Functional alterations of salience-related networks are associated with traits, staging, and the state of psychosis Aberrant salience is essentially implicated in psychosis, involving the midbrain-striatum-hippocampus and anterior cingulate cortex-insula (salience network: SN) systems. However, how these two systems contribute to psychosis traits, staging, and state remains unclear. Thus, we conducted an international multi-site resting functional magnetic resonance imaging study of 209 ultra-high-risk (UHR), first-episode (FEP), and chronic (ChrP) psychosis patients and 279 healthy controls. After intensive denoising and site effect-harmonization, we found 1) reduced connectivity and increased instability of two salience-related systems in the UHR and FEP, in which the SNs significance levels/effect sizes were in the order of UHR > FEP > ChrP 2) an association between stronger connectivity of the midbrain-striatum-hippocampus system and severer delusions and hallucinations in FEP 3) attenuation of finding 2 in patients with medication and non-affective psychosis. The results suggest that the two salience-related systems are associated with psychosis traits, staging, and state in different ways.

TeaserTwo salience-related functional networks are associated with psychosis traits, staging, and state, in different ways.
Psychological Distress Before and During the COVID-19 Pandemic Among Adults in the United Kingdom: Coordinated Analyses of 11 Longitudinal Studies ImportanceHow population mental health has evolved across the COVID-19 pandemic under varied lockdown measures is poorly understood, with impacts on health inequalities unclear.

ObjectiveWe investigated changes in mental health and sociodemographic inequalities from before and across the first year of the COVID-19 pandemic in 11 longitudinal studies.

Design, Setting and ParticipantsData from 11 UK longitudinal population-based studies with pre-pandemic measures of psychological distress were jointly analysed and estimates pooled. Multi-level regression was used to examine changes in psychological distress from pre-pandemic to during the first year of the COVID-19 pandemic.

ExposuresTrends in the prevalence of poor mental health were assessed pre-pandemic (TP0) and at three pandemic time periods: initial lockdown (TP1, Mar-June 20); easing of restrictions (TP2, July-Oct 20); and a subsequent lockdown (TP3, Nov 20-Mar 21). We stratified analyses by sex, ethnicity, education, age, and UK country.

Main Outcomes and MeasuresPsychological distress was assessed using the General Health Questionnaire 12 (GHQ-12), Kessler-6, 9-item Malaise Inventory, Short Mood and Feelings Questionnaire (SMFQ), Patient Health Questionnaire-8 and 9 (PHQ-8/9), Hospital Anxiety and Depression Scale (HADS) and Centre for Epidemiological Studies - Depression (CES-D), across different studies.

ResultsIn total, 49,993 adult participants (61.2% female; 8.7% Non-White) were analysed. Across the 11 studies, mental health deteriorated from pre-pandemic scores across all three pandemic time periods, but with considerable heterogeneity across the study-specific effect sizes estimated (pooled estimate TP1 Standardised Mean Difference (SMD): 0.15 (95% CI: 0.06, 0.25); TP2 SMD: 0.18 (0.09, 0.27); TP3 SMD: 0.21 (0.10, 0.32)). Changes in psychological distress across the pandemic were higher in females (TP3 SMD: 0.23 (0.11, 0.35)) than males (TP3 SMD: 0.16 (0.06, 0.26)), and lower in below-degree level educated persons at TP3 (SMD: 0.18 (0.06, 0.30)) compared to those who held degrees (SMD: 0.26 (0.14, 0.38)). Increased psychological distress was most prominent amongst adults aged 25-34 and 35-44 years compared to other age groups. We did not find evidence of changes in distress differing by ethnicity or UK country.

Conclusions and RelevanceThe substantial deterioration in mental health seen in the UK during the first lockdown did not reverse when lockdown lifted, and a sustained worsening was observed across the pandemic. Mental health declines have been unequal across the population, with females, those with higher degrees, and those aged 25-44 years more affected.
Integrating Health Behavior Theories to Predict COVID-19 Vaccine Acceptance: Differences between Medical Students and Nursing Students BackgroundThis study aimed to explore behavioral-related factors predicting the intention of getting a COVID-19 vaccine among medical and nursing students using an integrative model combining the Health Belief Model (HBM) and the Theory of Planned Behavior (TPB).

MethodsA cross-sectional online survey was conducted among medical and nursing students aged > 18 years in their clinical years in Israel between 27 August and 28 September 2020. Hierarchical logistic regression was used to predict acceptance of a COVID-19 vaccine.

