title: A multiplex serological assay for the characterization of IgG immune response to SARS-CoV-2

abstract:
BackgroundIn the fight against SARS-COV-2, the development of serological assays based on different antigenic domains represent a versatile tool to get a comprehensive picture of the immune response or differentiate infection from vaccination beyond simple diagnosis.

ObjectivesHere we use a combination of the Nucleoprotein (NP), the Spike 1 (S1) and Spike 2 (S2) subunits, and the receptor binding domain (RBD) and N-terminal domain (NTD) of the Spike antigens from the Syrius-CoViDiag(R) multiplex IgG assay, to follow the immune response to SARS-CoV-2 infection over a long time period and depending on disease severity.

ResultsUsing a panel of 209 sera collected from 61 patients up to eight months after infection, we observed that most patients develop an immune response against multiple viral epitope, but anti-S2 antibodies seemed to last longer. For all the tested IgGs, we have found higher titers for hospitalized patients than for non-hospitalized ones. Moreover the combination of the five different IgG titers increased the correlation to the neutralizing antibody titers than if considered individually.

ConclusionMultiplex immunoassays have the potential to improve diagnostic performances, especially for ancient infection or mild form of the disease presenting weaker antibody titers. Also the combined detection of anti-NP and anti-Spike-derived domains can be useful to differentiate vaccination from viral infection and accurately assess the antibody potential to neutralize the virus.


title: Validation of the Panbio COVID-19 Antigen Rapid Test (Abbott) to screen for SARS-CoV-2 infection in Sint Maarten: a diagnostic accuracy study

abstract:
ObjectivesControl of the pandemic has required countries to look for other forms of tests besides the gold standard real-time polymerase chain reaction (RT-PCR). Rapid antigen tests (RAT), though less sensitive than RT-PCR, offer the possibility of rapid, inexpensive and early detection of the most infectious COVID-19 cases. Only very few studies have assessed the performance of the Abbott Panbio COVID-19 RAT among asymptomatic people or in Latin America. This study set out to validate this test among people attending the public test street in Sint Maarten, Dutch Caribbean.

MethodsPeople of all ages were recruited from the public COVID-19 test street regardless of COVID-19 symptoms. They received a nasopharyngeal swab for the Abbott Panbio COVID-19 RAT and the RT-PCR Qtower. Diagnostic accuracy of the RAT was compared to the RT-PCR among the overall study population and for subgroups with/without symptoms, with/without close contact and different Ct values.

ResultsUsing a RT-PCR Ct cut-off value of <33, 119 out of 1,411 people (8.4%) tested positive for SARS-CoV-2. Most were asymptomatic (59%). The overall sensitivity and specificity of the RAT was 84% (95% CI 76.2-90.1) and 99.9% (95% CI 99.6-100) respectively. The sensitivity reduced to 67.6% (95% CI: 49.5%, 82.6%) among people without symptoms, regardless of whether they were in close contact with a known COVID-19 case. Sensitivity reduced considerably with a Ct cut-off value of <35.

ConclusionsThe Abbott Panbio RAT is a valid and cheaper alternative to RT-PCR when used on symptomatic individuals among the general population. However, among asymptomatic people it should not be used as a stand-alone test and negative results should be confirmed with RT-PCR.

category: infectious diseases


title: Fitting the Reproduction number from UK coronavirus case data, and why it is close to 1

abstract: We present a method for rapid calculation of coronavirus growth rates and R-numbers tailored to the publicly available data in the UK. The R-number is derived from time-series of case data, using bespoke data processing to remove systematic and errors and stochastic fluctuations. In principle, growth rate can be obtained by differentiating the reported case numbers, but in fact daily stochastic fluctuations disqualify this method. We therefore assume that the case data comprises a smooth, underlying trend which is differentiable and a noise term. The approach produces, up-to-date estimates of the R-number throughout the period of data availability. Our method is validated against published consensus R-numbers from the UK government, and shown to produce comparable results. A significant advantage of our method is that it is stable up to the most recent data, this enables us to make R-number estimates available over two weeks ahead of the published consensus. The short-lived peaks observed in the R-number and case data cannot be explained by a well-mixed model and are suggestive of spread on a localised network. Such a localised spread model tends to give an Rt number close to 1, regardless of how large R0 is. The case-driven approach is combined with Weight-Shift-Scale (WSS) methods to monitor trends in the epidemic and for medium term predictions. Using case-fatality ratios, we create a narrative for trends in the UK epidemic increased infectiousness of the alpha and delta variants, and the effectiveness of vaccination in reducing severity of infection.


title: Using one-to-many urine proteome comparisons to provide clues for fever of unknown origin

abstract:
ObjectiveTo provide diagnostic evidence and clues for patients with fever of unknown origin (FUO) through urine proteomics analysis.

MethodsUrine samples of FUO were one-to-many analysed by using liquid chromatography tandem mass spectrometry(LC-MS/MS) to identify differential proteins and related biological pathways. One-to-many analysis means a comparative analysis of one sample to many controls.

ResultsWe observed biological pathways related to fever, such as LXR/RXR activation, FXR/RXR activation and acute phase response signaling, etc., which indicates that urine can obviously distinguish disease from health status. In addition, we found that the results of each sample were different, which highlight the necessity of one-to-many analysis.

ConclusionsThe combined method of urine proteomics and one-to-many analysis can provide clues for FUO, and might also be applied to the exploration of any unknown disease.


title: Tracking the temporal variation of COVID-19 surges through wastewater-based epidemiology during the peak of the pandemic: a six-month long study in Charlotte, North Carolina

abstract: The global spread of SARS-CoV-2 has continued to be a serious concern after WHO declared the virus the causative agent of the coronavirus disease 2019 (COVID-19) a global pandemic. Monitoring of wastewater is a useful tool for assessing community prevalence given that fecal shedding of SARS-CoV-2 occurs in high concentrations by infected individuals, regardless of whether they are asymptomatic or symptomatic. Using tools that are part of the wastewater-based epidemiology (WBE) approach, combined with molecular analyses, wastewater monitoring becomes a key piece of information used to assess trends and quantify the scale and dynamics of COVID-19 infection in a specific community, municipality, or area of service. This study investigates a six-month long SARS-CoV-2 RNA quantification in influent wastewater from four municipal wastewater treatment plants (WWTP) serving the Charlotte region of North Carolina (NC) using both RT-qPCR and RT-ddPCR platforms. Influent wastewater was analyzed for the nucleocapsid (N) genes N1 and N2. Both RT-qPCR and RT-ddPCR performed well for detection and quantification of SARS-CoV-2 using the N1 target, while for the N2 target RT-ddPCR was more sensitive. SARS-CoV-2 concentration ranged from 103 to105 copies/L for all four plants. Both RT-qPCR and RT-ddPCR showed a significant moderate to a strong positive correlation between SARS-CoV-2 concentrations and the 7-day rolling average of clinically reported COVID-19 cases using a lag that ranged from 7 to 12 days. A major finding of this study is that despite small differences, both RT-qPCR and RT-ddPCR performed well for tracking the SARS-CoV-2 virus across WWTP of a range of sizes and metropolitan service functions.

category: epidemiology


title: Low Gut Ruminococcaceae Levels are Associated with Occurrence of Antibiotic-associated Diarrhea

abstract: AO_SCPLOWBSTRACTC_SCPLOWPatients receiving antibiotics often suffer from antibiotic-associated diarrhea (AAD). AAD is of clinical significance as it can result in premature antibiotic discontinuation and suboptimal treatment of infection. The drivers of AAD however, remain poorly understood. We sought to understand if differences in the gut microbiome, both at baseline and during antibiotic administration, would influence the development of AAD. We administered a 3-day course of oral amoxicillin-clavulanate to 30 healthy adult volunteers, and performed a detailed interrogation of their stool microbiome at baseline and up to 4-weeks post antibiotic administration, using 16S rRNA gene sequencing. Lower levels of Ruminococcaceae were significantly and consistently observed from baseline till Day 7 in participants who developed AAD. The probability of AAD could be predicted based on qPCR-derived levels of Faecalibacterium prausnitzii, the most dominant species within the Ruminococcaceae family. Overall, participants who developed AAD experienced a greater decrease in microbial diversity during antibiotic dosing. Our findings suggest that a lack of gut Ruminococcaceae at baseline influences development of AAD. In addition, quantification of F. prausnitzii in stool prior to antibiotic administration may help identify patients at risk of AAD, and aid clinicians in devising individualised treatment regimens to minimise such adverse effects.

category: gastroenterology


title: PANDEMIC POLICY DESIGN VIA FEEDBACK: A MODELLING STUDY

abstract:
BackgroundThe COVID-19 pandemic has had an enormous toll on human health and well-being and led to major social and economic disruptions. Public health interventions in response to burgeoning case numbers and hospitalizations have repeatedly bent down the epidemic curve in many jurisdictions, effectively creating a closed-loop dynamic system. We aim to formalize and illustrate how to incorporate principles of feedback control into pandemic projections and decision making.

MethodsStarting with a SEEIQR epidemiological model, we illustrate how feedback control can be incorporated into pandemic management using a simple design (proportional-integral or PI control), which couples recent changes in case numbers or hospital occupancy with explicit policy restrictions. We then analyse a closed-loop system between the SEEIQR model and the designed feedback controller to illustrate the potential benefits of pandemic policy design that incorporates feedback.

FindingsWe first explored a feedback design that responded to hospital measured infections , demonstrating robust ability to control a pandemic despite simulating large uncertainty in reproduction number R0 (range: 1.04-5.18) and average time to hospital admission (range: 4-28 days). The second design compared responding to hospital occupancy to responding to case counts, showing that shorter delays reduced both the cumulative case count and the average level of interventions. Finally, we show that feedback is robust to changing public compliance to public health directives and to systemic changes associated with new variants of concern and with the introduction of a vaccination program.

