Phase 2 Randomized Trial of an AS03 Adjuvanted Plant-Based Virus-Like Particle Vaccine for Covid-19 in Healthy Adults, Older Adults and Adults with Comorbidities The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and the needs of specific populations. We report herein a pre-specified interim analysis of the phase 2 portion of an ongoing Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein adjuvanted with AS03 (NCT04636697). A total of 753 subjects were recruited between 25 November 2020 and 24 March 2021 into three groups: Healthy Adults (18-64 years: N=306), Older Adults ([&ge;] 65 years: N=282) and Adults with Comorbidities ([&ge;]18 years: N=165) and randomized 5:1 to receive two intramuscular doses of either vaccine CoVLP (3.75 g/dose + AS03) or placebo 21 days apart. This report presents safety, tolerability and immunogenicity data collected up to 21 days after the second dose. The immune outcomes presented include neutralizing antibody (NAb) titres and cellular (IFN-{gamma} and IL-4 ELISpot) responses. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults. CoVLP+AS03 induced seroconversion in >35% of subjects in each group after the first dose and in [~]98% of subjects 21 days after the second dose. In all treatment groups, NAb levels were [~]10-fold higher than those in a panel of convalescent sera. A significant minority ([~]20%) of subjects had evidence of a pre-existing IFN-{gamma} response to the S protein and almost all subjects in all groups (>88%) had detectable cellular responses (IFN-{gamma}, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after dose two. These data demonstrated that CoVLP+AS03 will likely be well-tolerated and highly immunogenic in adults [&ge;]18 years of age with and without comorbidities.
Quantifying impacts of the COVID-19 pandemic through life expectancy losses: a population-level study of 29 countries Variations in the age patterns and magnitudes of excess deaths, as well as differences in population sizes and age structures make cross-national comparisons of the cumulative mortality impacts of the COVID-19 pandemic challenging. Life expectancy is a widely-used indicator that provides a clear and cross-nationally comparable picture of the population-level impacts of the pandemic on mortality. Life tables by sex were calculated for 29 countries, including most European countries, Chile, and the USA for 2015-2020. Life expectancy at birth and at age 60 for 2020 were contextualised against recent trends between 2015-19. Using decomposition techniques, we examined which specific age groups contributed to reductions in life expectancy in 2020 and to what extent reductions were attributable to official COVID-19 deaths. Life expectancy at birth declined from 2019 to 2020 in 27 out of 29 countries. Males in the USA and Lithuania experienced the largest losses in life expectancy at birth during 2020 (2.2 and 1.7 years respectively), but reductions of more than an entire year were documented in eleven countries for males, and eight among females. Reductions were mostly attributable to increased mortality above age 60 and to official COVID-19 deaths. The COVID-19 pandemic triggered significant mortality increases in 2020 of a magnitude not witnessed since WW-II in Western Europe or the breakup of the Soviet Union in Eastern Europe. Females from 15 countries and males from 10 ended up with lower life expectancy at birth in 2020 than in 2015.
Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes. Endometriosis symptoms are heterogeneous with controversy on whether it constitutes a single disease or multiple distinct types. Our previous work found recurrent somatic cancer-driver alterations in endometriosis; however, these have not been found ubiquitously. A handful of cases spread across studies also suggest mutations might be shared (clonal) between lesions of the same type. As current classification systems correlate poorly with symptoms or outcomes, somatic genomics may improve the current system. Here, we investigate heterogeneity of somatic cancer-driver mutations within patients and across endometriosis types. We examined anatomically distinct types of endometriosis (ovarian, deep infiltrating, and superficial endometriosis) in 27 individual patients all of whom had at least two types of endometriosis. Specimens were analyzed using high-sensitivity targeted sequencing with orthogonal validation from droplet digital PCR and mutation-surrogate immunohistochemistry. Results found 13/27 patients had informative somatic driver mutation in endometriosis, 9/13 had identical mutations across distinct lesions. Endometriomas tended to have a higher mutational complexity, with functionally redundant driver mutations in same gene and within the same lesions.

