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.
Evaluation of Clinical Threshold Policies for Cataract Surgery and the Regional Variation in Rates of Surgery Background/AimsTo characterise the national patterns in rates of cataract surgery across England, review clinical thresholds against NICE guidance, and determine how far variable access to cataract surgery is attributable to regional variation in policy stringency and social deprivation.

Methods127 Clinical Commissioning Groups ("CCGs") provided cataract surgery data and threshold policies in response to a Freedom of Information request. Local cataract surgery rates were grouped by threshold stringency and analysed on an age group-corrected basis. ANOVA testing was used to assess effect of policy stringency on regional rates of cataract surgery.

ResultsIn England, rates of cataract surgery vary threefold across CCGs, from 1,980 to 6,427 per 100,000 population over 60, with a standard deviation (784.76) of 22% of the mean value, 3,598. Threshold policies vary across CCGs: 33 had no policy, 45 utilised policies accessible on the basis of Quality of Life ("QoL") impact, and 39, against NICE guidance, required a Visual Acuity ("VA") threshold be exceeded. Rates of surgery by CCG were negatively correlated with restrictiveness of policy ({eta}2=0.18, p<0.01), and positively correlated with the Index of Multiple Deprivation (IMD), (r2{square}={square}0.11, p<0.01). Prior approval processes are not significantly associated with reduced rates of surgery.

ConclusionOver two-thirds of CCGs continue to use threshold-based policies for access to cataract surgery, with one-third doing so solely on the basis of VA requirements, despite NICE guidance to the contrary. For NHS operations, variation in policy restrictiveness accounts for more of the variation in surgery rates than socioeconomic deprivation.
Vascular risk is not associated with PET measures of Alzheimer's disease neuropathology among cognitively normal older adults Cardiovascular disease (CVD) is associated with a higher risk of developing dementia. Studies have found that vascular risk factors are associated with greater amyloid-{beta} (A{beta}) and tau burden, which are hallmark neuropathologies of Alzheimers disease (AD). Evidence for these associations during the preclinical stages of AD, when A{beta} and tau pathologies first become detectable, is mixed. Quantifying the effect of vascular risk among cognitively normal individuals can help focus the efforts to develop therapeutic approaches aimed at modifying the course of preclinical AD.

Using Bayesian analysis, we examined the relationship of A{beta} and tau pathology with concurrent vascular risk among 87 cognitively normal individuals (median age 77, interquartile range 70- 83) in the Baltimore Longitudinal Study of Aging. We quantified vascular risk as the probability of developing CVD within 10 years using published equations from the Framingham Heart Study. A{beta} and tau pathologies were measured using positron emission tomography.

As expected, A{beta} positive participants had greater tau in the entorhinal cortex (EC) and inferior temporal gyrus (ITG) (difference in means = 0.09, p < 0.05 for each region), and 10-year CVD risk was positively correlated with white matter lesion burden (r = 0.24, p = 0.03). However, we did not find any associations between CVD risk and A{beta} or tau. The data provided over two- and four-fold evidence towards the lack of a correlation between CVD risk and tau in the EC (Bayes factor BF = 2.4) and ITG (BF = 4.0), respectively. We found over three-fold evidence towards the lack of a difference in mean CVD risk by A{beta} group (BF = 3.4). These null findings were replicated using a data-driven vascular risk score in the BLSA based on a principal component analysis of eight indicators of vascular health.

Our data provide moderate evidence towards the lack of an association between vascular risk and concurrent AD neuropathology among cognitively normal older adults. This finding suggests that vascular risk and AD neuropathology may constitute independent pathways in the development of cognitive impairment and dementia.

HighlightsO_LIVascular risk is associated with white matter lesion load, but not amyloid-{beta} or tau
C_LIO_LIModerate evidence for lack of association between vascular risk & early AD pathology
C_LIO_LIVascular risk and Alzheimers neuropathology may constitute independent pathways
C_LI Combination of Mifepristone and Methotrexate for the Treatment of Ectopic Pregnancy: A Systematic Review Protocol AimThe increase in ectopic pregnancies (EP) in recent years and their impact on female fertility forces physicians to find an effective medical treatment that can avoid surgery as soon as possible. Methotrexate and mifepristone are widely used in conservative treatments, but the effectiveness of this combination is not completely clear. Therefore, the aims in this meta-analysis are to systematically analyze the efficacy of mifepristone combined with methotrexate in the treatment of EP through existing studies and draw a conclusion, to evaluate the advantages and disadvantages of inclusion trials and propose improvement measures and scientific designing schemes.