InterpretationThe negative impact of a pandemic on human health and societal disruption can be reduced by coupling models of disease propagation with models of the decision-making process. This creates a closed-loop system that better represents the coupled dynamics of a disease and public health responses. Importantly, we show that feedback control is robust to delays in both measurements and responses and to uncertainty in model parameters and the efficacy of control measures.

FundingA Natural Sciences and Engineering Research Council Grant to SPO (RGPIN-2016-03711). NSERC Discovery Grant to GAD (RGPIN-2018-05151).

O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSA search on Pubmed on August 24 2021 for the keywords ((COVID[Title/Abstract]) AND (model[Title/Abstract])) AND ((projection[Title/Abstract]) OR (forecast[Title/Abstract])) returned 422 articles, reflecting challenges in accurate modeling of the pandemic. This pandemic has put both the influence and limitations of modeling into the public eye. A google search with the keywords "covid death model" AND "wrong" returns scientific articles as well as opinion and newspaper articles including in influential media. Many of the modeling papers include simulation scenarios evaluating possible interventions and control strategies. We found very few articles that take the inherent feedback into account that happens when intervention policies are determined in practice. An exception is the widely simulated ad hoc on-off policy where interventions are triggered when case or hospitalization levels are reached. A google scholar search using the keywords "covid 19 feedback control" returns over 30 articles in engineering journals that explicitly address the inherent feedback in the decision-making process. Many of these articles are highly technical and one of our goals in this study is to connect the engineering community with the public health and epidemiology community.

Added value of this studyThis study aims to provide the public health community with a brief overview of feedback control principles and how they apply to decision-making for a pandemic such as COVID-19. In this work we shift the focus from prediction to the design of interventions. We used a standard SEEIQR model with a simple controller to simulate the implication of feedback in the decision-making process. We show that, in contrast to highly varying open-loop projections, incorporating feedback explicitly in the decision-making process is more reflective of real-world situations and illustrates that effective decision making can be made even with only moderately accurate models. We show that effective feedback policy can be designed using daily case counts or hospitalizations and that it is not necessary to know the fraction of cases that is detected to control the pandemic. We illustrate how fundamental limitations of feedback impact the achievable level of control.

Implications of all the available evidenceIt is recommended that models of propagation of the virus be augmented with models of the decision-making process to produce a closed-loop system that is more representative of the real-world situation. Policy decisions resulting from systematic intervention design, rather than ad hoc decisions, will make projections more reliable and can encourage taking earlier and smaller actions, which reduce both case counts and the severity of interventions. Using feedback principles, effective control strategies can be designed even if the pandemic characteristics remain highly uncertain. Case numbers as well as total interventions can be reduced by minimizing all delays in the chain of information from testing and reporting to decision making and public response.

C_TEXTBOX

category: public and global health


title: Outcomes of gastrointestinal fistulas: Results from a multi-continent, multi-national, multicenter cohort

abstract:
RationaleGastrointestinal fistulas (GIF) represent a severe and potentially lethal complication of the hospital surgical activity. However, evidences are lacking about prognosis and outcomes of GIF in Latin America (LATAM) hospitals.

ObjectiveTo describe the prognosis and outcomes GIF in LATAM hospitals.

Study designProspective, longitudinal, cohort-type study. The cohort fostered three cross-sectional examinations: First examination: On admission of the patient in the study; Second examination: Thirty days later; and Third (and last) examination: Sixty days after patients admission.

Study serieOne hundred seventy-seven patients (Males: 58.2 %; Average age: 51.0 {+/-} 16.7 years; Ages [≥] 60 years: 36.2 %) diagnosed with, and assisted for, GIF (ECF: Enterocutaneous: 64.9 % vs. EAF: Enteroathmospheric: 35.1 %) in 76 LATAM hospitals (13 countries) and Europe (4).

MethodsCondition (Alive vs. Deceased) and hospital status (Hospitalized vs. Discharged) of the patient, and the GFI patency (Closed vs. Non closed) were recorded in each of the cohorts examination. Indicators of GFI prognosis thus constructed were correlated demographical, sanitary, surgical and nutritional characteristics of the patients

ResultsOn conclusion of the study indicators of GIF prognosis behaved as follows: Mortality:14.7 %; Prolonged hospitalization: 47.4 %; Spontaneous closure of GIF: 36.2 %. Type of GIF influenced upon patients survival: ECF: 87.0 % vs. EAF: 82.3 % ({Delta} = +4.7 %;{chi} 2 = 6.787; p < 0.05). In each examination of the cohort, the number of surviving subjects was always greater among those with ECF: After 30 days: ECF: 92.1 % vs. EAF: 83.9 % ({Delta} = +8.2 %); After 60 days: ECF: 98.1 % vs. EAF: 90.4 % ({Delta} = +7.7 %;{chi} 2 = 13.764; p < 0.05). On the other hand, hospital stay was prolonged in the subjects of elective surgery (Elective surgery: 61.4 % vs. Emergency surgery: 38.3 % ({Delta} = +23.1 %;{chi} 2 = 9.064; p < 0.05) and those with a reduced calf circumference ({chi}2 = 12.655; p < 0.05). Location of the fistula also influenced upon prolongation of hospital stay ({chi}2 = 7.817; p < 0.05).

ConclusionsType of GIF influences upon survival of the patient. On the hand, hospital stay was dependent upon type of surgery previously performed, location of the fistula, and calf circumference value on admission in the study serie.

category: surgery


title: Pre-clinical Research of Human Amnion-derived Mesenchymal Stem Cells and its First Clinical Treatment for a Severe Uremic Calciphylaxis Patient

abstract: Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. We reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers and mummified legs. Because of her rapid progression and refractory to conventional therapy, human amnion-derived mesenchymal stem cells (hAMSCs) treatment was approved. Establishment and release inspection of hAMSCs, efficacy and safety assessment including cytokines secretory ability, immunocompetence, tumorigenicity and genetics analysis in vitro were introduced. We further performed acute and long-term hAMSC toxity evaluations in C57BL/6 mice/rats, abnormal immune response tests in C57BL/6 mice and tumorigenic tests in the neonatal NU nude mice. After pre-clinical research, she was treated by hAMSCs with intravenous and local intramuscular injection and external supernatants application to her ulcers. When followed up to 15 months, her blood-based markers of bone and mineral metabolism were improved, with regeneration of skin soft tissue and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1 month treatment showed vascular regeneration with mature non-calcified vessels within dermis and 20 months later re-epithelialization restored the integrity of damaged site. No infusion or local treatment related adverse events occurred. To the best of our knowledge, this is the first evidence for the clinical use of hAMSCs. These findings suggest hAMSCs warrant further investigation as a potential regenerative treatment for uremic calciphylaxis with effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multi-differentiation, re-epithelialization and restorage of integrity.

category: nephrology


title: Characterization of a base-resolution common deletion region within CDKN2A gene in cancers and its biological and clinical significances

abstract:
BackgroundCDKN2A is most frequently inactivated by somatic copy number deletion (SCND) in human cancers. An accurate method to detect CDKN2A SCND is absent.

MethodsTo look for the pattern of CDKN2A SCND in cancer cells, interstitial base-resolution deletion/fusion coordinates for CDKN2A were extracted from published articles and our whole genome sequencing (WGS) datasets. A multiplex PCR assay was setup to quantify CDKN2A copy number and confirmed with WGS and loss of heterozygosity (LOH) assays using gastric carcinoma (GC) samples from two sets of patients (n=156 and 140), respectively.

ResultsWe characterized a 5.1-kb common deletion region (CDR) from the CDKN2A/P16INK4A promoter to intron-2 in >90% (83/92) of cancer cell lines and 100% (18/18) of GC samples by WGS. The CDR includes exon-2 that is shared by P16INK4A and P14ARF genes. Then, a highly reproducible and quantitative assay, P16-Light, targeted to the CDR was setup with a lower limit of detection at 20%. P16-Light was further compared with WGS (gold standard) and LOH assay by denaturing high performance liquid chromatography. The positive rate of CDKN2A SCND by P16-Light was more than two times of that by WGS in GCs from a patients cohort (25.6% vs. 10.9%), and was significantly correlated with each other (p<0.028). While CDKN2A SCND was significantly associated with GC distant metastasis (p=0.023), such association was not observed for CDKN2A LOH.

ConclusionBased on our finding that there is a 5.1-kb CDR within the CDKN2A gene, a vary convenient P16-Light assay was setup to detect CDKN2A SCND for routine clinical applications.

category: oncology


title: Detection of Somatic Copy Number Deletion of CDKN2A Gene for Clinical Practices Based on Discovery of A Base-Resolution Common Deletion Region


title: Loss of function mutation in ELF4 causes autoinflammatory and immunodeficiency disease in human

abstract: Monogenic autoinflammatory diseases (mAIDs) are a heterogeneous group of diseases affecting primarily innate immunity, with various specific genetic causes. Genetic diagnosis of mAIDs can assist in the patients management and therapy. However, a large number of sporadic and familial cases remain genetically uncharacterized. Here, we described a pediatric patient suffering from recurrent viral and bacterial respiratory infection, refractory oral ulcer and constipation, who was clinically diagnosed of inborn errors of immunity (IEI). In an effort to establish genetic diagnosis, no known causative genes were identified by whole-exome sequencing. However, manually going through bioinformatically predicted candidate genes, we suspected and prioritized ELF4 (chrX:129205133 A>G, c.691T>C, p.W231R) as the genetic cause for our patient. We then evaluated the pathogenicity of this mutation by both various bioinformatic methods and preliminary but definitive experimental approach. Our data suggested that W231R mutant ELF4 is a "loss of function" mutation causing decreased protein stability and decreased trans-activation activity. Thus, we identified a novel mAID, which we termed "X-linked autoinflammatory and immunodeficiency disease associated with ELF4, X-AIDE".

category: allergy and immunology


title: Unrecognized introductions of SARS-CoV-2 into the state of Georgia shaped the early epidemic

abstract: In early 2020, as SARS-CoV-2 diagnostic and surveillance responses ramped up, attention focused primarily on returning international travelers. Here, we build on existing studies characterizing early patterns of SARS-CoV-2 spread within the U.S. by analyzing detailed clinical, molecular, and viral genomic data from the state of Georgia through March 2020. We find evidence for multiple early introductions into Georgia, despite relatively sparse sampling. Most sampled sequences likely stemmed from a single introduction from Asia at least two weeks prior to the states first detected infection. Our analysis of sequences from domestic travelers demonstrates widespread circulation of closely-related viruses in multiple U.S. states by the end of March 2020. Our findings indicate that the early attention directed towards identifying SARS-CoV-2 in returning international travelers may have led to a failure to recognize locally circulating infections for several weeks, and points towards a critical need for rapid and broadly-targeted surveillance efforts in the future.


title: Three month FVC change: a potential trial endpoint for IPF based on individual participant data meta-analysis

abstract:
RationaleNovel therapies for idiopathic pulmonary fibrosis (IPF) are in development, but there remains uncertainty about the optimal trial endpoint. An earlier endpoint would enable assessment of a greater number of therapies in adaptive trial designs.