ResultsA total number of 628 participants completed the survey. Medical students expressed higher intentions of getting vaccinated against COVID-19 than nursing students (88.1% vs. 76.2%, p < 0.01). The integrated model based on HBM and TPB was able to explain 66% of the variance (adjusted R2 = 0.66). Participants were more likely to be willing to get vaccinated if they reported higher levels of perceived susceptibility, benefits, barriers, cues to action, attitude, self-efficacy and anticipated regret. Two interaction effects revealed that male nurses had a higher intention of getting vaccinated than did female nurses and that susceptibility is a predictor of the intention of getting vaccinated only among nurses.

ConclusionsThis study demonstrates that both models considered (i.e., HBM and TPB) are important for predicting the intention of getting a COVID-19 vaccine among medical and nursing students, and can help better guide intervention programs, based on components from both models. Our findings also highlight the importance of paying attention to a targeted group of female nurses, who expressed low vaccine acceptance. Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis: a cohort study in UK Biobank ObjectivesTo evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC).

DesignPopulation based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women.

Setting and participantsUK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts.

Main outcome measuresPrediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models.

FindingsPRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds.

ConclusionsIntegrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted.

Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIRisk stratification based on genetic or environmental risk factors could improve cancer screening outcomes
C_LIO_LINo previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond age
C_LIO_LIQCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRC
C_LI

What this study addsO_LIAdding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention
C_LI Three-dimensional cephalometric landmarking and Frankfort horizontal plane construction: reproducibility of conventional and novel landmarks ObjectivesTo assess manual landmarking repeatability and reproducibility (R&R) of a set of three-dimensional (3D) landmarks and to evaluate R&R of vertical cephalometric measurements using two Frankfort Horizontal (FH) planes as references for horizontal 3D imaging reorientation.

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

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

ConclusionsThe "dental" and "foraminal" landmarks tended to be more reliable than the "conventional" landmarks. Despite the poor overall reliability of the landmarks orbitale and porion, the construction of the conventional FH plane using 3 landmarks provided a reliable horizontal reference for 3D craniofacial CT scan reorientation. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) Comparing the impact of vaccination strategies on spread of COVID-19, including a novel household-targeted vaccination strategy With limited availability of vaccines, an efficient use of the limited supply of vaccines in order to achieve herd immunity will be an important tool to combat the wide-spread prevalence of COVID-19. Here, we compare a selection of strategies for vaccine distribution, including a novel targeted vaccination approach (EHR) that provides a noticeable increase in vaccine impact on disease spread compared to age-prioritized and random selection vaccination schemes. Using high-fidelity individual-based computer simulations with Oslo, Norway as an example, we find that for a community reproductive number in a setting where the base pre-vaccination reproduction number R = 2.1 without population immunity, the EHR method reaches herd immunity at 48% of the population vaccinated with 90% efficiency, whereas the common age-prioritized approach needs 89%, and a population-wide random selection approach requires 61%. We find that age-based strategies have a substantially weaker impact on epidemic spread and struggle to achieve herd immunity under the majority of conditions. Furthermore, the vaccination of minors is essential to achieving herd immunity, even for ideal vaccines providing 100% protection. Hairpin structure facilitates multiplex high-fidelity DNA amplification in real-time PCR Clinically and biologically, it is essential to detect rare DNA-sequence variants for early cancer diagnosis or drug-resistance mutations identification. Some of the common quantitative PCR (qPCR)-based variant detection methods are restricted in the limit of detection (LoD) because the DNA polymerases used have a high polymerase misincorporation rate, thus the detection sensitivity is sometimes unsatisfactory. With the proofreading activity, high-fidelity (HiFi) DNA polymerases have a 50- to 250-fold higher fidelity. However, there are currently no proper probe-based designs as the fluorescence indicator allowing multiplexed HiFi qPCR reactions, thus restricting the application of HiFi DNA polymerases like the variant detection. We presented the Occlusion System, composed of a 5-overhanged primer with fluorophore modification and a probe with a short-stem hairpin and a 3 quencher modification. We demonstrated that the Occlusion System allowed multiplexing HiFi qPCR reaction, and it was compatible with the current variant-enrichment method to improve the LoD up to 10-fold. Thus, the Occlusion System satisfactorily functioned as efficient fluorescence indicator in HiFi qPCR reactions and allowed application of HiFi DNA polymerases in variant detection methods to improve detection sensitivity. RPE65-related retinal dystrophy: mutational and phenotypic spectrum in 45 affected patients. BackgroundBiallelic pathogenic RPE65 variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD). Most affected individuals show a severe progression, with 50% of patients legally blind by 20 years of age. A better knowledge of the mutational spectrum and the phenotype-genotype correlation in RPE65-related IRD is needed.

