Engagement in leisure activities and depression in older adults in the United States: Longitudinal evidence from the Health and Retirement Study ObjectivesReceptive cultural engagement (e.g., attending theaters and museums) can reduce depression in older adults. However, whether specific participatory leisure activities are associated with lower rates of depression remains unknown. We aimed to test whether engagement in a diverse range of leisure activities, all of which could involve artistic or creative elements, was associated with concurrent and subsequent depression.

MethodsUsing longitudinal data from 19,134 participants aged over 50 in the Health and Retirement Study, engagement in leisure activities was measured every four years, and depression every two years, between 2008 and 2016. Leisure activities included: reading books, magazines, or newspapers; writing; baking/cooking something special; making clothes, knitting, or embroidery (sewing); working on hobbies/projects; going to sport, social, or other clubs; and attending non-religious organization meetings. A score of three or more on the Center for Epidemiologic Studies Depression Scale indicated depression. We fitted population-averaged panel data models using generalized estimating equations with a logit link.

ResultsEngaging in some leisure activities, such as clubs, hobbies/projects, and baking/cooking was associated with reduced depression, independent of confounders. Concurrently, spending time on hobbies/projects (monthly OR = 0.80, 95% CI = 0.72-0.88; weekly OR = 0.81, 95% CI = 0.73-0.89) and clubs (monthly OR = 0.85, 95% CI = 0.77-0.94; weekly OR = 0.78, 95% CI = 0.69-0.88) was associated with lower odds of depression versus not engaging. Longitudinally, the odds of depression two years later were reduced amongst people engaging in weekly baking/cooking (OR = 0.85, 95% CI = 0.75- 0.95), hobbies (OR = 0.81, 95% CI = 0.71-0.92), and clubs (OR = 0.82, 95% CI = 0.71-0.94). Writing, reading, sewing, and attending non-religious organizations were not consistently associated with depression.

DiscussionEngagement in some leisure activities is associated with reduced odds of depression. We should consider how older adults can be supported to actively participate in leisure activities as health-promoting behaviors.
Transdiagnostic Profiles of Behaviour and Communication Relate to Academic and Socioemotional Functioning and Neural White Matter Organisation BackgroundBehavioural and language difficulties co-occur in multiple neurodevelopmental conditions. Our understanding of these problems has arguably been slowed by an overreliance on study designs that compare deficit/diagnostic groups and fail to capture the overlap across different neurodevelopmental disorders and the heterogeneity within them.

MethodsWe recruited a large transdiagnostic cohort of children with complex needs (N = 805) to identify distinct subgroups of children with common profiles of behavioural and language strengths and difficulties. We then investigated whether and how these data-driven groupings could be distinguished from a comparison sample (N = 158) on measures of academic and socioemotional functioning and patterns of global and local white matter connectome organisation. Academic skills were assessed via standardised measures of reading and maths. Socioemotional functioning was captured by the parent-rated version of the Strengths and Difficulties Questionnaire.

ResultsWe identified three distinct subgroups of children, each with different levels of difficulties in structural language, pragmatic communication, and hot and cool executive functions. All three subgroups struggled with academic and socioemotional skills relative to the comparison sample, potentially representing three alternative but related developmental pathways to difficulties in these areas. The children with the weakest language skills had the most widespread difficulties with learning, whereas those with more pronounced difficulties with hot executive skills experienced the most severe difficulties in the socioemotional domain. Each data-driven subgroup could be distinguished from the comparison sample based on both shared and subgroup-unique patterns of neural white matter organisation. Children with the most pronounced deficits in language, cool executive, or hot executive function were differentiated from the comparison sample by altered connectivity in predominately thalamocortical, temporal-parietal-occipital, and frontostriatal circuits, respectively.