Our data are consistent with clonality across endometriosis lesions regardless of subtype. Further the finding of redundancy in mutations with the same gene and lesions is also consistent with endometriosis representing an oligoclonal disease with dissemination likely to consist of multiple epithelial clones travelling together. This suggests the current anatomically defined classification of endometriosis does not fully recognize the etiology of the disease. A novel classification should take into account genomic and other molecular features. These findings could further contribute to development of a more personalized endometriosis diagnosis and care. Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant BackgroundThere has been an unprecedented global effort to produce safe and effective vaccines against SARS-CoV-2. However, production challenges, supply shortages and unequal global reach, together with an increased number of breakthrough infections due to waning of immunity and the emergence of new variants of concern (VOC), have prolonged the pandemic. To boost the immune response, several heterologous vaccination regimes have been tested and have shown increased antibody responses compared to homologous vaccination. Here we evaluated the effect of mRNA vaccine booster on immunogenicity in individuals who had been vaccinated with two doses of inactivated vaccines.

MethodsThe levels of specific antibodies against the receptor-binding domain (RBD) of the spike protein from wild-type virus and the Beta, Delta and Omicron variants were measured in healthy individuals who had received two doses of homologous inactivated (BBIBP-CorV or CoronoVac) or mRNA (BNT162b2 or mRNA-1273) vaccines, and in donors who were given an mRNA vaccine boost after two doses of either vaccine. Pre-vaccinated healthy donors, or individuals who had been infected and subsequently received the mRNA vaccine were also included as controls. In addition, specific memory B and T cell responses were measured in a subset of samples.

ResultsA booster dose of an mRNA vaccine significantly increased the level of specific antibodies that bind to the RBD domain of the wild-type (6-fold) and VOCs including Delta (8-fold) and Omicron (14-fold), in individuals who had previously received two doses of inactivated vaccines. The level of specific antibodies in the heterologous vaccination group was furthermore similar to that in individuals receiving a third dose of homologous mRNA vaccines or boosted with mRNA vaccine after natural infection. Moreover, this heterologous vaccination regime significantly enhanced the specific memory B and T cell responses.

ConclusionsHeterologous prime-boost immunization with inactivated vaccine followed by an mRNA vaccine boost markedly increased the levels of specific antibodies and B and T cell responses and may thus increase protection against emerging SARS-CoV-2 variants including Omicron. Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.

In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.

The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.

Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.

Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.

Ethics and DisseminationAs this study is a literature review, ethics approval is not required.

The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).

Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI Telecommuting frequency and preference among Japanese workers according to regional cumulative COVID-19 incidence: a cross-sectional study This study aimed to examine the relationship between telecommuting and the regional cumulative COVID-19 incidence. This was a cross-sectional study analyzing 13,468 office workers. The participant groups, according to the level of cumulative COVID-19 incidence by prefecture, were used as the predictor variable, and telecommuting frequency and preference were used as outcomes. We employed an ordinal logistic regression analysis. In regions with a high cumulative COVID-19 incidence, the proportion of participants who telecommuted more than two days per week was 34.7%, which was approximately 20% higher than in other regions. Telecommuting preference was stronger in areas with higher COVID-19 influence. However, in other regions, the proportion of participants who did not want to telecommute was higher than that of those who wanted to telecommute. We found that telecommuting frequency and preference were higher in regions with high cumulative COVID-19 incidence. Psychological factors associated with instrumental activities of daily living disability in older adults with knee osteoarthritis PurposeThe population of older adults with knee osteoarthritis (OA)-related disabilities is increasing globally. This study aimed to investigate the psychological factors associated with instrumental activities of daily living (IADL) disability in older adults with knee OA.

Materials and MethodsA cross-sectional study was conducted on 179 patients with knee OA aged [&ge;] 65 years. The six-item short form of the Pain Catastrophizing Scale (PCS-6), the four-item short form of the Pain Self-Efficacy Questionnaire (PSEQ-4), and the fifteen-item Geriatric Depression Scale (GDS-15) were used to assess psychological factors. IADL status was assessed using eight activity items. Participants were divided into IADL-disabled and non-disabled groups. Binary logistic regression analyses were performed with the IADL disability status as the dependent variable. The PCS-6, PSEQ-4, and GDS-15 tools were included as independent variables in the logistic regression model. Demographics, motor functions, and pain intensity were also included as confounders.

ResultsOf the total participants, 88 (49.1%) showed disability in conducting IADL. PSEQ-4 (odds ratio =0.90, 95%; confidence interval=0.82-0.99, p=0.02) was a significant independent variable among all psychological factors.