ObjectivesIndividual participant data (IPD) from placebo arms of interventional trials were sought to determine whether short-term changes in forced vital capacity (FVC), gas transfer for carbon monoxide (DLCO) and six-minute walk distance (6MWD) could act as surrogate endpoints to accelerate early-phase trials in IPF.

MethodsElectronic databases were searched on 1st December 2020, and IPD were sought and meta-analysed. The primary outcome was overall mortality according to baseline and/or three-month change in either FVC, DLCO or 6MWD, with a secondary outcome of disease progression at 12 months, adjusted for age, sex, smoking status and baseline physiology.

Measurements and main resultsIPD was available for 10/23 eligible studies totalling 1819 participants. Baseline and three-month change in all physiological variables were independently associated with disease outcomes. A 2.5% relative decline in FVC over three months was associated with mortality (adjusted hazard ratio 1.14, 95%CI 1.06;1.24, I2 = 59.9%) and disease progression (adjusted odds ratio 1.29; 95%CI 1.18;1.40, I2=67%). Optimal thresholds for three-month change in FVC for distinguishing disease outcomes were identified.

ConclusionsIPD meta-analysis of trial placebo arms demonstrated three-month change in physiological variables, particularly FVC, were associated with mortality and disease progression among individuals with untreated IPF. FVC change over three months may hold potential as a surrogate endpoint in IPF interventional adaptive trials.

category: respiratory medicine


title: Hope is No Plan: Uncovering Actively Missing Transition-Aged Youth with Congenital Heart Disease

abstract:
Background and ObjectivesStudies describing gaps in care for youth with congenital heart disease (CHD), focus on those who have returned to care, but rarely those actively missing from care. Our objective was to determine barriers for young adults with CHD actively missing from cardiac care and to re-engage them in care.

MethodsRetrospective single-center cohort study of cardiology clinic patients ages 15-21 years with CHD between 2012-2019 for patients actively missing from care ([≥]12 months beyond requested clinic follow-up). We conducted prospective interviews, offered clinic scheduling information and recorded cardiac follow-up. Data was analyzed using descriptive statistics, univariable, and multivariable logistic regression.

ResultsOf 1053 CHD patients, 33% (n=349) were actively missing. Of those missing, 58% were male and median age was 17 yrs (IQR 16-19). Forty-six percent were Non-Hispanic White, 33% Hispanic, and 9% Black. Moderately complex CHD was in 71%, and 62% had private insurance. Patients with simple CHD, older age at last encounter (18-21), and scheduled follow-up >12 months from last encounter were more likely to be actively missing. Interviews were completed by 125 patients/parents (36%). Lack of cardiac care was reported in 52%, and common barriers included: insurance (33%), appointment scheduling (26%), and unknown ACHD center care (15%). Roughly half (55%) accepted appointment information, yet only 3% successfully returned.

ConclusionsMany patients require assistance beyond CHD knowledge to maintain and re-engage in care. Future interventions should include scheduling assistance, focused insurance maintenance, understanding where to obtain ACHD care, and educating on need for lifelong care.

Article SummaryThere is a growing population of youth with congenital heart disease leaving cardiology care; we investigate patients actively missing from care and target their re-engagement.

Whats Known on This Subject?Maintaining cardiac care is a problem for many patients with congenital heart disease, especially teens and young adults, and characteristics of both patients and their healthcare environment contribute to the maintenance and ability to continue appropriate cardiac care.

What This Study AddsThis study uniquely investigates patients with congenital heart disease that are actively missing from care, and investigates if a simple intervention of contacting them while they are missing to re-engage them in care impacts their re-entry into cardiac care.

Contributors Statement PageJudson Moore conceptualized and designed the study, designed data collection instruments, collected data, drafted the initial manuscript, and completed necessary revisions to final manuscript.

Keila Lopez conceptualized and designed the study, designed data collection instruments, critically reviewed data, revised manuscript drafts, and provided content expertise.

Shreya Sheth conceptualized and designed the study, critically reviewed data, and revised the manuscript.

Wilson Lam contributed to study design, critically reviewed data for intellectual content, and revised the manuscript.

Alexander Alexander, Andre Espaillat, and John Shabosky designed data collection instruments, collected data, and reviewed/revised the manuscript.

Karla Dyer performed data extraction, data cleaning, and reviewed/revised the manuscript.

Nicole Broussard and Donna Lovick provided expert knowledge for interpretation of data and reviewed/revised the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

category: pediatrics


title: Covid-19 Per Capita Fatality Rate: A Path Analysis Model

abstract:
ObjectivesVarious individual factors have been shown to influence Covid-19 mortalities, but these factors do not exist in isolation. Unique to this study is a multivariate approach that has yet to be fully explored by previous research. Using an interconnected multifactor model, this work investigated social determinant, geographic, prior health, and political behavioral factors likely to influence Covid-19 per capita fatalities in Texas.

MethodsCounty-level income, rurality, insurance, health status, 2020 presidential vote percentage, and fatality rate data were collected and analyzed in a path analysis model with Covid-19 per capita fatalities as the key variable of interest.

ResultsThe analysis found strong support for the proposed model structure (R2 = 37.6%). The strongest overall effects on the Covid-19 per capita fatality rate came from income levels and voting behaviors.

ConclusionThe model explained a substantial amount of variability in mortalities attributed to Covid-19. Socioeconomic and political factors provided the strongest contribution to the per-capita Covid-19 death rate, controlling for the other variables studied. The Covid-19 pandemic was highly politicized by various leaders and media outlets. The current analysis showed that political trends were one of the key overall factors related to Covid-19 mortality. The strongest overall factor was median income. Income is used to enhance ones current health or acquire adequate treatment which may safeguard people from the most severe effects of Covid-19. Counties with lower income levels had higher rates of Covid-19 per capita fatalities.


title: Comparison of adverse events between COVID-19 and Flu vaccines

abstract:
BACKGROUNDAmong the various driving factors for vaccine hesitancy, confidence in the safety associated with the vaccine constitutes as one of the key factors. This study aimed at comparing the adverse effects of COVID-19 vaccines with the Flu vaccines.

METHODSThe VAERS data from 01/01/2020 to 08/20/2021 were used. The MedDRA terms coded by VAERS were further aggregated by a clinician into clinically meaningful broader terms.

RESULTSVarious common adverse events between Flu and COVID-19 vaccines have been identified. Adverse events such as headache and fever were very common across all age groups. Among the common adverse events between Flu and COVID-19 vaccine, the relative risk along with 95% CI indicated that such common adverse events were more likely to be experienced by COVID-19 vaccine users than Flu vaccine users. Our study also quantified the proportion of rare adverse events such as Guillain Barre Syndrome and Gynecological changes in the VAERS database for COVID-19 vaccines.

CONCLUSIONSBased on the available data and results, it appears that there were some common adverse events between Flu vaccines and COVID-19 vaccines. These identified common adverse events warrant further investigations based on the relative risk and 95% CI.


title: The impact of heating, ventilation, and air conditioning design features on the transmission of viruses, including the 2019 novel coronavirus: a systematic review of filtration

abstract:
Historically, viruses have demonstrated airborne transmission. Emerging evidence suggests the novel coronavirus (SARS-CoV-2) that causes COVID-19 may also spread by airborne transmission. This is more likely in indoor environments, particularly with poor ventilation. In the context of potential airborne transmission, a vital mitigation strategy for the built environment is heating, ventilation, and air conditioning (HVAC) systems. HVAC features could modify virus transmission potential. A systematic review following international standards was conducted to comprehensively identify and synthesize research examining the effectiveness of filters within HVAC systems in reducing virus transmission. Twenty-three relevant studies showed that: filtration was associated with decreased transmission; filters removed viruses from the air; increasing filter efficiency (efficiency of particle removal) was associated with decreased transmission, decreased infection risk, and increased viral filtration efficiency (efficiency of virus removal); increasing filter efficiency above MERV 13 was associated with limited benefit in further reduction of virus concentration and infection risk; and filters with the same efficiency rating from different companies showed variable performance. Increasing filter efficiency may mitigate virus transmission; however, improvement may be limited above MERV 13. Adapting HVAC systems to mitigate virus transmission requires a multi-factorial approach and filtration is one factor offering demonstrated potential for decreased transmission.