ConclusionThese findings advance our understanding of commonly co-morbid behavioural and language problems and their relationship to behavioural outcomes and neurobiological substrates. Transdiagnostic Profiles of Behaviour and Communication Relate to Academic and Socioemotional Functioning and Neural White Matter Organisation
Evaluating the effects of second-dose vaccine-delay policies in European countries: A simulation study based on data from Greece The results of a simulation-based evaluation of several policies for vaccine rollout are reported, particularly focusing on the effects of delaying the second dose of two-dose vaccines. In the presence of limited vaccine supply, the specific policy choice is a pressing issue for several countries worldwide, and the adopted course of action will affect the extension or easing of non-pharmaceutical interventions in the next months. We employ a suitably generalised, age-structure, stochastic SEIR (Susceptible [-&gt;] Exposed [-&gt;] Infectious [-&gt;] Removed) epidemic model that can accommodate quantitative descriptions of the major effects resulting from distinct vaccination strategies. The different rates of social contacts among distinct age-groups (as well as some other model parameters) are informed by a recent survey conducted in Greece, but the conclusions are much more widely applicable. The results are summarised and evaluated in terms of the total number of deaths and infections as well as life years lost. The optimal strategy is found to be one based on fully vaccinating the elderly/at risk as quickly as possible, while extending the time-interval between the two vaccine doses to 12 weeks for all individuals below 75 years old, in agreement with epidemic theory which suggests targeting a combination of susceptibility and infectivity. This policy, which is similar to the approaches adopted in the UK and in Canada, is found to be effective in reducing deaths and life years lost in the period while vaccination is still being carried out. Covid-19 Associated Hepatitis in children (CAH-C) during the second wave of SARS-CoV-2 infections in Central India: Is it a complication or transient phenomenon. Objective: While pediatric population has largely remained free of severe COVID-19, in some cases SARS-CoV-2 infection has been associated with complications like Multiple Inflammatory Syndrome in children (MIS-C). We mention another unique presentation subsequent to asymptomatic infection of SARS-CoV-2, a unique form of hepatitis designated by us as COVID-19 Associated Hepatitis in Children (CAH-C). The contrasting clinical presentations, temporal association and viral parameters of CAH-C cases, to the MIS-C cases are presented here. Methods: As a retrospective and follow-up observational study we reviewed all children testing positive for SARS-CoV-2 during study period. Children presenting with sudden onset of hepatitis, elevated transaminases, non-obstructive jaundice, lacking marked inflammatory responses and without evidence of (a) other known causes of acute hepatitis or previous underlying liver disease (b) multi-system involvement were classified as CAH-C, are described here. Results: Among 475 children who tested positive, 47 patients presented with hepatitis, 37 patients who had features of CAH-C, having symptoms of hepatitis only, with un-elevated inflammatory markers and uneventful recovery following supportive treatment. Whereas remaining 10 MIS-C hepatitis had protracted illness, multiple system involvement, required admission to critical care, and had mortality of 30%. Conclusion: With the emergence of newer variants of concern (VOC) including the Delta variant which predominated the second wave of infections in India and has now spread to more than 142 countries with changing presentations, CAH-C might be one of them. Cases of such new entities need to be identified early and differentiated from other emerging syndromes in children during the ongoing pandemic for preventing adversities by timely intervention. 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. Surgical interventions targeting the nucleus caudalis for craniofacial pain: a systematic and historical review. IntroductionChronic facial pain is a prevalent group of conditions and when refractory to common treatments poses a social and economic burden. The last decade has seen a multitude of advancements in the multimodal management of pain. Ablative or neuromodulatory interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex is one such treatment that has remained underutilized.

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

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

ConclusionThis systematic review highlights recent advancements in NC intervention technique and the wide range of facial pain syndromes for which these interventions show promising efficacy. New and less invasive techniques continue to emerge, however prospective studies remain absent in the literature. Future work should address efficacy comparisons between intervention type and preoperative diagnosis. The kidney releases a non-polymerizing form of Uromodulin in the urine and circulation that retains the external hydrophobic patch domain Uromodulin (Tamm-Horsfall protein, THP) is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs (TAL) apically in the urine, and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supra-molecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the C terminus. However, THP in the circulation is not polymerized, and it remains unclear if non-aggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a non-polymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP+EHP) and established its presence in the urine in a non-polymerized native state. Proteomic characterization of urinary THP+EHP revealed its C-terminus to end at F617. In the human kidney, THP+EHP was not only detected in TAL cells, but also diffusely in the renal parenchyma. Using immunoprecipitation followed by proteomic sequencing and immunoblotting, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury (AKI), admission urinary THP+EHP was significantly lower in patients who subsequently developed AKI during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of non-polymerizing THP in the circulation. Larger studies are needed to establish the utility of urinary THP+EHP as a sensitive biomarker of kidney health and susceptibility to injury. The Australian Parkinson's Genetics Study (APGS) - pilot (N = 1,532) PurposeParkinsons disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinsons Genetics Study (APGS) seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic, and environmental basis of PD susceptibility, symptoms and progression.