ConclusionOur study showed the importance of assessing self-efficacy using the PSEQ-4 in relation to IADL disability in older adults with knee OA. Effectiveness of a short term induction regimen of a biosimilar Adalimumab in the long term management of symptomatic Ankylosing Spondylitis Symptomatic Ankylosing Spondylitis: A Community Based Proof of Concept Observational Study IntroductionCost and drug toxicity often deter prolonged therapeutic use of anti-TNF agents in ankylosing spondylitis (AS). A planned study was completed to endorse our clinic based observation of long term relief following short-term administration of anti-TNF agent.

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

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

ConclusionA ten-week administration of biosimilar adalimumab in difficult to treat AS showed early substantial improvement which often persisted for 24 weeks. This unconventional strategy was socioeconomically appealing. It merits further validation and acceptance especially in resource strained settings. Genetic factors affecting immune phenotypes in type 1 diabetes Large inter-individual variability in immunological cell composition and function determines immune responses in general and susceptibility to immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes, the pathophysiological mechanisms through which these variations exert their effects are unknown. In this study, we characterize the genetic factors influencing immune responses in patients with type 1 diabetes. Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTL) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D. Among them, 12 have never been reported in healthy population studies, implying a disease-specific genetic regulation. Altogether this study provides new insights into the genetic factors that affect immunological responses in T1D. PENet: Continuous-Valued Pulmonary Edema Severity Prediction On Chest X-ray Using Siamese Convolutional Networks For physicians to take rapid clinical decisions for patients with congestive heart failure, the assessment of pulmonary edema severity in chest radiographs is vital. While deep learning has been promising in detecting the presence or absence, or even discrete grades of severity, of such edema, prediction of the continuous-valued severity yet remains a challenge. Here, we propose PENet, a deep learning framework to assess the continuous spectrum of pulmonary edema severity from chest X-rays. We present different modes of implementing this network, and demonstrate that our best model outperforms that of earlier work (mean area under the curve of 0.91 over 0.87, for nine comparisons), while saving training data and computation. A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

O_TBL View this table:
org.highwire.dtl.DTLVardef@134f5d7org.highwire.dtl.DTLVardef@1f8149forg.highwire.dtl.DTLVardef@11dbf0org.highwire.dtl.DTLVardef@7e854borg.highwire.dtl.DTLVardef@61272f_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

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

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

Roles and Responsibilities

Study Flow Chart

O_TBL View this table:
org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

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

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

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

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

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

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

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Characterising SARS-CoV-2 viral clearance kinetics to improve the design of antiviral pharmacometric studies A consensus methodology for pharmacometric assessment of candidate SARS-CoV-2 antiviral drugs would be useful for comparing trial results and improving trial design. The time to viral clearance, assessed by serial qPCR of nasopharyngeal swab samples, has been the most widely reported measure of virological response in clinical trials, but it has not been compared formally with other metrics, notably model-based estimates of the rate of viral clearance. We analysed prospectively gathered viral clearance profiles from 280 infection episodes in vaccinated and unvaccinated individuals. We fitted different phenomenological pharmacodynamic models (single exponential decay, bi-exponential, penalised splines) and found that the clearance rate, estimated from a mixed effects single exponential decay model, is a robust pharmacodynamic summary of viral clearance. The rate of viral clearance, estimated from viral densities during the first week following peak viral load, provides increased statistical power (reduced type 2 error) compared with time to clearance. We recommend that pharmacometric antiviral assessments should be conducted in early illness with serial qPCR samples taken over one week. Sub-diagnostic effects of genetic variants associated with autism While over a hundred genes are significantly associated with autism, little is known about the prevalence of variants affecting them in the general population. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Using data from more than 13,000 autistic individuals and 210,000 undiagnosed individuals, we provide a gene-level map of the odds ratio for autism associated to rare loss-of-function (LoF) variants in 185 genes robustly associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the phenotype of undiagnosed individuals heterozygous for such variants and show that they exhibit a decrease in fluid intelligence, qualification level and income, and an increase in material deprivation. These effects were larger for LoFs in autism-associated genes than in other LoF-intolerant genes and appeared largely independent of sex and polygenic scores for autism. Using brain imaging data from 21,049 UK-Biobank individuals, we provide evidence for smaller cortical surface area and volume among carriers of LoFs in genes with high odds ratios for autism. Our gene-level map is a key resource to distinguish genes with high and low odds ratio for autism, and highlights the importance of including quantitative data on both diagnosed and undiagnosed individuals to better delineate the effect of genetic variants beyond the categorical diagnosis. Data are available at https://genetrek.pasteur.fr/. Health-related quality of life of female sex workers living with HIV in South Africa: a cross-sectional study IntroductionHealth-related quality of life (HRQoL) is an important HIV outcome beyond viral suppression. However, there are limited data characterizing HRQoL of key populations including female sex workers (FSW) living with HIV.