Practical ImplicationsIn order for filtration to be an effective means of virus removal and transmission control, proper installation is required. As well, professionals should be aware of the fact that similarly rated filters from different companies may offer different virus reduction results. While increasing filtration efficiency (i.e., increasing MERV rating or moving from MERV to HEPA) is associated with virus mitigation, there appears to be diminishing returns for filters rated MERV 13 or higher. Although costs increase with filtration efficiency, filtration costs are lower than the cost of ventilation options with the equivalent reduction in transmission.


title: COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/ml 25(OH)D3: Results of a systematic review and meta-analysis

abstract:
BackgroundMuch research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic.

MethodsSystematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex and diabetes. Data were analyzed using correlation and linear regression.

ResultsOne population study and seven clinical studies were identified, which reported D3 blood levels pre-infection or on the day of hospital admission. They independently showed a negative Pearson correlation of D3 levels and mortality risk (r(17)=-.4154, p=.0770/r(13)=-.4886, p=.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/ml (17.4 - 26.8), and a significant Pearson correlation was observed (r(32)=-.3989, p=.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/ml D3.

ConclusionsThe two datasets provide strong evidence that low D3 is a predictor rather than a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/ml to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.

Trial registrationNot applicable.


title: A systematic review of COVID-19 vaccine efficacy and effectiveness against SARS-CoV-2 infection and disease

abstract: Billions of doses of COVID-19 vaccines have been administered globally, dramatically reducing SARS-CoV-2 incidence and severity in some settings. Many studies suggest vaccines provide a high degree of protection against infection and disease, but precise estimates vary and studies differ in design, outcomes measured, dosing regime, location, and circulating virus strains. Here we conduct a systematic review of COVID-19 vaccines through February 2022. We included efficacy data from Phase 3 clinical trials for 15 vaccines undergoing WHO Emergency Use Listing evaluation and real-world effectiveness for 8 vaccines with observational studies meeting inclusion criteria. Vaccine metrics collected include protection against asymptomatic infection, any infection, symptomatic COVID-19, and severe outcomes including hospitalization and death, for partial or complete vaccination, and against variants of concern Alpha, Beta, Gamma, Delta, and Omicron. We additionally review the epidemiological principles behind the design and interpretation of vaccine efficacy and effectiveness studies, including important sources of heterogeneity.


title: Oral, similar to intranasal, administration of oxytocin decreases top-down social attention, but additionally enhances bottom-up control

abstract: 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.

category: pharmacology and therapeutics


title: Oral, similar to intranasal, administration of oxytocin decreases top-down social attention


title: Postnatal maternal depressive symptoms and behavioural outcomes in term- and preterm-born toddlers

abstract:
ObjectivesTo examine the association between maternal depressive symptoms in the immediate postnatal period and offsprings mental health in a large cohort of term- and preterm-born toddlers.

Design and ParticipantsData were drawn from the Developing Human Connectome Project. Maternal postnatal depressive symptoms were assessed at term, and childrens outcomes were evaluated at a median corrected age of 18.4 months (range 17.3 - 24.3).

Exposure and outcomesPreterm birth was defined as <37 weeks completed gestation. Maternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS). Toddlers outcome measures were parent-rated Child Behaviour Checklist 11/2-5 Total (CBCL) and Quantitative Checklist for Autism in Toddlers (Q-CHAT) scores. Toddlers cognition was assessed with the Bayley Scales of Infant and Toddler Development - Third Edition (Bayley-III).

ResultsHigher maternal EPDS scores were associated with toddlers higher CBCL (B=0.93, 95% CI 0.43-1.44, p<0.001, f2=0.05) and Q-CHAT scores (B=0.27, 95% CI 0.03-0.52, p=.031, f2=0.01). Higher maternal EPDS scores were not associated with toddlers cognitive outcomes. Maternal EPDS, toddlers CBCL and Q-CHAT scores did not differ between preterm (n=97; 19.1% of the total sample) and term participants.

ConclusionsOur findings indicate that children whose mothers had increased depressive symptoms in the early postnatal period, including subclinical symptoms, exhibit more maternally-reported behavioural problems in toddlerhood. These associations were independent of gestational age. Further research is needed to confirm the clinical significance of these findings.

Strengths and limitations of this studyO_LIProspective study with a large sample, using multiple imputation to reduce non-response bias.
C_LIO_LIMaternal depressive symptoms assessed as a continuous variable, providing more nuanced information about the significance of subclinical symptoms.
C_LIO_LIMaternal depressive symptoms assessed earlier than in previous studies, enabling recognition of early screening opportunities for families.
C_LIO_LIPotential shared method variance bias through parent-completed child behavioural assessments.
C_LIO_LIUnknown paternal and parental factors, such as comorbid psychiatric conditions, that may confound our findings.
C_LI

category: psychiatry and clinical psychology


title: Effect of Long-Term Caloric Restriction on DNA Methylation Measures of Biological Aging in Healthy Adults: CALERIETM Trial Analysis

abstract: Calorie restriction (CR) slows aging and increases healthy lifespan in model organisms. We tested if CR slowed biological aging in humans using DNA methylation analysis of blood samples from N=197 participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) randomized controlled trial. We quantified CR effects on biological aging by comparing change scores for six epigenetic-clock and Pace-of-Aging measures between n=128 CR-group and n=69 ad-libitum-control-group participants at 12- and 24-month follow-ups. CR effects were strongest for DunedinPACE Pace of Aging (12-month Cohens d=0.3; 24-month Cohens d=0.2, p<0.01 for both), followed by DunedinPoAm and the GrimAge epigenetic clock, although effects for these measures were not statistically different from zero (p>0.08). CR effects for other epigenetic clocks were in the opposite direction (all p>0.15). CALERIE intervention slowed Pace of Aging but showed minimal effect on epigenetic clocks hypothesized to reflect longer term accumulation of aging burden.

category: nutrition


title: Cohort Study: The Accuracy of Screening Methods of COVID-19 in Pregnancy: Practical Approach in Low Resources Health Services

abstract:
BackgroundAll pregnant women in labor should be universally screened for Coronavirus Disease 2019 (COVID-19) during pandemic periods using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test. In many low-middle income countries, screening method was developed as an initial examination because of limited availability of RT-PCR tests.

ObjectivesThis study aims to evaluate the screening methods of COVID-19 accuracy in pregnant women.

Material and MethodsWe recruited all pregnant women with suspicion of COVID-19 from April - August 2020 at Universitas Airlangga hospital, Surabaya, Indonesia. The participant was divided into two groups based on RT-PCR results: COVID-19 and non-COVID-19 group. The proportion of positive signs & symptoms, rapid antibody test, abnormal findings in chest x-ray, and neutrophil to lymphocyte ratio (NLR) value were then compared between both groups. The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV), and diagnostic accuracy (DOR) were calculated.

ResultsA total 141 pregnant women with suspected COVID-19 cases were recruited for this study. This consist of 62 COVID-19 cases (43.9%) and 79 non COVID-19 pregnant women (56.1%). The sensitivity, spesificity, PPV, NPV, and diagnostic accuracy of each parameter are as follow: clinical sign & symptoms (24.19%, 75.95%, 3.92%, 96.11%, 65.87%), rapid antibody test (72.73%, 35.06%, 4.35%, 96.94%, 36.53%), chest x-ray (40.68%, 59.45%, 3.92%, 96.11%, 58.76%), and NLR > 5.8 (41.38%, 72%, 5.66%, 96.80%, 70.81%).

ConclusionsThe use of combined screening methods can classify pregnant women with high-risk COVID-19 before definitively diagnosed with RT-PCR. This practice will help to reduce RT-PCR need in a limited resources country.

category: obstetrics and gynecology


title: Factors affecting return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice

abstract:
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

category: orthopedics


title: Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice


title: The Impact of New SARS-CoV-2 Variants on Vaccine Breakthrough: a pilot study on spreading infection in the communities

abstract:
BackgroundCoronavirus disease 2019 (COVID-19) vaccines are effective at helping protect against severe disease and death from variants; however, incident of breakthrough infection in vaccinated patients has been increased. Therefore, we aimed to assess the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) new variants of concern in the communities and investigate vaccine breakthrough cases on our laboratory (Ayass Bioscience LLC) confirmed detection of COVID-19 variants in Dallas-Fort Worth (DFW), Texas.

MethodsEpidemiologic study has been performed at our laboratory. We studied the viral whole-genome sequence and genotyping analysis on 166 symptomatic cases of COVID-19 which were randomly selected from nasal swab positive cases assessed from June 1st to August 30th, 2021, by reverse transcription polymerase chain reaction (RT-PCR) cycle threshold (CT) values. COVID-19 variants were identified to be dominated by B.1.617.2 (89.2%) and followed by AY.3 (1.8%), B.1.1.7 (4.8%), a combination of B.1.526.1 and B.1.617.2 (3%), B.1.621 (0.6%), and P.2 (0.6%).

ResultThe CT values showed significant difference among the three age groups: <30 years, 31-60 years, and >60 years by one-way ANOVA (N1: F (2, 118) =4.96, p=0.009; N2: F (2, 118) =4.95, p=0.009). No significant difference was observed by symptom, status of immunization, or vaccine manufacturer. A two-way ANOVA was performed to examine the effect of gender and variant group (Delta and other variants) on the CT values. The analyses revealed a statistically significant interaction between the effect of gender and variant group (N1, F (1.117) = 3.906, p = 0.05; N2, F (1, 117) = 7.402, p = 0.008).

ConclusionOur study shows that Delta, the dominant variant of COVID-19, is spreading in the communities, and vaccine breakthrough cases occurred in the majority of Delta variant (91%) followed by AY.3 (5%), B.1.1.7 (2%) and 2% of the double variant of B.1.526.1 and B.1.617.2. The incidence of the breakthrough cases was not linked to a specific manufacturer. The CT value is likely to associate with age. This study also supports our laboratorys ongoing efforts to sequence the SARS-CoV-2 virus from positive patient samples to identify the new viral variants and possible vaccine breakthrough mutations in the community.


title: Association of comorbidities with COVID-19 infection rate and severity: nationwide cohort study with propensity score matching

abstract:
OO_SCPLOWBJECTIVEC_SCPLOWTo describe the association of comorbidities with coronavirus infection-19 (COVID-19) infection rates and severity of infection through Korean nationwide medical system.