MethodsSix databases will be searched, including PubMed, Embase, Cochrane Library, the China National Knowledge Infrastructure(CNKI), Chinese Science and Technology Periodical Database (VIP), and Wanfang Database (WF). Randomized controlled trials published up to October 2020 will be selected. Search terms include mifepristone, methotrexate, EP, and random (free word/synonym expansion). We will include trials in which the experimental group was treated with combination of mifepristone and methotrexate, and the control group was treated with mifepristone alone. Revman 5.4 will be used to evaluate the quality of the trials, and the effect model will be selected to analyze the results. Cure rate will be the main outcome index.

ResultOnly when we finish this meta analysis can we get the result.

DiscussionThe results of this study will provide evidence for the efficacy of mifepristone combined with methotrexate therapy in the treatment of EP. The site of onset of pregnancy should be taken into account.

PROSPERO registration numberCRD42021246757 Inequities in childhood immunisation coverage associated with socioeconomic, geographic, maternal, child, and place of birth characteristics in Kenya BackgroundThe global Immunisation Agenda 2030 highlights coverage and equity as a strategic priority goal to reach high equitable immunisation coverage at national levels and in all districts. We estimated inequities in full immunisation coverage associated with socioeconomic, geographic, maternal, child, and place of birth characteristics among children aged 12-23 months in Kenya.

MethodsWe analysed full immunisation coverage (1-dose BCG, 3-dose DTP-HepB-Hib (diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type B), 3-dose polio, 1-dose measles, and 3-dose pneumococcal vaccines) of 3,943 children aged 12-23 months from the 2014 Kenya Demographic and Health Survey. We disaggregated mean coverage by socioeconomic (household wealth, religion, ethnicity), geographic (place of residence, province), maternal (maternal age at birth, maternal education, maternal marital status, maternal household head status), child (sex of child, birth order), and place of birth characteristics, and estimated inequities in full immunisation coverage using bivariate and multivariate logistic regression.

ResultsImmunisation coverage ranged from 82% [81-84] for the third dose of polio to 97.4% [96.7-98.2] for the first dose of DTP-HepB-Hib, while full immunisation coverage was 68% [66-71] in 2014. After controlling for other background characteristics through multivariate logistic regression, children of mothers with primary school education or higher have at least 54% higher odds of being fully immunised compared to children of mothers with no education. Children born in clinical settings had 41% higher odds of being fully immunised compared to children born in home settings. Children in the Coast, Western, Central, and Eastern regions had at least 74% higher odds of being fully immunised compared to children in the North Eastern region, while children in urban areas had 26% lower odds of full immunisation compared to children in rural areas. Children in the middle and richer wealth quintile households were 43-57% more likely to have full immunisation coverage compared to children in the poorest wealth quintile households. Children who were sixth born or higher had 37% lower odds of full immunisation compared to first-born children.