MethodsWe used baseline data (June 22, 2018-March 23, 2020) of FSW who were diagnosed with HIV and enrolled into a randomized trial in Durban, South Africa. HRQoL information was collected by a generic preference-accompanied tool with five domains (EQ-5D), and summarized into a single score (range 0-1) which represents health utility. We employed multivariable beta regression models to identify determinants of HRQoL and to estimate subgroup-specific HRQoL score. Using external estimates of life expectancy and population size, we estimated the number of quality adjusted life years reduced among FSW living with HIV in South Africa associated with violence and drug use.

ResultsOf 1363 individuals (mean age: 32.4 years; mean HRQoL score: 0.857) in our analysis, 62.6% used drugs, 61.3% experienced physical or sexual violence, and 64.6% self-reported taking antiretroviral treatment (ART). The following were associated with a reduction in the average marginal HRQoL score: older age (per decade: 0.018 [95% confidence interval (CI): 0.008, 0.027]), drug use (0.022 [0.007, 0.036]), experience of violence (0.024 [0.010, 0.038]), and moderate (vs. no) level of internalized stigma (0.023 [0.004, 0.041]). Current ART use was associated with a 0.015-point (-0.001, 0.031) increase in the HRQoL score. The estimated mean (95%CI) HRQoL scores ranged from 0.838 (0.816, 0.860) for FSW who used drugs, experienced violence, and were not on ART; to 0.899 (0.883, 0.916) for FSW who did not use drugs nor experience violence and were on ART. Our results can be translated into a reduction in 37,184 and 39,722 quality adjusted life years related to drug use and experience of violence, respectively in South Africa.

ConclusionsThese results demonstrate the association of ART with higher HRQoL among FSW and the need to further address structural risks including drug use, violence, and stigma. Population-specific estimates of HRQoL score can be further used to calculate quality-adjusted life years in economic evaluations of individual and structural interventions addressing the needs of FSW living with HIV.

Clinical Trial RegistrationNCT03500172 (April 17, 2018) Survey of Contaminated Percutaneous Injuries in Anesthesia Practitioners BackgroundAnesthesia practitioners are at inherent risk for percutaneous injuries by blood-contaminated needles and sharp objects. These exposures may result in transmission of HIV and hepatitis viruses. Data about this occupational hazard from contaminated needles and sharp devices is limited and decades old. We conducted a web-based survey to assess the occurrence, reporting, characteristics, and outcome of contaminated percutaneous injuries (CPI) in anesthesia residents, fellows, and attendings.

MethodsAfter institutional research board approval, an email was sent to 217 anesthesia practitioners requesting their participation in an online survey about contaminated percutaneous injuries. Responses were collected from February through March 2020. Results are reported as absolute numbers and proportions with 95% confidence interval (CI).

ResultsThe overall survey response rate was 51% (110/217). 59% (65/110) (95% CI, 50-68) of participants reported having one or more contaminated percutaneous injury during their years of anesthesia practice (42% (21/50) of residents, 50% (4/8) of fellows, 77% (40/52) of anesthesia attendings). Prevalence of injuries related to attendings years of anesthesia practice was 69% (95% CI, 44-94) for 5-10 years, 62.5% (95% CI, 29-96) for 10-15 years, and 79% (95% CI, 63- 95) for greater than 15 years of practice.

35% (95% CI, 26-44) of participants reported having one or more CPI within the last 5 years (40% of residents, 50% of fellows, 29% of attendings). Occurrence of CPI within the last 5 years based on attending anesthesiologist years of practice was 57% for less than 5 years, 37.5% for 10-15 years, and 20% for 15-20 years of practice. 75% (95% CI, 65-85) reported the incident at the time of injury. 59% (95% CI, 48-70) of injuries were due to hollow bore needles. 50% (95% CI, 39-61) of total injuries were high risk. 26% of injured anesthesia practitioners received post-exposure prophylaxis and there were zero seroconversions.