ParticipantsIn the pilot phase reported here, 1,819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme (PBS) records. The average age at the time of the questionnaire was 64 {+/-} 6 years. We collected patient-reported PD information and socio-demographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred thirty-two participants (84.2%) met all inclusion criteria, and 1,499 provided a DNA sample via traditional post.

Findings to date65% of participants were male, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions.

Future plansWe plan to recruit sex- and age-matched unaffected controls, genotype all participants, and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia.

Article summaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIWe used a time- and cost-effective recruitment method that enabled us to reach out to a random sample of individuals who have been prescribed medications for Parkinsons disease across all over Australia to invite them to participate in this study.
C_LIO_LIThe identities of letter recipients remained private and confidential and were not shared with the researchers. However, those recipients who were interested and willing to participate were directed to a website where they could sign up and provide informed consent.
C_LIO_LIThe source database only captures individuals who have been prescribed medications to treat Parkinsons disease in Australia and who are eligible for Medicare. Those without an official diagnosis, not receiving treatment, or not eligible for government subsidies are not included.
C_LIO_LIWe collected a wide range of patient-reported variables relevant to disease onset, diagnosis, symptoms, medical comorbidities, lifestyle, and family history in a large cohort of participants. However, some variables might not be as accurate as when measured by a specialist clinician.
C_LIO_LIGiven the 9% response rate to our single-letter invitation, there is a substantial risk of self-selection bias. Thus, patient characteristics for this cohort might differ from those of the typical population of individuals with Parkinsons disease in Australia.
C_LI RELATIONSHIP BETWEEN ADVERSE EVENTS PREVALENCE, PATIENT SAFETY CULTURE AND PATIENT SAFETY PERCEPTION IN A SINGLE SAMPLE OF PATIENTS: A CROSS-SECTIONAL AND CORRELATIONAL STUDY ObjectiveTo assess the relationship between Adverse Events Prevalence, Patient Safety Culture and Patient Safety Perception.

DesignCross-sectional, ex post facto comparative study on a single sample of patients.

SettingFour medium-high-level hospitals were included in the study -- two public and two private from Zulia State in Venezuela.

Participants556 medical records and patients were studied for the prevalence and patient safety perception study, and 397 of the healthcare providers involved in the care of these patients were surveyed for the patient safety culture study, at two public and two private hospitals.

Outcome measurementThe primary outcome of this study was the Association between Adverse Events Prevalence, Patient Safety Culture and Patient Safety Perception, and according to hospital funding type, private and public.

ResultsAn inverse association was observed between Adverse Events Prevalence and its severity and Patient Safety Culture Index (PSCI: rho=-0.8 p=0.5) (95% CI=0.26-0.10) and Patient Safety Perception Index (PSPI: rho=-0.6 p=0.18) (95% CI=0.10-0.28), which were protective factors for patient safety. No association was identified between Patient Safety Culture and Patient Safety Perception (rho=0.0001). No statistical differences were identified by hospital type (p=0.93) (95% CI=0.70-1.2).

ConclusionsThe analysis of the variable correlations studied (AEP, PSC and PSP) within the same sample offers an interesting and useful perspective. In this sample, although no correlation was observed between the three variables as an interacting set, some correlation patterns were observed between pairs of variables that could guide further studies.