ConclusionsChildren of mothers with no education, born in home settings, in regions with limited health infrastructure, living in poorer households, and of higher birth order are associated with lower rates of full immunisation. Targeted programmes to reach under-immunised children in these subpopulations will lower the inequities in childhood immunisation coverage in Kenya. Deep learning for caries detection using optical coherence tomography Early detection of dental caries has been one of the most predominant topics studied over the last few decades. Conventional examination through visual-tactile inspection and radiography can be inaccurate and destructive to the tooth structure. The development of optical coherence tomography (OCT) has given dentistry an alternative diagnostic technique, which has been proven by numerous studies, that it has better sensitivity, specificity, and non-invasive characteristics. The growing popularity of artificial intelligence (AI) also contributes to a more efficient and effective way of image-based detection and decision-making. However, previous studies, which have attempted to employ AI for caries assessment, did not incorporate high-quality ground truth data. Therefore, this study aims to bypass this issue and highlights the importance of high-quality data. A two-phase study was carried out to explore different methods for caries detection. Initially, the comparison of caries detection based on OCT and apical radiography by 5 experienced clinicians was conducted. Then, five convolutional neural networks (CNNs), including AlexNet, VGG-16, ResNet-152, Xception, and ResNext-101, in the scope of AI were employed to detect caries and compared with the findings of the 5 clinicians. The data was preprocessed and labeled with the ground truth corresponding to microcomputed tomography (micro-CT) with rigorous definition. The weighted Kappa statistics suggested that OCT ({varkappa}= .699, SD = .090) showed a higher accuracy rate than radiography ({varkappa}= .407, SD = .049), and CNNs ({varkappa}= .860, SD = .049) were rated higher than clinicians ({varkappa}= .679, SD = .113), both at a .05 significance level. The best result was carried out by ResNet-152, which demonstrated a high accuracy rate of 95.21% and a sensitivity of 98.85%. These findings illustrate the importance of ground truth data for AI training and the potential of deep CNN algorithms combined with OCT for diagnosing dental caries. 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. Development of machine learning models for the prediction of complications after colonic, colorectal and small intestine anastomosis in psychiatric and non-psychiatric patient collectives (PSTUDY) Psychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.

MethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).

ResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years. Croup during the COVID-19 Omicron Variant Surge Croup is a common upper respiratory disease usually associated with parainfluenza virus, resulting in stridor, hoarse voice, barky cough, and variable respiratory distress. Here we examine the data at our center confirming a sharp increase in cases of croup associated with the Omicron variant. Data was retrospectively extracted from patient charts among those seen in the Emergency Department at Seattle Childrens Hospital. Inclusion criteria were patients who were assigned a diagnosis containing "croup" during either 5/30/2021-11/30/2021, a time period correlating with predominance of the COVID-19 Delta variant (B.1.617.2), or the initial phase of the Omicron variant surge (12/1/2021-1/15/2022). Contemporaneous publicly available local data on the proportion of SARS-CoV-2 samples in surrounding King County, Washington, with spike gene target failure on TaqPath PCR assays was used as a proxy for the proportion of infections caused by the Omicron variant. A total of 401 patients were diagnosed with croup during the Delta surge and 107 patients were diagnosed with croup during the Omicron surge. Patients who presented during the Omicron surge were more likely to test positive for COVID-19 (48.2% vs 2.8%, p < 0.0001). Children with a clinical diagnosis of croup during the Omicron surge were more likely to be prescribed racemic epinephrine as part of their care (21.5% vs 13.0%, p = 0.032). There were no differences in presenting age, rate of admission, rate of return to the ED within 72 hours, or admission among those who returned within 72 hours. During the Omicron surge, the incidence of croup nearly doubled compared to the rate in prior months, while at the same time the number of cases of parainfluenza virus identified decreased. Consistent with prior case reports, we have identified a sharp rise in cases of croup seen in our pediatric ED in parallel with the replacement of the SARS-CoV-2 Delta variant by Omicron as the dominant variant in our community. 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. 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 Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders. Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

MethodsIn a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.

Results175 dialysis patients (40% women, 65{+/-}15 years), 252 kidney transplant patients (33% women, 54{+/-}14 years) and 71 controls (65% women, 44{+/-}14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p<0.05). Moreover, higher antibody titers associated with fewer events, HR 0.41 for each unit increased in log10titer (p<0.05).

ConclusionsDialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.

SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

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

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

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

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

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

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

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Prospectively validated disease-agnostic predictive medicine with augmented intelligence Despite numerous superhuman achievements in complex challenges1,2, standalone AI does not free life science from the long-term bottleneck of linearly extracting new knowledge from exponentially growing new data3, severely limiting the success rate of drug discovery4. Inspired by the state-of-the-art AI training methods, we trained a human-centric hybrid augmented intelligence5 (HAI) to learn a foundation model6 that extracts all-encompassing knowledge of human physiology and diseases. To evaluate the quality of HAIs extracted knowledge, we designed the public, prospective prediction of pivotal ongoing clinical trial outcomes at large scale (PROTOCOLS) challenge to benchmark HAIs real-world performance of predicting drug clinical efficacy without access to human data. HAI achieved a 10.5-fold improvement from the baseline with 99% confidence7 in the PROTOCOLS validation, readily increasing the average clinical success rate of investigational new drugs from 7.9%8 to 90% for almost any human diseases9,10. The validated HAI confirms that exponentially extracted knowledge alone is sufficient for accurately predicting drug clinical efficacy, effecting a total reversal of Erooms law4. HAI is also the worlds first clinically validated model of human aging that could substantially speed up the discovery of preventive medicine for all age-related diseases11. Our results demonstrate that disruptive breakthroughs necessitate the smallest team size to attain the largest HAI for optimal knowledge extraction from high-dimensional low-quality data space, thus establishing the first prospective proof of the previous discovery that small teams disrupt12. The global adoption of training HAI provides a well-beaten economic path to mass-produce scientific and technological breakthroughs via exponential knowledge extraction and better designs of data labels for training better-performing AI13. 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. Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-Drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Cohort Study BackgroundAnti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease

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

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

ConclusionIn patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed. Cell-free DNA ultra-low-pass whole genome sequencing to distinguish malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion: a cross-sectional study BackgroundThe leading cause of mortality for patients with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome is development of Malignant Peripheral Nerve Sheath Tumor (MPNST), an aggressive soft tissue sarcoma. In the setting of NF1, this cancer type frequently arises from within its common and benign precursor, plexiform neurofibroma (PN). Transformation from PN to MPNST is challenging to diagnose due to difficulties in distinguishing cross-sectional imaging results and intralesional heterogeneity resulting in biopsy sampling errors.

Methods and FindingsThis multi-institutional study from the National Cancer Institute and Washington University in St. Louis used fragment size analysis and ultra-low-pass whole genome sequencing (ULP-WGS) of plasma cell-free DNA (cfDNA) to distinguish between MPNST and PN in patients with NF1. Following in-silico enrichment for short cfDNA fragments and copy number analysis to estimate the fraction of plasma cfDNA originating from tumor (tumor fraction), we developed a noninvasive classifier which differentiates MPNST from PN with 86% pre-treatment accuracy (91% specificity, 75% sensitivity), and 89% accuracy on serial analysis (91% specificity, 83% sensitivity). Healthy controls without NF1 (subjects = 16, plasma samples = 16), PN (subjects = 23, plasma samples = 23), and MPNST (subjects = 14, plasma samples = 46) cohorts showed significant differences in tumor fraction in plasma (P = 0.001 as well as cfDNA fragment length (P < 0.001) with MPNST samples harboring shorter fragments and being enriched for tumor-derived cfDNA relative to PN and healthy controls. Mutational analysis demonstrated focal NF1 copy number loss in PN and MPNST patient plasma but not in healthy controls. Greater genomic instability including alterations associated with malignant transformation (focal copy number gains in chromosome arms 1q, 7p, 8q, 9q, and 17q; focal copy number losses in SUZ12, SMARCA2, CDKN2A/B, and chromosome arms 6p and 9p) was more prominently observed in MPNST plasma. Furthermore, the sum of longest tumor diameters (SLD) visualized by cross-sectional imaging correlated significantly with paired tumor fractions in plasma from MPNST patients (r = 0.39, P = 0.024). On serial analysis, tumor fraction levels in plasma dynamically correlated with treatment response to therapy and minimal residual disease (MRD) detection before relapse. Study limitations include a modest MPNST sample size despite accrual from two major referral centers for this rare malignancy, and lack of uniform treatment and imaging protocols representing a real-world cohort.

ConclusionsTumor fraction levels derived from cfDNA fragment size and copy number alteration analysis of plasma cfDNA using ULP-WGS significantly correlated with MPNST tumor burden, accurately distinguished MPNST from its benign PN precursor, and dynamically correlated with treatment response. In the future, our findings could form the basis for improved early cancer detection and monitoring in high-risk cancer-predisposed populations.