ConclusionMost anesthesiologists will sustain a contaminated percutaneous injury during their careers. Incidence of these injuries decreases with years of practice. Occurrence of these injuries is high among anesthesia residents, with the majority reporting their injuries. Half of the injuries are high risk with a quarter requiring postexposure prophylaxis. More education and interventions are needed to reduce percutaneous injuries and improve reporting. Meta-analytic findings on reading in children with cochlear implants This meta-analysis study aims to quantify the group differences in reading skills between children with cochlear implants and their hearing peers and between children with cochlear implants and children with hearing aids (aged between 3 to 18 years old). Of the 5,642 articles screened, 47 articles met predetermined inclusion criteria (published between 2002 and 2019). The robust variance estimation based meta-analysis models were used to synthesize all the effect sizes. Children with cochlear implants scored significantly lower than their hearing peers in phonological awareness (g = - 1.62, p < .001), vocabulary (g = -1.50, p < .001), decoding (g = -1.24, p < .001), and reading comprehension (g = -1.39, p < .001), but not for fluency (g = -.67, p = .054). Compared to children with hearing aids, children with cochlear implants scored significantly lower in phonological awareness (g = -.30, p = .028). The percentage of unilateral cochlear implant negatively impacts the group difference between children with cochlear implants and their hearing peers. Findings from this study confirm a positive shift in reading outcomes for profoundly deaf children due to cochlear implantation. Some children with cochlear implants may need additional supports in educational settings. Frequencies of TP53 Germline Variations and Identification of Two Novel 3'UTR Variants in a Series of Head and Neck Cancer Cases TP53 is a tumour suppressor gene. Its inactivation plays a significant role in the molecular pathology of cancers. TP53 germline mutations increase the risk of developing multiple primary cancers. However, the role of alterations in TP53 germline DNA in head and neck cancers (HNCs) is not well-established. HNCs comprise one of the most frequent cancers in South Asia. The present discovery study reports the investigation of germline variations in the TP53 gene in a cohort of 30 HNC patients from Karachi, Pakistan. Blood samples were collected and genomic DNA was extracted from white blood cells. TP53 has 11 exons, where exon 1 is not transcribed. After quality control of DNA, amplification of seven selected exons along with their splice sites, two intronic regions (introns 2-3 and 3-4), and 3UTR were carried out. Sanger sequencing was carried out in order to identify germline variations. Comparison with wild type sequence revealed rs1642785 G>C (intron 2-3) variation in 63.2%, PIN3 duplication (rs17878362) in intron 3-4 in 94.7%, and rs1042522 G>C in exon 4 (p.R72P) in 66.6% of the cases. In 3UTR, 13.4% of the analyzed cases carried either one of two variants, i.e., 17:7669567_8delCA or 17:7669560C>G. The latter variations are reported for the first time in literature. In conclusion, we report three highly frequent germline variations and two newly discovered variations in 3UTR of TP53 germline DNA in HNC patients from Pakistan. These results shall contribute to delineating the genetic component of HNCs with potential translational implications. I wanna live and not think about the future; What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study BackgroundLittle is known about how people with multiple sclerosis and their families comprehend advance care planning (ACP) and its relevance in their lives.

AimTo explore under what situations, with whom, how, and why do people with MS and their families engage in ACP

MethodsWe conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.

ResultsParticipants narratives focused on three major themes :(i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate discussions. Some shared concerns of a lack of confidence when having ACP discussions.

ConclusionThese findings support the need for a whole systems strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services. How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. Colorectal Cancer Disparities Across the Continuum of Cancer Care with a Focus on Surgery and Black Patients: A Systematic Review and Meta-Analysis ImportanceDespite increases in screening among vulnerable populations, colorectal cancer disparities persist.

ObjectiveTo direct future efforts towards high impact opportunities in addressing these disparities, we performed a systematic review and meta-analysis of the colorectal cancer disparities literature with a focus on the utilization of Surgery, the primary treatment for colorectal cancer.

Data SourcesTwo electronic databases (PubMed and SCOPUS) were searched for prospective and retrospective studies reporting on colorectal cancer disparities between 2011 and March 29, 2021.

Study SelectionStudies for the systematic review were selected if: (1) reported on disparities within colorectal, colon, or rectal cancer (2) articles were published in the English language (3) articles used only United States-sourced data.

Studies for the meta-analysis were selected if: (1) reported on at least one of three utilization of surgery outcomes: receipt of colorectal, colon, or rectal surgery, refusal of surgery, or receipt of laparoscopic versus open surgery (2) Outcomes were reported as Odds ratio according to multivariate analysis.