Strengths and limitations of this studyO_LIThe association analysis of the three main variables (adverse events prevalence, patient safety culture and patient safety perception) in the same sample of patients and health professionals and over the same time period during which the care process and, consequently, the adverse events took place is an unprecedented and innovative approach, which contributes to the body of knowledge on this field of study.
C_LIO_LIThe relational theoretical framework produced provides a "map" that can facilitate decision-taking and which establishes the variables that should be considered a priority. As a result, it is highly likely to have an impact on the clinical efficiency and safety of healthcare institutions and services.
C_LIO_LIThe study was carried out at both private and public hospitals, enabling the behaviour of the aforementioned variables to be compared and analysed at each type of institution. The literature to date on this approach is scarce and offers little information.
C_LIO_LIAlthough the sample of hospitals selected is not representative of Venezuela, it is representative of the hospitals of one of the most productive and populated states in the country.
C_LIO_LIDuring stages 1 and 2, some resistance to collaborating with and completing the evaluation instruments was identified among the health professionals.
C_LI Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS BackgroundHIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 p26 amino acid variations are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific CTL responses common in slower disease progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. We therefore aimed to determine if intrahost evolution of HIV-2 p26 is associated with disease progression.

MethodsTwelve treatment-naive, HIV-2 mono-infected participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data and clinical follow-up were included in the analysis. CD4% change over time was analysed via linear regression models to stratify participants into relative faster and slower disease progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Amino acid polymorphisms were mapped to existing p26 protein structures.

ResultsIn total, 369 heterochronous HIV-2 p26 sequences from 12 male patients with a median age of 30 (IQR: 28-37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates ({rho} = -0.8, P=0.02), but not CD4% level. However, Bayes factor (BF) testing indicated that the association between evolutionary rates and CD4% kinetics was supported by weak evidence (BF=0.5). The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5/p26 hexamer interface surface.

ConclusionsFaster p26 evolutionary rates were associated with faster progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate the HIV-2 p26 may be an attractive vaccine or therapeutic target. Decision curve analysis to identify optimal candidates of liver resection for intermediate-stage hepatocellular carcinoma with hepatitis B cirrhosis：A cohort study BackgroundThe selection criterion for liver resection (LR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) is still controversial. This study aims to compare LR and transarterial chemoembolization in the range of predicted death risk

MethodsThe multivariable Cox regression model (MVR) was estimated to predict mortality at 5yr. The cut-off values were determined by a two-piece-wise linear regression model, decision curve analysis with MVR model, and hazard ratio curve for treatment plotted against the predicted mortality.

Results825 IM-HCC with hepatitis B cirrhosis were included for analysis (TACE, n=622; LR, n=203). The 5-yr overall survival rate of LR patients was higher than the TACE group (52.8% vs. 20.8%; P<0.0001). The line of LR and TACE were crossing with predicted death risk at 100% (P for interaction =0.008). The benefit of LR versus TACE decreased progressively as predicted death risk>0.55 (95%CI: 0.45,0.62). When predicted death risk over 0.7, decision curve analysis suggested that LR and TACE did not increase net benefit. Patients were then divided into four subgroups by the cut-off values (<0.45, 0.45[&ge;] /<0.62, 0.62[&ge;] /<0.7, [&ge;] 0.7). The stratified analysis of treatment in different subgroups, hazard ratios were 0.39 (95%CI: 0.27, 0.56), 0.36 (95%CI: 0.23, 0.56), 0.51 (95%CI: 0.27, 0.98), and 0.46 (95%CI: 0.27, 0.80), respectively.

ConclusionsLR reached the maximal relative utility in the interval of 0.45 to 0.62, and both LR and TACE did not increase net benefit at the 5-yr death risk over 0.7. 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. A cross-sectional study of psychosocial factors and sickness presenteeism in Japanese workers during the COVID-19 pandemic BackgroundWe examined the association between socioeconomic and health status, and lifestyle and sickness presenteeism among Japanese workers during the COVID-19 epidemic.

MethodsA cross-sectional study using an Internet-monitor survey was conducted in December, 2020 in Japan. Of 33,302 survey participants, we analyzed 27,036 participants (13,814 men and 13,222 women) who reported experience with sickness presenteeism.

