summary we found evidence of a possible intrauterine effect of high maternal pre-pregnancy BMI on offspring MIH. We did not find robust evidence for an intrauterine effect of maternal pregnancy smoking or alcohol consumption on offspring MIH. Our findings provide further support for women of reproductive age to maintain a healthy weight. Future studies are warranted to explore possible mechanisms on how the pregnancy environment may relate to offspring MIH. Prognostic association supports indexing size measures in echocardiography by body surface area Abstract and keywordsO_ST_ABSAimsC_ST_ABSBody surface area (BSA) is the most commonly used metric for body size indexation of echocardiographic measures, but its use in patients who are underweight or obese is questioned (body mass index (BMI) <18.5 kg/m2 or [&ge;]30 kg/m2, respectively). We aim to use survival analysis to identify an optimal body size indexation metric for echocardiographic measures that would be a better predictor of survival than BSA regardless of BMI.

Methods and ResultsAdult patients with no prior valve replacement were selected from the National Echo Database Australia. Survival analysis was performed for echocardiographic measures both unindexed and indexed to different body size metrics, with 5-year cardiovascular mortality as the primary endpoint. Indexation of echocardiographic measures (left ventricular end-diastolic diameter [n=337,481] and mass [n=330,959], left atrial area [n=136,989], aortic sinus diameter [n=125,130], right atrial area [n=81,699], right ventricular diameter [n=3,575], right ventricular outflow tract diameter [n=2,841]) by BSA had better prognostic performance vs unindexed measures (healthy/overweight: C-statistic 0.656 vs 0.618, average change in Akaike Information Criteria ({Delta}AIC) 800; underweight: C-statistic 0.669 vs 0.654, {Delta}AIC 15; obese: C-statistic 0.630 vs 0.612, {Delta}AIC 113). Indexation by other body size metrics (lean body mass or height and/or weight raised to various powers) did not improve prognostic performance versus BSA by a clinically relevant magnitude (average C-statistic increase [&le;]0.01), with smaller differences in higher BMI subgroups.

ConclusionIndexing measures of cardiac and aortic size by BSA improves prognostic performance regardless of BMI, and no other body size metric has a clinically meaningful better performance. The effect of D-cycloserine on brain processing of breathlessness over pulmonary rehabilitation - an experimental medicine study BackgroundPulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.

Methods72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions.

ResultsNo difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference.

ConclusionsThis is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.

Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSDoes the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity?

What is the bottom line?Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation.

Why read on?This study highlights both the value of functional magnetic resonance imaging in "de-risking" expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness. A year of Covid-19 GWAS results from the GRASP portal reveals potential SARS-CoV-2 modifiers Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of novel genetic associations with Covid-19 phenotypes could help developing new therapeutic strategies to reduce its burden.

Between May 2020 and June 2021, we used Covid-19 data released periodically by UK Biobank and performed 65 Genome-Wide Association Studies (GWAS) in up to 18 releases of Covid-19 susceptibility (N=18,481 cases in June 2021), hospitalization (N=3,260), severe outcomes (N=1,244) and death (N=1,104), stratified by sex and ancestry.

In coherence with previous studies, we observed 2 independent signals at the chr3p21.31 locus (rs73062389-A, OR=1.21, P=4.26x10-15 and rs71325088-C, OR=1.62, P=2.25x10-9) modulating susceptibility and severity, respectively, and a signal influencing susceptibility at the ABO locus (rs9411378-A, OR=1.10, P=3.30x10-12), suggesting an increased risk of infection in non-O blood groups carriers. Additional signals at the APOE (associated with severity and death) LRMDA (susceptibility in non-European) and chr2q32.3 (susceptibility in women) loci were also identified but did not replicate in independent datasets. We then devised an original approach to extract variants exhibiting an increase in significance over time. When applied to the susceptibility, hospitalization and severity analyses, this approach revealed the known DPP9, RPL24 and MAPT loci, amongst thousands of other signals. Finally, this significance trajectory analysis was applied to the larger Covid-19hgi meta-analyses, where additional loci of interest, related to the immune system, were identified.

These results, freely available on the GRASP portal, provide new insights on the genetic mechanisms involved in Covid-19 phenotypes. Effectiveness of a short term induction regimen of a biosimilar Adalimumab in the long term management of symptomatic Ankylosing Spondylitis Symptomatic Ankylosing Spondylitis: A Community Based Proof of Concept Observational Study IntroductionCost and drug toxicity often deter prolonged therapeutic use of anti-TNF agents in ankylosing spondylitis (AS). A planned study was completed to endorse our clinic based observation of long term relief following short-term administration of anti-TNF agent.

Methods50 consenting patients with symptomatic active chronic AS under rheumatology care in a community clinic were enrolled. They had no past history of anti-TNF use. 40 mg standard biosimilar adalimumab (BS-ADA, Exemptia trade name)was injected subcutaneously every fortnight for six injections (10 weeks). Patients were monitored at several time points. Improvement was assessed at regular interval as per protocol which included standard indices (Bath and Assessment Spondyloarthritis International Society /ASAS). An intention to treat analysis with significant p<0.05 was carried out.

ResultsPatients showed early and substantial significant improvement in pain, NSAID requirement, function and in several indices (ASAS 20 & 40, ASAS partial remission, BASDAI, BASFI, ASDAS) which persisted after stopping injections. 84% and 52 % of patients respectively showed ASAS 20 improvement at week 12 and 48: corresponding ASAS partial remission 34% and 24%. Over 50% patients maintained prolonged improvement and provided proof of concept (defined a-priori). Serum Interleukin-6 assay showed a sharp reduction at 24 weeks. None developed TB or serious drug toxicity. 11 patients withdrew (mostly inadequate response). Absence of control was a limitation.

ConclusionA ten-week administration of biosimilar adalimumab in difficult to treat AS showed early substantial improvement which often persisted for 24 weeks. This unconventional strategy was socioeconomically appealing. It merits further validation and acceptance especially in resource strained settings. 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.