Author summaryO_ST_ABSWhy was this study done?C_ST_ABS[tpltrtarr] Neurofibromatosis 1 (NF1) is the most common inherited cancer predisposition syndrome.
[tpltrtarr]The leading cause of mortality in NF1 is malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma that arises from a benign plexiform neurofibroma (PN) precursor lesion.
[tpltrtarr]Transformation from PN to MPNST is challenging to detect by imaging (due to difficulty in distinguishing PN from MPNST radiologically) or by biopsy (due to intralesional heterogeneity), which often delays the diagnosis of MPNST and results in a worsened prognosis.


What did the researchers do and find?[tpltrtarr] We conducted a multi-institutional study involving two large NF1 referral centers, the National Cancer Institute and Washington University in St. Louis, involving 73 patients from whom plasma cell-free DNA (cfDNA) was analyzed using ultra-low-pass whole genome sequencing (ULP-WGS).
We found that cfDNA from patients with MPNST harbors a shorter fragmentation profile compared to patients with PN or healthy donors. Using sequencing reads from this fragmentation profile, we quantified genome-wide copy number alterations (CNAs) in cfDNA and used CNAs to estimate the fraction of plasma cfDNA originating from tumor.
[tpltrtarr]Tumor fraction in plasma cfDNA distinguished pre-treatment MPSNT from PN with 86% accuracy. Plasma cfDNA from MPNST and PN patients harbored focal copy number loss of NF1, not found in healthy donors. Strikingly, MPNST patient cfDNA also had significantly greater tumor genomic instability compared to PN, with copy number alterations in key genomic loci previously observed in MPNST tissue (i.e., gain of chromosome arm 8q and loss of 9p), which enabled sensitive and specific liquid biopsy discrimination of MPNST from PN.
[tpltrtarr]Plasma-derived tumor fraction correlated with tumor size from imaging in MPNST patients, and serial cfDNA analysis demonstrated the potential for noninvasive detection of minimal residual disease, treatment response assessment, and the potential for even greater assay sensitivity.


What do these findings mean?[tpltrtarr] Our findings suggest that cfDNA fragment analysis followed by ULP-WGS has the potential to be developed as a biomarker for treatment response, and as a screening assay for early detection of MPNST.
[tpltrtarr]This study provides, to our knowledge, the first evidence for the ability of liquid biopsy to distinguish between benign and malignant tumors in a heritable cancer predisposition syndrome. 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. What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Precision MRI Phenotyping Enables Detection of Small Changes in Body Composition for Longitudinal Cohorts Longitudinal studies provide unique insights into the impact of environmental factors and lifespan issues on health and disease. Here we investigate changes in body composition in 3,088 free-living participants, part of the UK Biobank in-depth imaging study. All participants underwent neck-to-knee MRI scans at the first imaging visit and after approximately two years (second imaging visit). Image-derived phenotypes for each participant were extracted using a fully-automated image processing pipeline, including volumes of several tissues and organs: liver, pancreas, spleen, kidneys, total skeletal muscle, iliopsoas muscle, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), as well as fat and iron content in liver, pancreas and spleen. Overall, no significant changes were observed in BMI, body weight, or waist circumference over the scanning interval, despite some large individual changes. A significant decrease in grip strength was observed, coupled to small, but statistically significant, decrease in all skeletal muscle measurements. Significant increases in VAT and intermuscular fat in the thighs were also detected in the absence of changes in BMI, waist circumference and ectopic-fat deposition. Adjusting for disease status at the first imaging visit did not have an additional impact on the changes observed. In summary, we show that even after a relatively short period of time significant changes in body composition can take place, probably reflecting the obesogenic environment currently inhabited by most of the general population in the United Kingdom. Genetic control of fetal placental genomics contributes to development of health and disease As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we performed distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At P < 2.5 x 10-6, we detected 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explained 4 early-life traits but no later-in-life traits. 89 GTAs showed significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells showed that knockdown of mediator gene EPS15 upregulated predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course. Complementary frailty and mortality prediction models on older patients as a tool for assessing palliative care needs BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.

ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.

MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.

ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.

ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es.