MethodsForty-five affected subjects from 27 unrelated families with a clinical diagnosis of RPE65-related IRD were included. Clinical evaluation consisted on self-reported ophthalmological history and objective ophthalmological examination. Patients genotype was classified accordingly to variant class (truncating or missense) or to variant location at different protein domains. Main phenotypic outcome was age at onset (AAO) of the symptomatic disease and a Kaplan-Meier analysis of disease symptom event-free survival was performed.

ResultsTwenty-nine different RPE65 variants were identified in our cohort, 7 of them novel. Most frequent variants were p.(Ile98Hisfs*26), p.(Pro111Ser) and p.(Gly187Glu) accounting for the 24% of the detected alleles. Patients carrying two missense alleles showed a later disease onset than those with 1 or 2 truncating variants (Log Rank test p<0.05). While the 60% of patients carrying a missense/missense genotype presented symptoms before or at the first year of life, almost all patients with at least 1 truncating allele (91%) had an AAO [&le;]1 year (p<0.05).

ConclusionOur findings suggest an association between the type of the RPE65 carried variant and the AAO. Thus, our results provide useful data on RPE65-associated IRD phenotypes which may help to improve clinical and therapeutic management of these patients. Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium PurposeBy optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Muller glia.

MethodIn clinical OCT (61 eyes, 44 AMD patients, 79.4 {+/-} 7.7 years; 29 female; follow-up = 4.7 {+/-} 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy (GA), 6; 3 neovascular AMD (nvAMD). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semi-quantitatively by one observer (none, some cells, all cells).

ResultsTrajectories of RPE plume and cellular debris paralleled Muller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Muller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.

ConclusionGain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Muller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PrecisHyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. Evaluating a first fully automated interview grounded in Multiple Mini Interview (MMI) methodology: results from a feasibility study ObjectivesGlobal, Covid-driven restrictions around face-to-face interviews for healthcare student selection have forced admissions staff to rapidly adopt adapted online systems before supporting evidence is available. We have developed, what we believe is, the first fully automated interview grounded in Multiple Mini-Interview (MMI) methodology. This study aimed to explore test re-test reliability, acceptability and usability of the system.

Design, setting and participantsmixed-methods feasibility study in Physician Associate (PA) programmes from two UK and one US university during 2019 - 2020.

Primary, secondary outcomesFeasibility measures (test retest reliability acceptability and usability) were assessed using intra-class correlation (ICC), descriptive statistics, thematic and content analysis.

MethodsVolunteers took (T1), then repeated (T2), the automated MMI, with a seven-day interval (+/- 2) then completed an evaluation questionnaire. Admissions staff participated in focus group discussions.

ResultsSixty-two students and seven admission staff participated; 34 students and four staff from UK and 28 students and three staff from US universities.

Good-excellent test-retest reliability was observed with T1 and T2 ICC between 0.62-0.81 (p<0.001) when assessed by individual total scores (range 80.6-119), station total scores 0.6-0.91, p<0.005, individual site (all ICC[&ge;] 0.76 p<0.001) and mean test retest across sites 0.82 p<0.001 (95% CI 0.7-0.9).

Admissions staff reported potential to reduce resource costs and bias through a more objective screening tool for pre-selection or to replace some MMI stations in a  hybrid model. Maintaining human interaction through  touch points was considered essential.

Users positively evaluated the system, stating it was intuitive with an accessible interface. Concepts chosen for dynamic probing needed to be appropriately tailored.

ConclusionThese preliminary findings suggest that the system is reliable, generating consistent scores for candidates and is acceptable to end-users provided human touchpoints are maintained. Thus, there is evidence for the potential of such an automated system to augment healthcare student selection processes. Trends and clinical characteristics of COVID-19 vaccine recipients: a federated analysis of 57.9 million patients primary care records in situ using OpenSAFELY. BackgroundOn December 8th 2020, NHS England administered the first COVID-19 vaccination as part of an ambitious vaccination programme during a global health emergency.

AimsTo describe trends and variation in vaccine coverage by key clinical and demographic groups; to create a framework for near-real-time monitoring of vaccine coverage in key subgroups.