ResultsThe odds ratio (OR) of sickness presenteeism associated with unmarried versus married status was 1.15. Respective figures for other variables were 1.11 for manual laboring work compared to desk work; 1.79 and 2.29 for loss of employment at the time the pandemic began and continuation of unemployment compared to maintaining employment during the pandemic; and 3.34 for a feeling of financial instability compared to stability.

ConclusionThe issue of sickness presenteeism has become more prominent under the COVID-19 epidemic. Sensitivity of Estimated Tacrolimus Population Pharmacokinetic Profile to Inaccurate Assumptions about Dose Timing and Absorption: An Investigation in Real-World and Simulated Data A population pharmacokinetic (PK) study with 363 subjects was performed using real-world data extracted from electronic heath records (EHRs) to estimate the tacrolimus population PK profile. As population PK studies for oral medications performed using EHR data often assume a regular dosing schedule as prescribed without incorporating exact dosing time, we assessed the sensitivity of the PK parameter estimates to assumptions about dose timing using last-dose times extracted by our own natural language processing system, medExtractR. We also investigated the sensitivity of estimations to absorption rate constants that are often fixed at a published value in tacrolimus population PK analysis. There was no appreciable difference in parameters estimates with vs. without last-dose time incorporated in the data and our sensitivity analysis revealed little difference between parameters estimated assuming a range of absorption rate constants. We also conducted simulation studies to investigate how drug PK profiles and experimental designs such as concentration measurements affects sensitivity to incorrect assumptions about dose timing and absorption rates. Our findings suggest that drugs with a slower elimination rate (or a longer half-life) are less sensitive to dose timing errors and that experimental designs which only allow for trough blood concentrations are usually insensitive to deviation in absorption rate. 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. Prognostic implications of structural heart disease and premature ventricular contractions in recovery of exercise BackgroundPremature ventricular contractions (PVCs) during recovery of exercise stress testing are associated with increased cardiovascular mortality, but the cause remains unknown. We aimed to evaluate the association of PVCs during recovery with echocardiographic abnormalities, and their combined prognostic performance.

MethodsEchocardiographic abnormalities (reduced left ventricular (LV) ejection fraction, valvular heart disease, LV dilatation, LV hypertrophy, or increased filling pressures) and PVCs during recovery ([&ge;]1/min) were identified among patients having undergone echocardiography within median [interquartile range] 0 [0-2] days of an exercise stress test. The association between such changes and cardiovascular mortality was analyzed using Cox regression adjusted for age, sex, clinical and exercise variables.

ResultsAmong included patients (n=3,106), PVCs during recovery were found in 1,327 (43%) patients, among which the prevalence of echocardiographic abnormalities was increased (58% vs. 44%, p<0.001). Overall, PVCs during recovery were associated with increased cardiovascular mortality (219 total events, 7.9 [5.4-11.1] years follow-up; adjusted hazard ratio (HR [95% confidence interval]) 1.6 [1.2-2.1], p<0.001). When combined with echocardiographic abnormalities, PVCs during recovery were associated with increased risk when such were present (HR 3.3 [1.9-5.5], p<0.001) but not when absent (HR 1.5 [0.8-2.8], p=0.22), in reference to those with neither.

ConclusionPVCs during recovery were associated with increased prevalence of echocardiographic abnormalities. Increased risk of cardiovascular mortality was observed only for subjects with PVCs if concomitant echocardiographic abnormalities were present. Our findings provide mechanistic insights to the increased CV risk reported in patients with PVCs during recovery. Effectiveness of the Covid-19 vaccines in preventing infection in dental practitioners: results of a cross-sectional questionnaire based survey India started its vaccination program at the beginning of 2021, the main beneficiaries being health workers and frontline workers including police, paramilitary forces, sanitation workers, and disaster management volunteers in the first phase. By the time, the second wave of Covid-19 impacted India, approximately 14 million healthcare and frontline workers, including dentists had been vaccinated.

AimTo study the effectiveness of vaccination on a subset of high-risk healthcare workers i.e. dentists in preventing Covid-19 during the second wave of the pandemic.