DO_SCPLOWESIGNC_SCPLOWNationwide population-based retrospective cohort study.

SO_SCPLOWETTINGC_SCPLOWKorean national health insurance claims database between January 1, 2020, and May 30, 2020.

PO_SCPLOWARTICIPANTSC_SCPLOWPatients with positive COVID-19 test and 12 folded controls matched by age, sex and region.

MO_SCPLOWAINC_SCPLOW OO_SCPLOWUTCOMESC_SCPLOW MO_SCPLOWEASURESC_SCPLOWOutcomes were confirmation of the comorbidities affecting the infection rate and the severity of COVID-19. Patients and outcomes were propensity score matching of factors which may affect COVID-19 infection rate and severity was performed. COVID-19 infections were confirmed through laboratory testing. Severe infection was defined as those who underwent tracheostomy, continuous renal replacement therapy, intensive care unit admission, ventilator use, cardiopulmonary resuscitation, or died.

RO_SCPLOWESULTSC_SCPLOWA total of 8070 individuals with positive covid-19 test and 12015 controls were identified. In people aged 60 or older, in those insured with Medicaid, and in the disabled, the proportion corresponding to the severe group of patients showed a tendency to increase. The infection rate of COVID-19 was highest in pulmonary disease (adjusted odds ratio 1.88, 95% confidence interval 1.70 to 2.03), and hyperlipidemia (0.73, 0.67 to 0.80) had a lower infection rate. Disease severity was highest in kidney disease (5.59, 2.48 to 12.63), and lower in hyperlipidemia (0.78, 0.60 to 1.00).

CO_SCPLOWONCLUSIONSC_SCPLOWThere is less bias as the government pays for all tests and treatments related to COVID-19 included in the data used in this study. Using propensity matching to reduce statistical bias, we found that most comorbidities increased the infection rate and severity of COVID-19, whereas hyperlipidemia reduced the rate and severity of infection. These results can be utilized to effectively manage COVID-19 infections.


title: Young Zambian infants with symptomatic RSV and pertussis infections are frequently prescribed inappropriate antibiotics

abstract: Pediatric community-acquired pneumonia (CAP) remains a pressing global health concern, particulary in low-resource settings where diagnosis and treatment rely on empiric, symptoms-based guidelines such as the WHOs Integrated Management of Childhood Illness (IMCI). This study details the delivery of IMCI-based health care in a cohort of 1,320 young infants and their mothers in a low-resource urban community in Lusaka, Zambia. We prospectively monitored mother/infant pairs across infants first four months of life, recording symptoms of respiratory infection and antibiotics prescriptions (predominantly penicillins), and tested nasopharyngeal (NP) samples for Respiratory syncytial virus (RSV) and Bordetella pertussis. Symptoms and antibiotics use were more common in infants (43% and 15.7%) than in mothers (16.6% and 8%), while RSV and B. pertussis were observed at similar rates in infants (2.7% and 32.5%) and mothers (2% and 35.5%), albeit frequently at very low levels. In infants, we observed strong associations between symptoms, pathogen detection, and antibiotics use. Critically, we demonstrate that non-macrolide antibiotics were commonly prescribed for pertussis infections, some of which persisted across many weeks. We speculate that improved diagnostic specificity and/or clinician education paired with timely, appropriate treatment of pertussis could substantially reduce the burden of this disease while reducing the off-target use of penicillins.


title: Persistent while declined neutralizing antibody responses in the convalescents of COVID-19 across clinical spectrum during the 16 months follow up

abstract: Elucidation the kinetics of neutralizing antibody response in the coronavirus disease 2019 (COVID-19) convalescents is crucial for the future control of the COVID-19 pandemic and vaccination strategies. Here we tested 411 sequential plasma samples collected up to 480 days post symptoms onset (d.a.o) from 214 convalescents of COVID-19 across clinical spectrum without re-exposure history after recovery and vaccination of SARS-CoV-2, using authentic SARS-CoV-2 microneutralization (MN) assays. COVID-19 convalescents free of re-exposure and vaccination could maintain relatively stable anti-RBD IgG and MN titers during 400[~]480 d.a.o after the peak at around 120 d.a.o and the subsequent decrease. Undetectable neutralizing activity started to occur in mild and asymptomatic infections during 330 to 480 d.a.o with an overall rate of 14.29% and up to 50% for the asymptomatic infections. Significant decline in MN titers was found in 91.67% COVID-19 convalescents with [≥] 50% decrease in MN titers when comparing the available peak and current MN titers ([≥] 300 d.a.o). Antibody-dependent immunity could also provide protection against most of circulating variants after one year, while significantly decreased neutralizing activities against the Beta, Delta and Lambda variants were found in most of individuals. In summary, our results indicated that neutralizing antibody responses could last at least 480 days in most COVID-19 convalescents despite of the obvious decline of neutralizing activity, while the up to 50% undetectable neutralizing activity in the asymptomatic infections is of great concern.


title: The importance of sustained compliance with physical distancing during COVID-19 vaccination rollout

abstract:
Mass vaccination campaigns against SARS-CoV-2 are ongoing in many countries with increasing vaccination coverage enabling relaxation of lockdowns. Vaccination rollout is frequently supplemented with advisory from public health authorities for continuation of physical distancing measures. Compliance with these measures is waning while more transmissible virus variants such as Alpha (B.1.1.7) and Delta (B.1.617.2) have emerged. In this work, we considered a population where the waning of compliance depends on vaccine coverage. We used a SARS-CoV-2 transmission model which captures the feedback between compliance, infection incidence, and vaccination coverage to investigate factors that contribute to the increase of the prevalence of infection during the initial stages of the vaccination rollout as compared to no vaccination scenario. We analysed how the vaccine uptake rate affects cumulative numbers of new infections three and six months after the start of vaccination. Our results suggest that the combination of fast waning compliance in non-vaccinated population, low compliance in vaccinated population and more transmissible virus variants may result in a higher cumulative number of new infections than in a situation without vaccination. These adverse effects can be alleviated if vaccinated individuals do not revert to pre-pandemic contact rates, and if non-vaccinated individuals remain compliant with physical distancing measures. Both require convincing, clear and appropriately targeted communication strategies by public health authorities.

Significance StatementSARS-CoV-2 vaccination campaigns are in progress in many countries around the world. As the vaccination coverage increases, the compliance with physical distancing measures aimed at reducing virus transmission may decline. Using a socio-epidemiological model we identify factors that are the drivers of increased transmission when SARS-CoV-2 prevalence is higher than the projected prevalence without vaccination. To maximize the benefits of vaccination campaigns, compliance in vaccinated and non-vaccinated groups should be targeted prioritizing one group over the other depending on the vaccination rate, the efficacy of vaccine in blocking the infection, and the circulating variant.


title: Demographic characteristics of SARS-CoV-2 B.1.617.2 (Delta) variant infections in Indian population

abstract:
ImportanceHigher risks of contracting infection, developing severe illness and mortality are known facts in aged and male sex if exposed to the wild type SARS-CoV-2 strains (Wuhan and B.1 strains). Now, accumulating evidence suggests greater involvement of lower age and narrowing the age and sex based differences for the severity of symptoms in infections with emerging SARS-CoV-2 variants. Delta variant (B.1.617.2) is now a globally dominant SARS-CoV-2 strain, however, current evidence on demographic characteristics for this variant are limited. Recently, delta variant caused a devastating second wave of COVID-19 in India. We performed a demographic characterization of COVID-19 cases in Indian population diagnosed with SARS-CoV-2 genomic sequencing for delta variant.

ObjectiveTo determine demographic characteristics of delta variant in terms of age and sex, severity of the illness and mortality rate, and post-vaccination infections.

DesignA cross sectional study

SettingDemographic characteristics, including vaccination status (for two complete doses) and severity of the illness and mortality rate, of COVID-19 cases caused by wild type strain (B.1) and delta variant (B.1.617.2) of SARS-CoV-2 in Indian population were studied.

ParticipantsCOVID-19 cases for which SARS-CoV-2 genomic sequencing was performed and complete demographic details (age, sex, and location) were available, were included.

ExposuresSARS-CoV-2 infection with Delta (B.1.617.2) variant and wild type (B.1) strain.

Main Outcomes and MeasuresThe patient metadata containing details for demographic and vaccination status (two complete doses) of the COVID-19 patients with confirmed delta variant and WT (B.1) infections were analyzed [total number of cases (N) =9500, Ndelta=6238, NWT=3262]. Further, severity of the illness and mortality were assessed in subsets of patients. Final data were tabulated and statistically analyzed to determine age and sex based differences in chances of getting infection and the severity of illness, and post-vaccination infections were compared between wild type and delta variant strains. Graphs were plotted to visualize the trends.

ResultsWith delta variant, in comparison to wild type (B.1) strain, higher proportion of lower age groups, particularly <20 year (0-9 year: 4.47% vs. 2.3%, 10-19 year: 9% vs. 7%) were affected. The proportion of women contracting infection were increased (41% vs. 36%). The higher proportion of total young (0-19 year, 10% vs. 4%) (p=.017) population and young (14% vs. 3%) as well as adult (20-59 year, 75% vs. 55%) women developed symptoms/hospitalized with delta variant in comparison to B.1 infection (p< .00001). The mean age of contracting infection [Delta, men=37.9 ({+/-}17.2) year, women=36.6 ({+/-}17.6) year; B.1, men=39.6 ({+/-}16.9) year and women= 40.1 ({+/-}17.4) year (p< .001)] as well as developing symptoms/hospitalization [Delta, men=39.6({+/-} 17.4) year, women=35.6 ({+/-}16.9) year; B.1, men=47({+/-}18) year and women= 49.5({+/-}20.9) year (p< .001)] was considerably lower. The total mortality was about 1.8 times higher (13% vs. 7%). Risk of death increased irrespective of the sex (Odds ratio: 3.034, 95% Confidence Interval: 1.7-5.2, p<0.001), however, increased proportion of women (32% vs. 25%) were died. Further, multiple incidences of delta infections were noted following complete vaccination.