MethodsWorking on behalf of NHS England we analysed 57.9 million patient records in situ and in near-real-time within the infrastructure of the Electronic Health Record (EHR) software vendors EMIS and TPP using OpenSAFELY. We describe vaccine coverage and time trends across a range of demographic and fine-grained clinical subgroups in eight Joint Committee on Vaccination and Immunisation (JCVI) priority cohorts.

Results20,852,692 patients (36%) received a COVID-19 vaccine between December 8th 2020 and March 17th 2021. Of patients aged [&ge;]80 not in a care home (JCVI group 2) 94.7% received a vaccine, but with substantial variation by ethnicity (White 96.2% vaccinated, Black 68.3%) and deprivation (least deprived 96.6%, most deprived 90.7%). Overall, patients with pre-existing medical conditions were equally or more likely to be vaccinated with two exceptions: severe mental illness (89.5% vaccinated) and learning disability (91.4%). 275,205 vaccine recipients were identified as care home residents (priority group 1; 91.2% coverage). 1,257,914 (6.0%) recipients have had a second dose. Detailed characteristics of recipients in all cohorts are reported.

ConclusionsThe NHS in England has rapidly delivered mass vaccination. We were able to deploy a data monitoring framework using publicly auditable methods and a secure, in-situ processing model, using linked but pseudonymised patient-level NHS data on 57.9 million patients with very short delays from vaccine administration to completed analysis. Targeted activity may be needed to address lower vaccination coverage observed among certain key groups: ethnic minorities, those living in deprived areas, and people with severe mental illness or learning disabilities. Problems with Evidence Assessment in COVID-19 Health Policy Impact Evaluation (PEACHPIE): A systematic review of study design and evidence strength IntroductionAssessing the impact of COVID-19 policy is critical for informing future policies. However, there are concerns about the overall strength of COVID-19 impact evaluation studies given the circumstances for evaluation and concerns about the publication environment. This study systematically reviewed the strength of evidence in the published COVID-19 policy impact evaluation literature.

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

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

DiscussionThe reviewed literature directly evaluating the impact of COVID-19 policies largely failed to meet key design criteria for inference of sufficient rigor to be actionable by policy-makers. This was largely driven by the circumstances under which policies were passed making it difficult to attribute changes in COVID-19 outcomes to particular policies. More reliable evidence review is needed to both identify and produce policy-actionable evidence, alongside the recognition that actionable evidence is often unlikely to be feasible. 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. A User Preference Analysis Of Commercial Breath Ketone Sensors To Inform The Development Of Portable Breath Ketone Sensors For Diabetes Management In Young People BackgroundPortable breath ketone sensors may help people with Type 1 Diabetes Mellitus (T1DM) avoid episodes of diabetic ketoacidosis; however the design features preferred by users have not been studied. We aimed to elucidate breath analysis and design preferences associated with commercial breath ketone devices among young people with T1DM aged 12-16 years and their parents in order to inform the development of a breath ketone sensor prototype for diabetes management.

Research Designs and MethodsTwo commercially available breath ketone sensors, designed for ketogenic diet monitoring, were explored over one week by ten young people with T1DM to get an insight into breath measurements. Participants interacted with the devices at least twice daily for five days, taking breath ketone, blood ketone and blood glucose measurements. Semi-structured interviews were conducted post-testing with the young participants and their caregivers to elicit preferences related to breath analysis and to inform the co-design of a diabetes breath ketone sensor prototype. To validate the results from a professional healthcare perspective, we interviewed two diabetes educators working in pediatric care about their perspective of young people using breath ketone sensors.

ResultsParticipants acknowledged the non-invasiveness of breath sensors as compared to blood testing. Affordability, reliability and accuracy were identified as prerequisites for breath ketone sensors used for diabetes management. Design features valued by young people included portability, ease of use, sustainability, readability and suitability for use in public. The time required to use breath sensors was similar to that for blood testing. The requirement to maintain a 10-second breath exhalation posed a challenge for users. Diabetes educators highlighted the ease of use of breath devices especially for young people with insufficient blood ketone testing.

ConclusionsBreath ketone sensors for diabetes management bear potential to facilitate ketone testing in young people. Our study affirms features for young people that drive usability of breath sensors among this population, and provides a model of user preference assessment.