Study designA questionnaire based pan-India online survey was carried out to record the Covid-related experiences of dentists prior to and after vaccination.

ResultThe sample size for this survey was 4493 respondents from across India. During the second wave, 9.18% (n=364) respondents became positive in spite of the vaccine, while 14.69%(n=78) became positive in the unvaccinated group. A chi-square test of independence was performed to examine the relation between vaccination and the Covid positivity rate in all age groups. The relation between these variables was highly significant, [X2 (1, N = 4493) = 15.9809, p=.000064].

ConclusionOur pan-India online survey inferred that vaccination has a definitive role to play in reducing the positivity rate amongst dentists during the second wave of the pandemic across all age groups. 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 Trajectory of Growth of SARS-CoV-2 Variants in Houston, Texas, January through May 2021 Based on 12,476 Genome Sequences Genetic variants of the SARS-CoV-2 virus are of substantial concern because they can detrimentally alter the pandemic course and disease features in individual patients. Here we report SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist healthcare system diagnosed from January 1, 2021 through May 31, 2021. The SARS-CoV-2 variant designated U.K. B.1.1.7 increased rapidly and caused 63%-90% of all new cases in the Houston area in the latter half of May. Eleven of the 3,276 B.1.1.7 genomes had an E484K change in spike protein. Compared with non-B.1.1.7 patients, individuals with B.1.1.7 had a significantly lower cycle threshold value (a proxy for higher virus load) and significantly higher rate of hospitalization. Other variants (e.g., B.1.429, B.1.427, P.1, P.2, and R.1) also increased rapidly, although the magnitude was less than for B.1.1.7. We identified 22 patients infected with B.1.617 "India" variants; these patients had a high rate of hospitalization. Vaccine breakthrough cases (n=207) were caused by a heterogeneous array of virus genotypes, including many that are not variants of interest or concern. In the aggregate, our study delineates the trajectory of concerning SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, and heralds the arrival and spread of B.1.617 variants in the metroplex. A collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia BackgroundThe COVID-19 pandemic has resulted in a range of unprecedented disruptions to the delivery of maternity care globally and has been associated with regional changes in perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne endured one of the longest and most stringent lockdowns in 2020. This paper presents the protocol for a collaborative maternity dashboard project to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic.

MethodsDe-identified maternal and newborn outcomes will be collected monthly from all public maternity services in Melbourne, allowing rapid analysis of a multitude of perinatal indicators. Weekly outcomes will be displayed as run charts according to established methods for detecting non-random  signals in health care. A pre-pandemic median for all indicators will be calculated for the period of January 2018 to March 2020. A significant shift is defined as [&le;] six consecutive weeks, all above or below the pre-pandemic median. Additional statistical analyses such as regression, time-series, and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests.

Ethics and DisseminationThis study has been registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976).

Strengths and weaknesses of this study This project is the first clinician-led, multi-centre perinatal data collection system for metropolitan Melbourne.
 It complements the state government data collection, with the significant benefits of more timely and flexible reporting of outcomes, and granular detail on emerging areas of concern.
 The study relies on primary source coding of exposure and outcomes from each hospital that have not been internally validated during the study period.
 Data from private maternity hospitals, containing 25% of Melbourne births, are not available.
 This resource will support data-informed hospital pandemic responses through to the end of 2022. Significant Sparse Polygenic Risk Scores across 813 traits in UK Biobank We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,500 traits using genetic and phenotype data in the UK Biobank. We report 813 sparse PRS models with significant (p < 2.5 x 10-5) incremental predictive performance when compared against the covariate-only model that considers age, sex, types of genotyping arrays, and the principal component loadings of genotypes. We report a significant correlation between the number of genetic variants selected in the sparse PRS model and the incremental predictive performance (Spearmans {rho} = 0.61, p = 2.2 x 10-59 for quantitative traits, {rho} = 0.21, p = 9.6 x 10-4 for binary traits). The sparse PRS model trained on European individuals showed limited transferability when evaluated on non-European individuals in the UK Biobank. We provide the PRS model weights on the Global Biobank Engine (https://biobankengine.stanford.edu/prs).