Conclusions and RelevanceThe increased involvement of young (0-19 year) and women, lower mean age for contracting infection and symptomatic illness/hospitalization, higher mortality, and frequent incidences of post-vaccination infections with delta variant compared to wild type strain raises significant epidemiological concerns.

Key PointsO_ST_ABSQuestionC_ST_ABSDid SARS-CoV-2 B.1.617.2 (Delta) variant infections show varied demographic characteristics in comparison to wild type strains?

FindingsIn this cross sectional study viral genomic sequences of 9500 COVID-19 patients were analyzed. As the key findings, increased involvement of young (0-19 year) and women, lower mean age for contracting infection and symptomatic illness/hospitalization, higher mortality, and frequent incidences of post-vaccination infections with delta variant in comparison to wild type (WT) strain (B.1) were observed.

MeaningThe findings of this study suggest that delta variant has varied demographic characteristics reflecting increased involvement of the young and women, and increased lethality in comparison to wild type strains.


title: Impact of vaccine hesitancy on secondary COVID-19 outbreaks in the US

abstract: The COVID-19 outbreak has become the worst pandemic in at least a century. To fight this disease, a global effort led to the development of several vaccines at an unprecedented rate. There have been, however, several logistic issues with its deployment, from their production and transport, to the hesitancy of the population to be vaccinated. For different reasons, an important amount of individuals is reluctant to get the vaccine, something that hinders our ability to control and - eventually - eradicate the disease. In this work, we analyze the impact that this hesitancy might have in a context in which a more transmissible SARS-CoV-2 variant of concern spreads through a partially vaccinated population. We use age-stratified data from surveys on vaccination acceptance, together with age-contact matrices to inform an age-structured SIR model set in the US. Our results clearly show that higher vaccine hesitancy ratios led to larger outbreaks. A closer inspection of the stratified infection rates also reveals the important role played by the youngest groups. Our results could shed some light on the role that hesitancy will play in the near future and inform policy-makers and the general public of the importance of reducing it.


title: Molecular network analyses implicate death-associated protein kinase 3 (DAPK3) as a key factor in colitis-associated dysplasia progression

abstract: Ulcerative colitis (UC) is a progressive disorder that elevates the risk of cancer development through a colitis-dysplasia-carcinoma sequence. Differential gene expression (DEGs) profiles of three UC clinical subtypes and healthy controls were developed for the GSE47908 microarray dataset [n = 15 (healthy controls), n = 20 (left-sided colitis), n = 19 (pancolitis), and n = 6 (colitis-associated dysplasia, CAD)] using limma R. Gene ontology (GO) enrichment analysis of DEGs revealed a shift in transcriptome landscape as UC progressed from left-sided colitis to pancolitis to CAD, from being immune-centric to being cytoskeleton-dependent. Hippo signaling (via Yes-associated protein, YAP) and Ephrin receptor signaling were the top canonical pathways progressively altered in concert with the pathogenic progression of UC. Molecular interaction network analysis of DEGs in left-sided colitis, pancolitis, and CAD revealed one pairwise line or edge that was topologically important to the network structure. This edge was found to be highly enriched in actin-based processes, and death-associated protein kinase 3 (DAPK3) was a critical member and sole protein kinase associated with this edge. DAPK3 is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. Differential correlation analyses revealed a negative correlation for DAPK3-YAP in healthy controls which flipped to positive in left-sided colitis. With UC progression to CAD, the DAPK3-YAP correlation grew progressively more positive. In summary, DAPK3 was identified as a candidate gene involved in UC progression to dysplasia.


title: Initial emergency department vital signs may predict PICU admission in pediatric patients presenting with asthma exacerbation

abstract:
ObjectiveSevere asthma exacerbations account for a large share of asthma morbidity, mortality, and costs. Here, we aim to identify early predictive factors for pediatric intensive care unit (PICU) admission that could help improve outcomes.

MethodsWe performed a retrospective observational study of 6,014 emergency department (ED) encounters at a large childrens hospital, including 95 (1.6%) resulting in PICU admission between 10/1/2015 and 8/31/2017 with ICD9/ICD10 codes for "asthma," "bronchospasm," or "wheezing". Vital signs and demographic information were obtained from EHR data and analyzed for each encounter. Predictive factors were identified using adjusted regression models, and our primary outcome was PICU admission.

ResultsHigher mean heartrates (HR) and respiratory rates (RR) and lower SpO2 within the first hour of ED presentation were independently associated with PICU admission. Odds of PICU admission increased 63% for each 10-beats/minute higher HR, 97% for each 10-breaths/minute higher RR, and 34% for each 5% lower SpO2. A binary predictive index using 1-hour vitals yielded OR 11.7 (95%CI 7.4-18.3) for PICU admission, area under the receiver operator characteristic curve (AUROC) 0.82 and overall accuracy of 81.5%. Results were essentially unchanged (AUROC 0.84) after adjusting for asthma severity and initial ED management. In combination with a secondary standardized clinical asthma distress score, positive predictive value increased by seven-fold (5.9% to 41%).

ConclusionsA predictive index using HR, RR and SpO2 within the first hour of ED presentation accurately predicted PICU admission in this cohort. Automated vital signs trend analysis may help identify vulnerable patients quickly upon presentation.


title: Prevalence of SARS-CoV-2 infection among people experiencing homelessness in Toronto during the first wave of the COVID-19 pandemic

abstract:
BackgroundPeople experiencing homelessness are at increased risk of SARS-CoV-2 infection. This study reports the point prevalence of SARS-CoV-2 infection during testing conducted at sites serving people experiencing homelessness in Toronto during the first wave of the COVID-19 pandemic. We also explored the association between site characteristics and prevalence rates.

MethodsThe study included individuals who were staying at shelters, encampments, COVID-19 physical distancing sites, and drop-in and respite sites and completed outreach-based testing for SARS-CoV-2 during the period April 17 to July 31, 2020. We examined test positivity rates over time and compared them to rates in the general population of Toronto. Negative binomial regression was used to examine the relationship between each shelter-level characteristic and SARS-CoV-2 positivity rates. We also compared the rates across 3 time periods (T1: April 17-April 25; T2: April 26-May 23; T3: May 24-June 25).

ResultsThe overall prevalence of SARS-CoV-2 infection was 8.5% (394/4657). Site-specific rates showed great heterogeneity with infection rates ranging from 0% to 70.6%. Compared to T1, positivity rates were 0.21 times lower (95% CI: 0.06, 0.75) during T2 and 0.14 times lower (95% CI: 0.043, 0.44) during T3. Most cases were detected during outbreak testing (384/394 [97.5%]) rather than active case finding.

InterpretationDuring the first wave of the pandemic, rates of SARS-CoV-2 infection at sites for people experiencing homelessness in Toronto varied significantly over time. The observation of lower rates at certain sites may be attributable to overall time trends, expansion of outreach-based testing to include sites without known outbreaks and/or individual site characteristics.


title: Prevalence and risk factors for in-school transmission of SARS-CoV-2 in Massachusetts K-12 public schools, 2020-2021

abstract:
IntroductionThe SARS-CoV-2 secondary attack rate (SAR) in schools is low when mitigation measures are adopted, Data on the relative impact of such strategies are limited. We evaluated the SARS-CoV-2 SAR in Massachusetts schools during 2020-21 and factors associated with transmission risk.

MethodsIn a convenience sample of 25 Massachusetts public K-12 school districts, de-identified information about SARS-CoV-2 cases and their school-based contacts was reported using a standardized contact-tracing tool. Index cases were included if they were in school while infectious. SAR was defined as the proportion of in-school contacts acquiring SARS-CoV-2 infection and designated as possible or probable in-school transmission by school-based teams. We compared exposure-specific SAR using unadjusted risk ratios (RR) with 95% confidence intervals (CI); p-values were calculated using Fishers exact tests.

ResultsEight districts (70 schools with >33,000 enrolled students) participated. There were 435 index cases and 1,771 school-based contacts (Table 1). Most contacts (1327/1771 [75%]) underwent SARS-CoV-2 testing and 39/1327 (2.9%) contacts tested positive. Of 39 positive contacts, 10 (25.6%) had clear out-of-school exposures and were deemed not in-school transmissions, so were excluded from further calculations. Twenty-nine (74.4%) contacts were deemed possible or probable in-school transmissions, resulting in an in-school SAR of 2.2%. Of the 29 in-school transmissions, 6 (20.7%) were staff-to-staff, 7 (24.1%) were staff-to-student, 3 (10.3%) were student-to-staff, and 13 (44.8%) were student-to-student; 6 (20.7%) occurred from index cases attending work/school while symptomatic. The unadjusted SAR (Table 2) was significantly higher if the index case was a staff member versus a student (RR 2.18, 95% CI 1.06-4.49; p=0.030), if the index case was identified via in-school contact tracing versus via school-based asymptomatic testing (RR 8.44, 95% CI 1.98-36.06; p=0.001), if the exposure occurred at lunch versus elsewhere (RR 5.74, 95% CI 2.11-15.63; p<0.001; all lunch transmissions were staff-to-staff), and if both parties were unmasked versus both masked (RR 6.98, 95% CI 3.09-15.77; p<0.001). For students, SAR did not differ by grade level.