Data Extraction and SynthesisQuality appraisal and data extraction were performed independently by 2 reviewers using the Newcastle-Ottawa Scale for quality assessment. For the meta-analysis, pooled multivariate odds ratios for the three outcomes regarding utilization of surgery were separately calculated according to fixed or random-effects models. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines.

Main Outcomes and MeasuresSystematic Review: The volume of publications attributed to the following sectors of the colorectal cancer care continuum: (1) Prevention, Screening, or Diagnosis (2) Treatment (3) Survivorship (4) End-of-life Care. Meta-analysis: Receipt of Colorectal, Colon, or Rectal Surgery and Black Race, Refusal of Surgery and Black Race, or Receipt of Laparoscopic versus Open Surgery and Black Race.

ResultsThe systematic review included 1,199 relevant publications. Among them, 60% were focused on Prevention, Screening, or Diagnosis, followed by Survivorship (20%), Treatment (15%), and End-of-Life Care (1%). Within the studies reporting on treatment disparities, 46% were focused on Race/Ethnicity, followed by Socioeconomic Status (28%), Age (17%), Gender (6%), Disabilities/Comorbidities (3%), and LGBTQI+ (0%). A total of 16 studies, including 1,110,674 patients, were applied to three separate meta-analyses regarding utilization of Surgery. Patients of black race were less likely to receive colorectal, or colon, or rectal surgery (OR 0.75, 95% CI 0.67-0.83), less likely to receive laparoscopic versus open colorectal cancer surgery (OR 0.91, 95% CI 0.88-0.94), and twice as likely to refuse colon surgery (OR 2.41, 95% CI 1.91-3.06).

Conclusions and RelevanceThe majority of research, to date, related to colorectal cancer disparities is focused on prevention, screening, or diagnosis and a minimal amount is dedicated to treatment. Additionally, all of the limited publications related to colorectal cancer surgery, as a treatment modality, are observational in nature. The application of this knowledge of past efforts and current continuing adverse outcomes is required in order to shift the focus of the research community towards treatment. In particular, research addressing surgical disparities is necessary, as surgery remains the primary treatment for colorectal cancer. Estimating real-world COVID-19 vaccine effectiveness in Israel using aggregated counts The vaccination roll-out of the COVID-19 vaccines in Israel has been highly successful. By February 22th, approximately 47% of the population has already been administered at least one dose of the BNT162b2 vaccine. Efforts to estimate the true real-world effectiveness of the vaccine have been hampered by disease dynamics and social-economic discrepancies. Here, using counts of positive and hospitalized cases of vaccinated individuals, we conduct a sensitivity analysis of the vaccine effectiveness. Under an assumption of no effectiveness on the first two weeks after the 1st dose, we observe very low effectiveness on the third week. After the 2nd dose, on weeks 1 and 2 we find 73-85% effectiveness in reducing positive cases, hospitalizations, and severe cases, which increase to 89-97% effectiveness 14 days after the 2nd dose. As more granular data will be available, it will be possible to extract more exact estimates; however, the emerging evidence suggests that the vaccine is highly effective. Distinct patterns of cognitive outcome in young children with autism spectrum disorder receiving the Early Start Denver Model Evidence-based, early intervention significantly improves developmental outcome in young children with autism. Nonetheless, there is high interindividual heterogeneity in developmental trajectories during the therapy. It is currently not possible to predict a childs developmental outcome after receiving an early intervention based on his skills and symptoms at baseline. In this study, we analyze developmental trajectories of preschoolers with autism who received 2 years of intervention using the Early Start Denver Model (ESDM) approach in Geneva, Switzerland (n = 47). Our aim was to identify early predictors of response to treatment. We applied a cluster analysis to distinguish between 3 subgroups based on their cognitive level at intake, and rates of cognitive change over the course of treatment. The first subgroup of children only had a mild cognitive delay at intake, and nearly no cognitive delay by the end of treatment (Higher Cognitive at baseline: HC). The children in the two other subgroups all presented with severe cognitive delay at baseline, however, they had two very different patterns of response to treatment. The majority significantly improved developmental scores within their first year of intervention (Optimal Responders: OptR). Whereas a minority of children showed little to no improvement over the course of treatment (Minimal Responders: MinR). Our findings suggest that children who end up having an optimal two-year treatment outcome show rapid developmental improvement. Inversely, less significant progress by the sixth month of intervention may predict a less optimal response to treatment.