Highlights/new findingsO_LIPortable breath ketone sensors potentially offer a non-invasive alternative to blood ketone testing in diabetes management, especially for young people with diabetes.
C_LIO_LIA user preference assessment of portable non-medical breath ketone devices among young people with Type 1 Diabetes Mellitus demonstrates the key values associated with breath ketone devices for diabetes management.
C_LIO_LIThe time to test for breath ketones was similar to that of blood ketone testing.
C_LIO_LIYoung people can and should be engaged in co-creation of medical devices that they will use.
C_LI The Preventive Treatment of Migraine with Low-Dose Naltrexone/Acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders We tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period.

The magnitude of the treatment effect for the naltrexone and acetaminophen combination observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09).

In the open-label phase, treatment with the naltrexone and acetaminophen combination (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild to moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery.

We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), in future phase 3 studies we will test a range of naltrexone and acetaminophen combination doses. Caffeine and Methylliberine: A Human Pharmacokinetic Interaction Study Methylliberine and theacrine are methylurates found in the leaves of various Coffea species and Camellia assamica var. kucha, respectively. We previously demonstrated that the methylxanthine caffeine increased theacrines oral bioavailability in humans. Consequently, we conducted a double-blind, placebo-controlled study pharmacokinetic study in humans administered methylliberine, theacrine, and caffeine to determine methylliberines pharmacokinetic interaction potential with either caffeine or theacrine. Subjects (n = 12) received an oral dose of either methylliberine (25 or 100 mg), caffeine (150 mg), methylliberine (100 mg) plus caffeine (150 mg), or methylliberine (100 mg) plus theacrine (50 mg) using a randomized, double-blind, crossover design. Blood samples were collected over 24 hours and analyzed for methylliberine, theacrine, and caffeine using UPLC-MS/MS. Methylliberine exhibited linear pharmacokinetics that were unaffected by co-administration of either caffeine or theacrine. However, methylliberine co-administration resulted in decreased oral clearance (41.9 {+/-} 19.5 vs. 17.1 {+/-} 7.80 L/hr) and increased half-life (7.2 {+/-} 5.6 versus 15 {+/-} 5.8 hrs) of caffeine. Methylliberine had no impact on caffeines maximum concentration (440 {+/-} 140 vs. 458 {+/-} 93.5 ng/mL) or oral volume of distribution (351 {+/-} 148 vs. 316 {+/-} 76.4 L). We previously demonstrated theacrine bioavailability was enhanced by caffeine, however, caffeine pharmacokinetics were unaffected by theacrine. Herein, we found that methylliberine altered caffeine pharmacokinetics without a reciprocal interaction, which suggests caffeine may interact uniquely with different methylurates. Understanding the mechanism(s) of interaction between methylxanthines and methylurates is of critical importance in light of the recent advent of dietary supplements containing both purine alkaloid classes. Clinical observation of high-flow nasal cannula with non-rebreather mask use on severe or critically ill COVID-19 diabetic patients Background and aimsPrevalence of diabetes is a vital factor in COVID-19s clinical prognosis. This study aimed to investigate and compare the efficacy of High-flow Nasal Cannula (HFNC) with/without non-rebreather mask (NRM) use on critical COVID-19 patients with/without diabetes.

MethodsFor analysis and comparison, epidemiological, biochemical, and clinical data were collected from 240 HFNC ({+/-}NRM) treated severe and critical COVID-19 patients (diabetic = 136; non-diabetic = 104) admitted into ICUs of five hospitals in Chattogram, Bangladesh.

Results59.1% of patients with fever had diabetes (p=0.012). ICU stay was longer for diabetic patients (9.06{+/-}5.70) than non-diabetic patients (7.41{+/-}5.11) (p=0.020). Majority of the hypertensive patients were diabetic (68.3%; p<0.001). Majority of diabetic patients (70.4%; p<0.005) had elevated creatinine levels. Partial pressure of oxygen (mmHg) after HFNC (only) administration was significantly (p=0.031) higher in non-diabetic patients (69.30{+/-}23.56) than in diabetic patients (61.50{+/-}14.49). Diabetic (62.64{+/-}13.05) and non-diabetic patients (59.40{+/-}13.22) had almost similar partial pressure of oxygen (mmHg) from HFNC with NRM. Patients with elevated RBS required NRM with HFNC five times (AOR=5.1, 1.2-20.8) higher than others. Besides age, and hypertension were significantly associated with the HFNC+NRM treated diabetic patients. Factors those affected the HFNC only treated patients were fever and impaired glucose tolerance.