O_TBL View this table:
org.highwire.dtl.DTLVardef@1b1f706org.highwire.dtl.DTLVardef@d0cea9org.highwire.dtl.DTLVardef@afcd27org.highwire.dtl.DTLVardef@1c5e7e7org.highwire.dtl.DTLVardef@1fc0731_HPS_FORMAT_FIGEXP  M_TBL O_FLOATNOTable 1:C_FLOATNO O_TABLECAPTIONNumber of SARS-CoV-2 index cases, possible and probable in-school transmissions, secondary attack rates, and number of contacts per index case in 8 Massachusetts K-12 public school districts, 2020-21

C_TABLECAPTION C_TBL O_TBL View this table:
org.highwire.dtl.DTLVardef@13c5853org.highwire.dtl.DTLVardef@cac231org.highwire.dtl.DTLVardef@1931f5eorg.highwire.dtl.DTLVardef@1f095c1org.highwire.dtl.DTLVardef@1f7bc21_HPS_FORMAT_FIGEXP  M_TBL O_FLOATNOTable 2:C_FLOATNO O_TABLECAPTIONNumber of index cases and contacts and secondary attack rate by type of exposure: 8 public MA K-12 districts, 2020-21

C_TABLECAPTION C_TBL ConclusionsSecondary attack rates for SARS-CoV-2 were low in public school settings with comprehensive mitigation measures in place before the emergence of the delta variant; lack of masking and staff-to-staff dining were associated with increased risk.


title: Functional components of a community of practice to improve community health worker performance: A qualitative study

abstract:
BackgroundCommunities of Practice (CoPs) are a low-cost strategy for health workers to share and create knowledge through social interactions to improve the delivery of high-quality care. However, there remain critical gaps in understanding the behavioral mechanisms through which CoPs can facilitate community health workers (CHWs) performance. Therefore, we carried out a qualitative study of a CoP to identify the behavior change techniques (BCTs) and intervention functions that improved CHWs performance.

MethodsWe organized CHWs from two tuberculosis (TB) clinics in Kampala, Uganda into a CoP from February to August 2018. We conducted interviews with CoP members to understand their perceptions of how the CoP influenced delivery of TB contact investigation. Using an abductive approach, we first applied inductive codes characterizing CHWs perceptions of how the CoP activities affected their delivery of contact investigation. We then systematically mapped these codes into their functional categories using the BCT Taxonomy and Behavior Change Wheel framework. We triangulated all interview findings with detailed field notes.

ResultsAll eight members of the CoP agreed to participate in the interviews. CHWs identified five CoP activities as improving the quality of their work: (1) individual review of feedback reports, (2) collaborative improvement meetings, (3) real-time communications among members, (4) didactic education sessions, and (5) clinic-wide staff meetings. These activities represented nine different BCTs and five distinct intervention functions. Taken together, CoP meetings enabled members to foster social support, problem solving, and knowledge sharing. The CoP enabled CHWs to identify barriers they face in the field and develop solutions. The CoP was motivating, strengthened their social and professional identities within and outside of the group, and improved their self-efficacy.

ConclusionsWe identified several behavioral mechanisms through which CoPs may improve CHW performance. Future studies should evaluate the importance of these mechanisms in mediating the effects of CoPs on program effectiveness.


title: Real-Time Semi-Automated and Automated Voxel Placement for Repeated Acquisition Magnetic Resonance Spectroscopy

abstract: Magnetic resonance spectroscopy (MRS) is heavily dependent on the investigative team to prescribe, or demarcate, the desired tissue volume-of-interest. Manual prescription, the current standard in the field, requires expertise in neuroanatomy to ensure spatial consistency within and across subjects. Spatial precision of MRS voxel placement thus presents challenges for cross-sectional studies, and even more so for repeated-measure and multi-acquisition designs. Furthermore, voxel prescriptions based-solely on anatomical landmarks may not be ideal in regions with substantial functional and cytoarchitectural variability or to examine individualized/targeted interventions. Here we propose and validate robust and real-time methods to automate MRS voxel placement using functionally defined coordinates within the left dorsolateral prefrontal cortex in clinical cohorts of chronic pain and depression. We hypothesized that increased automation would produce more consistent voxel placement across repeated acquisitions particularly in reference to standard manual prescription. Data were collected and analyzed using two independent prospective transcranial magnetic stimulation studies: 1) a single-day multi-session sandwich design and 2) a longitudinal design. Participants with fibromyalgia syndrome (N=50) and major depressive disorder (N=35) underwent MRI as part of ongoing clinical studies. MEGA-PRESS and Optimized-PRESS MRS acquisitions were acquired at 3-tesla. Evaluation of the reproducibility of spatial location and tissue segmentation was assessed for: 1) manual, 2) semi-automated, and 3) automated voxel prescription approaches. Variability of grey and white matter voxel tissue composition was reduced using automated placement protocols as confirmed by common MRS software processing pipelines (Gannet; SPM-based segmentation) and via Freesurfer-based segmentation. Spatially, post-to pre-voxel center-of-gravity distance was reduced and voxel overlap increased significantly across datasets using automated compared to manual procedures. These results demonstrate the within subject reliability and reproducibility of a method for reducing variability introduced by spatial inconsistencies during MRS acquisitions. The proposed method is a meaningful advance toward improved consistency of MRS data in neuroscience and can be leveraged for multi-session and longitudinal studies that target precisely defined regions-of-interest via a coordinate-based approach.

category: radiology and imaging


title: Evidence of Persisting Autoreactivity in Post-Acute Sequelae of SARS-CoV-2 Infection

abstract: Recent studies have demonstrated significant breadth of emerging autoreactivity in severe SARS-CoV-2 infection. Importantly, we have identified a relaxation of peripheral tolerance within early antibody secreting cells that emerge in patients with COVID-19 as important drivers of those responses. While often viral-specific, these extrafollicular-derived cells also display cross reactivity to autoantigens present in the inflammatory lung environment, and despite resolution of most autoreactivity within 6 months, they persisted in some patients. These results raise questions regarding autoreactive antibodies that arise during acute SARS-CoV-2 infection and their persistence in patients with symptoms in Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Through clinical autoreactive antibody screening of 95 patients with PASC and no history of autoimmune disease, we identify significant autoreactive profiles in patients with ongoing symptoms post-recovery, with 80% of patients returning positive tests for at least one autoantigen, and 40% showing breaks in tolerance to 2 or more. Anti-nuclear antigen positivity was most common, displaying positivity in 63% of patients, however, positive tests were broad and included reactivities against carbamylated protein responses, RNA polymerase III, and phospholipids. We also identify patients with reactivity against dsDNA in the PASC cohort - a reactivity not observed in acute infection even in the critically ill. These results demonstrate evidence of elevated serum autoantibodies in patients who present to PASC clinics with persistent symptoms up 14 months following SARS-CoV-2 infection, and further confirm the growing linkage between COVID-19 and observed clinical autoreactivity - even into the recovery phase of disease.

category: rheumatology


title: Decrease of heart rate variability during exercise: an index of cardiorespiratory fitness

abstract: The present study proposes to measure and quantify the heart rate variability (HRV) changes during effort and to test the capacity of the produced indices to predict cardiorespiratory fitness measures. Therefore, the beat-to-beat cardiac time interval series of 18 adolescent athletes (15.2 {+/-} 2.0 years) measured during maximal graded effort test were detrended using a dynamical first-order differential equation model. Heart rate variability was then calculated as the standard deviation of the detrended RR intervals within successive windows of one minute. The variation of this measure of HRV during exercise is properly adjusted by an exponential decrease of the heart rate. The amplitude and the decay rate of this exponential trend are strongly associated with maximum oxygen consumption, maximal aerobic power, and ventilatory thresholds. It indicates that among athletes with better fitness, HRV has higher values at low heart rate and decreases faster when the heart rate increases during exercise. This analysis, based only on cardiac measurements, provides a promising tool for the study of cardiac measurements generated by portable devices.

category: sports medicine


title: Self-modulation of motor cortex activity after stroke alters behavior and corticospinal tract structure: a randomized controlled trial

abstract: Real-time functional magnetic resonance imaging (fMRI) neurofeedback allows individuals to self-modulate their ongoing brain activity. This may be a useful tool in clinical disorders which are associated with altered brain activity patterns. Motor impairment after stroke has previously been associated with decreased laterality of motor cortex activity. Here we examined whether chronic stroke survivors were able to use real-time fMRI neurofeedback to increase laterality of motor cortex activity and assessed effects on motor performance and on brain structure and function. We carried out a randomized, double-blind, sham-controlled trial in which 24 chronic stroke survivors with mild to moderate upper limb impairment experienced three training days of either Real (n=12) or Sham (n=12) neurofeedback. Stroke survivors were able to use Real neurofeedback to increase laterality of motor cortex activity within, but not across, training days. Improvement in gross hand motor performance assessed by the Jebsen Taylor Test (JTT) was observed in the Real neurofeedback group compared to Sham. However, there were no improvements on the Action Research Arm Test (ARAT) or the Upper Extremity Fugl-Meyer (UE-FM) score. Additionally, decreased white-matter asymmetry of the corticospinal tracts was detected 1-week after neurofeedback training, indicating that the tracts become more similar with Real neurofeedback. Changes in the affected corticospinal tract was positively correlated with neurofeedback performance. Therefore, here we demonstrate that chronic stroke survivors are able to use fMRI neurofeedback to self-modulate motor cortex activity, and that training is associated with improvements in hand motor performance and with white matter structural changes.

category: neurology


title: Downsizing food: A systematic review and meta-analysis examining the effect of reducing served food portion sizes on daily energy intake and body weight

abstract:
BackgroundPortion sizes of many foods have increased over time and reducing food portion sizes has been proposed as a public health strategy to reduce obesity. However, the extent to which reducing food portion sizes affects daily energy intake and body weight is unclear.