Author summaryPolygenic risk scores (PRSs), an approach to estimate genetic predisposition on disease liability by aggregating the effects across multiple genetic variants, has attracted increasing research interest. While there have been improvements in the predictive performance of PRS for some traits, the applicability of PRS models across a wide range of human traits has not been clear. Here, applying penalized regression using Batch Screening Iterative Lasso (BASIL) algorithm to more than 269,000 individuals of white British ancestry in UK Biobank, we systematically characterize PRS models across more than 1,500 traits. We report 813 traits with PRS models of statistically significant predictive performance. While the statistical significance does not necessarily directly translate into clinical relevance, we investigate the properties of the 813 significant PRS models and report a significant correlation between predictive performance and estimated SNP-based heritability. We find that the number of genetic variants selected in our sparse PRS model is significantly correlated with the incremental predictive performance in both quantitative and binary traits. Our transferability assessment of PRS models in UK Biobank revealed that the sparse PRS models trained on individuals of European ancestry had a lower predictive performance for individuals of African and Asian ancestry groups. Early Stopping in Experimentation with Real-time Functional Magnetic Resonance Imaging Using a Modified Sequential Probability Ratio Test IntroductionFunctional magnetic resonance imaging (fMRI) often involves long scanning durations to ensure the associated brain activity can be detected. However, excessive experimentation can lead to many undesirable effects, such as from learning and/or fatigue effects, discomfort for the subject, excessive motion artifacts and loss of sustained attention on task. Overly long experimentation can thus have a detrimental effect on signal quality and accurate voxel activation detection. Here, we propose dynamic experimentation with real-time fMRI using a novel statistically-driven approach that invokes early stopping when sufficient statistical evidence for assessing the task-related activation is observed.

MethodsVoxel-level sequential probability ratio test (SPRT) statistics based on general linear models (GLMs) were implemented on fMRI scans of a mathematical 1-back task from 12 healthy teenage subjects and 11 teenage subjects born extremely preterm (EPT). This approach is based on likelihood ratios and allows for systematic early stopping based on statistical error thresholds. We adopt a two-stage estimation approach that allows for accurate estimates of GLM parameters before stopping is considered. Early stopping performance is reported for different first stage lengths, and activation results are compared with full durations. Finally, group comparisons are conducted with both early stopped and full duration scan data. Numerical parallelization was employed to facilitate completion of computations involving a new scan within every repetition time (TR).

ResultsUse of SPRT demonstrates the feasibility and efficiency gains of automated early stopping, with comparable activation detection as with full protocols. Dynamic stopping of stimulus administration was achieved in around half of subjects, with typical time savings of up to 33% (4 minutes on a 12 minute scan). A group analysis produced similar patterns of activity for control subjects between early stopping and full duration scans. The EPT group, individually, demonstrated more variability in location and extent of the activations compared to the normal term control group. This was apparent in the EPT group results, reflected by fewer and smaller clusters.

ConclusionA systematic statistical approach for early stopping with real-time fMRI experimentation has been implemented. This dynamic approach has promise for reducing subject burden and fatigue effects. KRAS mutations impact clinical outcome in metastatic non-small cell lung cancer PurposeThere is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PD) and immune checkpoint blockade (ICB) with pembrolizumab. Here we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (stage IV) non-small cell lung cancer (NSCLC).

MethodsAll consecutive patients molecularly assessed and diagnosed between 2016-2018 with stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. Primary study outcome was overall survival (OS).

ResultsOut of 580 stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.288, 95% CI 1.091-1.521, p = 0.003). When treated with first-line platinum doublet (n = 195), KRASMUT is a negative factor for survival (p = 0.018) with median OS 9 months vs KRASWT 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95%CI 1.124-2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1high KRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significant (p = 0.006) better outcome than KRASWT with a median OS 23 vs 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95%CI 0.148-0.822, p = 0.016).

ConclusionsKRAS mutations is a positive predictive factor for treatment with pembrolizumab and a negative predictive factor for platinum doublet chemotherapy as well as general OS in stage IV NSCLC. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. 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
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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
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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
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