ConclusionsThe results of this study imply that oxygen supply with HFNC and NRM may be beneficial for the elderly/hypertensive diabetic patients with COVID-19 associated AHRF; and that increased blood glucose level could be a determinant for the need of HFNC + NRM treatment.

HighlightsO_LIElderly diabetic patients required both HFNC and NRM to increase oxygen saturation.
C_LIO_LIHypertension may be a factor for diabetic patients with COVID-19 requiring HFNC and NRM together.
C_LIO_LI HFNC + NRM-combination therapy might be needed when blood glucose levels rise.
C_LI Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times. 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. Melodic Intonation Therapy for aphasia: A multi-level meta-analysis of randomised controlled trials and individual participant data AO_SCPLOWBSTRACTC_SCPLOWMelodic Intonation Therapy (MIT) is a prominent rehabilitation programme for individuals with post-stroke aphasia. The present meta-analysis investigated the efficacy of MIT while considering outcome measure quality, experimental design, influence of spontaneous recovery, MIT protocol, and level of generalisation.

An extensive literature search identified 606 studies in major databases and trials registers; of those, 22 studies, overall 129 participants, met all eligibility criteria. Multi-level mixed- and random-effects models served to separately meta-analyse RCT and non-RCT data.

RCT evidence on validated measures revealed a small-to-moderate standardised effect in non-communicative language expression for MIT, with substantial uncertainty. Unvalidated measures attenuated MITs effect size compared to validated tests. MITs effect size was 5.7 times larger for non-RCT data compared to RCT data. Effect size in non-RCT data decreased with number of months post-stroke, suggesting confound through spontaneous recovery. Variation from the original MIT protocol did not systematically alter benefit from treatment. Progress on validated tests arose mainly from gains in repetition tasks rather than other domains of verbal expression such as everyday communication ability.

The current results confirm the promising role of MIT in improving trained/untrained performance with unvalidated measures, alongside validated repetition tasks; whilst highlighting possible limitations in promoting everyday communication ability. Deep Covid -Covid Diagnosis Using Deep Neural Networks and Transfer Learning Coronavirus is a global emergency as of May 2021. If not acted upon by drugs at the right time, coronavirus may result in the death of individuals. Hence early diagnosis is very important along the progress of the disease. This paper focuses on coronavirus detection using x-ray images, for automating the diagnosis pipeline using convolutional neural networks and transfer learning. This could be deployed in places where radiologists are not easily available in order to detect the disease at very early stages. In this study we propose our deep learning architecture for the classification task, which is trained with modified images, through multiple steps of preprocessing. Our classification method uses convolutional neural networks and transfer learning architecture for classifying the images. Our findings yield an accuracy value of 91.03%, precision of 89.76 %, recall value of 96.67% and F1 score of 93.09%. Elevated Levels of IL-6 in IgA Nephropathy patients are induced by an Epigenetically Driven Mechanism Triggered by Viral and Bacterial RNA Recently, a several models has been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN), and among them the multihit and the gut-microbiota. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed further predisposing factors are present, including immunological, genetic, environmental, or nutritional factors that can influence the pathogenesis and that could be useful for development of precision nephrology and personalized therapy.

Newly, the role of IL-6 in pathogenesis is becoming increasingly important. It is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice, even if the reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA also known as precursor of miR-886 (pre-mi-RNA). Consistently, the VTRNA2-1 expression was found down-regulated in IgAN patients.

Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain causes, in turn, the activation of CREB by PKR. We found CREB, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, overactivated both in IgAN and in TP-IgAN patients. Effectively, in the same patients, we found elevated levels of IL-6 correlating with CREB and PKR phosphorylation.

Since PKR is normally activated by bacterial and viral RNA we hypothesized that these microrganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production, explaining both the high levels of IL-6, both infection involvement in the disease, both cases of IgAN associated with COVID-19 infection and with COVID-19 RNA-vaccination, and recent data showing microbiota involvment in IgAN.

Effectively, we found that Effectively, we sfound that both the RNA poly(I:C) and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in IgAN patient PBMCs.

The PKR/CREB/IL-6 pathway may be very important also in the setting of renal transplantation. We found that this pathway is upregulated also in IgAN transplanted patients. Recent studies showed that the cumulative risk of IgA nephropathy recurrence increases after transplant and is associated with a 3.7-fold greater risk of graft loss. Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin.

In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients. 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.