ObjectiveTo systematically review and meta-analyse experimental studies that have examined the effect that serving smaller vs. larger portion sizes has on total daily energy intake.

DesignWe used systematic review methodology to search identify eligible articles that used an experimental design to manipulate portion size served to human participants and measured energy intake for a minimum of one day. Multi-level meta-analysis was used to used to pool effects of portion size on daily energy intake.

ResultsFourteen eligible studies were included and 85 effects were included in the primary meta-analysis. There was a moderate-to-large reduction in daily energy intake when comparing smaller vs. larger portions (SMD = -.709 [95% CI: -.956 to -.461], p < .001, I2 = 80.6%) and evidence of a dose dependent response. Larger reductions to portion size and reducing portion sizes of multiple meals per day both resulted in larger decreases in daily energy intake. There was also evidence of a curvilinear relationship between portion size and daily energy intake, whereby reductions to daily energy intake were markedly smaller when reducing portion size from very large portions. In a subset of studies that measured body weight (n=5), being served smaller portions was associated with less weight gain than larger portions (SMD = .536 ([95% CI: .268 to .803], p < .001, I2 = 47.0%).

ConclusionsSmaller food portion sizes substantially decrease daily energy intake and there is evidence that over time this results in lower body weight. Reducing food portion sizes may be an effective population level strategy to reduce obesity.


title: Prediction of radiation-induced hypothyroidism using radiomic data analysis does not show superiority over standard normal tissue complication models

abstract: State-of-art normal tissue complication probability (NTCP) models do not take into account more complex individual anatomical variations, which can be objectively quantitated and compared in radiomic analysis. The goal of this project was development of radiomic NTCP model for radiation-induced hypothyroidism (RIHT) using imaging biomarkers (radiomics). We gathered CT images and clinical data from 98 patients, who underwent intensity-modulated radiation therapy (IMRT) for head and neck cancers with a planned total dose of 70.0 Gy (33-35 fractions). During the 28-month (median) follow-up 27 patients (28%) developed RIHT. For each patient, we extracted 1316 radiomic features from original and transformed images using manually contoured thyroid masks. Creating models based on clinical, radiomic features or a combination thereof, we considered 3 variants of data preprocessing. Based on their performance metrics (sensitivity, specificity), we picked best models for each variant ((0.8, 0.96), (0.9, 0.93), (0.9, 0.89) variant-wise) and compared them with external NTCP models ((0.82, 0.88), (0.82, 0.88), (0.76, 0.91)). Our models reach accuracy comparable with or better than previously presented non-radiomic NTCP models. The benefit of our approach is obtaining the RIHT predictions before treatment planning to adjust IMRT plan to avoid the thyroid region in most susceptible patients.


title: Social and emotional characteristics of girls and young women with DDX3X-linked intellectual disability: A descriptive and comparative study

abstract:
BackgroundDDX3X variants are a common cause of intellectual disability (ID) in females. Previous studies have reported high rates of autism spectrum disorder and emotional-behavioural difficulties within this group. However, no study has compared social and emotional characteristics in individuals with DDX3X variants to individuals with other monogenic causes of ID.

MethodsTwenty-three females with pathogenic or likely pathogenic DDX3X variants were recruited via UK regional genetics centres, genetic research cohorts, and family support groups. Twenty-three females with ID and variants in other genes were recruited via the same routes. Phenotypic data were collected through semi-structured interviews and standardised questionnaires.

ResultsIn line with previous research, we found a wide range of adaptive, social and emotional function within the DDX3X group. Autism characteristics assessed via the Social Responsiveness Scale (SRS) did not differ between DDX3X and comparison groups, while levels of anxiety and self-injurious behaviour (SIB) scores assessed via the Developmental Behaviour Checklist (DBC) were significantly higher in the DDX3X group. Autistic characteristics, anxiety and SIB scores were positively correlated within the DDX3X group. Individuals with DDX3X missense variants had poorer adaptive abilities than those with protein truncating variants as previously reported, but DDX3X variant type did not significantly predict emotional and behavioural characteristics.

ConclusionsWe provide quantitative evidence that overall incidence of autistic characteristics is not higher amongst girls and women with DDX3X variants than expected for ID. However, the DDX3X group demonstrates more SIBs and anxiety symptoms than expected, with close relationships between SIBs and anxiety, and between anxiety and autistic characteristics. Future work is warranted to explore the multilevel mechanisms contributing to social and emotional development in individuals with DDX3X variants, and consider whether these mechanisms are specific to this genetic diagnosis or shared with a subset of people with ID due to other causes.

category: genetic and genomic medicine


title: Social inequalities, length of hospital stay for chronic conditions and the mediating role of comorbidity and discharge destination: A multilevel analysis of hospital administrative data linked to the population census in Switzerland

abstract: Social factors are recognized determinants of morbidity and mortality and also have an impact on use of medical services. The objective of this study was to assess the associations of educational attainment, social and financial resources and migration factors with length of hospital stays for chronic conditions and to investigate the role of comorbidity and discharge destination in mediating these associations. The study made use of nationwide inpatient data that was linked with Swiss census data. The study sample included n=141,307 records of n=92,623 inpatients aged 25 to 84 years, hospitalized between 2010 and 2016 for a chronic condition. Cross-classified multilevel models were performed. Patients with upper secondary and compulsory education stayed longer in hospital compared to those with tertiary education ({beta} 0.24 days, 95% CI 0.14-0.33; {beta} 0.37, 95% CI 0.27-0.47, respectively) when taking into account demographic factors, main diagnosis and clustering on patient and hospital level. However, these effects were almost fully mediated by burden of comorbidity. The effect of living alone on length of stay ({beta} 0.60 days, 95% CI 0.50-0.70) was partially mediated by both burden of comorbidities (33%) and discharge destination (30.4%). (Semi-) private insurance was associated with prolonged stays, but an inverse effect was observed for colon and breast cancer. Allophone patients had also prolonged hospital stays ({beta} 0.34, 95% CI 0.13-0.55). Hospital stays could be a window of opportunity to discern patients who need additional time and support to better cope with everyday life after discharge, reducing the risks of future hospital stays. However, inpatient care in Switzerland seems to take into account rather obvious individual needs due to lack of immediate support at home, but not necessarily more hidden needs of patients with low health literacy and less resources to assert their interests within the health system.

category: health systems and quality improvement


title: Status Quo and Influencing Factors of Family Doctors Performance in Dongguan City

abstract:
BackgroundThe low-performance rate of family doctors is the most important problem in the implementation of the contract service system of family doctors in China, and improving the performance rate of family doctors has become a topic of common concern. We investigated the performance behavior of family doctors in Dongguan, Guangdong Province, to understand the current situation of family doctors performance in Dongguan, and to explore the influencing factors of their performance.

ObjectivesTo understand the status quo of family doctors performance in Dongguan City, Guangdong Province, and to explore the influencing factors of family doctors agreement fulfillment rate.

MethodsThe multi-stage sampling method was used to randomly select family doctors in Dongguan City, Guangdong Province, to investigate the status quo of family doctors performance in community health service institutions in Dongguan City. Logistic regression analysis was used to investigate the influencing factors of family doctors performance, and decision trees and associations were used to further identify the influencing factors of family doctors performance.

Results100 family doctors participated in the survey, and 75% of them were generally able to perform their duties. Logistic regression analysis shows that whether a family doctor signs a contract with a resident is the influencing factor of family doctor performance behavior, and the higher the family doctor signing rate, the higher the family doctor performance rate. The results of decision tree analysis showed that the biggest influence factor of family doctors performance behavior is whether the family doctors are contracted residents or not. ROC curve was 0.860, and pAUC was 0.073 respectively. The most influential factor in decreasing the average Gini index of random forest is whether the family doctor signed a contract or not. The results of association rules showed that there was a correlation between whether the family doctor signed a contract or not and the performance of the family doctor.

ConclusionsThe performance rate of family doctors in Dongguan City, Guangdong Province is relatively high. Whether family doctors sign contracts with residents is the influencing factor of family doctors performance. Improving the contract rate of family doctors is the key to improve the performance rate of family doctors.


title: The unmutated common ancestor of Gp41 conformational epitope targeting variable heavy chain 1-02 utilizing antibodies maintains antibody dependent cell cytotoxicity

abstract:
In studies on monoclonal Abs (mAbs) from long-term non-progressors (LTNPs), our laboratory has previously described highly mutated Abs against a complex conformational epitope with contributions from both gp41 heptad repeat regions. Despite using the VH1-02 gene segment, known to contribute to some of the broadest neutralizing Abs against HIV, members of these Abs, termed group 76C Abs, did not exhibit broad neutralization.

Because of the excessive mutations and use of VH1-02, our goal was to characterize the non-neutralizing functions of Abs of group 76C, to assess targeting of the epitope in various clinical presentations, and to assess the development of these Abs by comparison to their predicted common ancestor. Serum competition assays showed group 76C Abs were enriched in LTNPs, in comparison to VRC-01. Specific group 76C clones 6F5 and 6F11, expressed as recombinant Abs, both have robust ADCC activity, despite their sequence disparity. Sequence analysis predicted the common ancestor of this clonal group would utilize the germline non-mutated variable gene. We produced a recombinant ancestor Ab (76Canc) with a heavy chain utilizing the germline variable gene sequence paired to the 6F5 light chain. Competition with group 76C recombinant Ab 6F5 confirms 76Canc binds HIV envelope constructs near the original group C epitope. 76Canc demonstrates comparable ADCC to 6F5 and 6F11 when targeting both clade B and C HIV constructs. The functional capability of Abs utilizing germline VH1-02 has implications for disease control and vaccine development.

category: hiv aids