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Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called ‘long COVID’, are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app1. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76-4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.

CONTEXT: Autonomic dysreflexia (AD), characterized by a transient increase in systolic blood pressure (BP), is experienced by individuals with spinal cord injury (SCI) and can be purposefully induced (‘boosting’) to counteract autonomic dysfunction that impairs cardiovascular responses to exercise. Herein, we demonstrate the impact of unintentional boosting observed during cardiopulmonary exercise testing (CPET) in an inactive male with SCI (C5, motor-complete). FINDINGS: On two separate occasions the individual performed a standard arm-crank CPET (1-min stages, 7W increase in resistance) following by a longer CPET (4-min stages, 12W increase in resistance), both to volitional exhaustion. The second CPET was performed to confirm the accuracy of exercise intensity prescription and verify peak exercise parameters. Immediately following the second CPET on the initial visit, the individual reported symptoms of AD, verified as a 58mmHg increase in systolic BP from baseline. Relative to the first CPET, performed only 35 min earlier, there were pronounced differences in peak exercise responses. In comparison to the longer CPET performed on the second visit without a concomitant episode of AD (thereby controlling for the type of CPET protocol administered), peak exercise outcomes were considerably elevated: power output (Δ19W), oxygen uptake (Δ3.61 ml·( )kg·(−1)min(−1)), ventilation (Δ11.4 L ·min(−1)) and heart rate (Δ9 b·min(−1)). CONCLUSION/CLINICAL RELEVANCE: This case raises important considerations around the nuances of CPET in this population. In individuals susceptible to BP instability, the physiologically boosted state may explain a significant proportion of the variance in peak aerobic capacity and should be closely monitored before and after clinical CPET.

Individuals classified clinically as having a motor-complete spinal cord injury (mcSCI) should lack voluntary motor function below their injury level. Neurophysiological assessments using electromyography (EMG) and transcranial magnetic stimulation (TMS), however, have demonstrated that persons with mcSCI retain limited cortical descending innervation and voluntary activation of muscles below their level of injury, including muscles of the trunk and lower limb. We explored the possibility of whether there is also preserved innervation of the pelvic floor muscles (PFM) in persons with mcSCI. The PFM are controlled by widespread cortical and subcortical areas and typically coactivated with trunk and gluteal muscles to maintain continence and regulate intra-abdominal pressure. Nine mcSCI and eight control subjects participated in this cross-sectional study. Surface EMG was used to record activity in the PFM. Data were recorded while participants attempted various maneuvers of the trunk and pelvis. We also applied TMS at incrementing levels of intensity over the primary motor cortex area to record motor evoked potentials (MEPs) in the PFM. When performing the maneuvers, activation of the PFM was possible in all controls and the majority of SCI participants. However, the PFM were only activated in the SCI participants during maneuvers that engaged other trunk muscles, however. MEP responses in the PFM were also elicited in all controls and SCI participants, but MEP response characteristics were significantly altered in the SCI group. Our results suggest that persons with mcSCI retain some residual innervation of the PFM after injury, possibly via indirect cortical descending pathways.

We provide a protocol for generating forebrain structures in vivo from mouse embryonic stem cells (ESCs) via neural blastocyst complementation (NBC). We developed this protocol for studies of development and function of specific forebrain regions, including the cerebral cortex and hippocampus. We describe a complete workflow, from methods for modifying a given genomic locus in ESCs via CRISPR–Cas9-mediated editing to the generation of mouse chimeras with ESC-reconstituted forebrain regions that can be directly analyzed. The procedure begins with genetic editing of mouse ESCs via CRISPR–Cas9, which can be accomplished in ~4–8 weeks. We provide protocols to achieve fluorescent labeling of ESCs in ~2–3 weeks, which allows tracing of the injected, ESC-derived donor cells in chimeras generated via NBC. Once modified ESCs are ready, NBC chimeras are generated in ~3 weeks via injection of ESCs into genetically programmed blastocysts that are subsequently transferred into pseudo-pregnant fosters. Our in vivo brain organogenesis platform is efficient, allowing functional and systematic analysis of genes and other genomic factors in as little as 3 months, in the context of a whole organism. Embryonic stem cells undergo CRISPR–Cas9-mediated editing and are then used to reconstitute forebrain regions in mouse chimeras via neural blastocyst complementation.

The relationship between OA and osteoporosis characteristics remains controversial. This study revealed that age-adjusted hand OA is associated with lower hand/arm BMD levels. Wrist fracture occurrence is associated with increased OA hand scores and low arm BMD. Conversely, age-adjusted knee and spine OA is associated with high spine, hip, and total BMDs. Osteoarthritis (OA) and osteoporosis are two common musculoskeletal diseases which contribute a high burden of disability, yet assessments of their relationship remains controversial. The aim of this study was to clarify the association between bone mineral densities (BMD) of the hand, arm, spine, hip, and total body, and OA of the hand and knee and lumbar disc degeneration in two different ethnic groups. Radiographic assessments of the hand, knee, and spine were collected and coded for joint space narrowing, osteophytes, and the Kellgren-Lawrence score from Chuvashian (n = 1504) and British (n = 2280) individuals. BMD measurements of standard skeletal sites were estimated by dual X-ray absorptiometry. Age- and familial-adjusted regression analyses were conducted to determine associations. Knee OA affection was positively associated with elevated hip, spine, and total body BMD levels (p

Chronic musculoskeletal pain affects all aspects of human life. However, mechanisms of its genetic control remain poorly understood. Genetic studies of pain are complicated by the high complexity and heterogeneity of pain phenotypes. Here, we apply principal component analysis to reduce phenotype heterogeneity of chronic musculoskeletal pain at four locations: the back, neck/shoulder, hip, and knee. Using matrices of genetic covariances, we constructed four genetically independent phenotypes (GIPs) with the leading GIP (GIP1) explaining 78.4% of the genetic variance of the analyzed conditions, and GIP2–4 explain progressively less. We identified and replicated five GIP1-associated loci and one GIP2-associated locus and prioritized the most likely causal genes. For GIP1, we showed enrichment with multiple nervous system-related terms and genetic correlations with anthropometric, sociodemographic, psychiatric/personality traits and osteoarthritis. We suggest that GIP1 represents a biopsychological component of chronic musculoskeletal pain, related to physiological and psychological aspects and reflecting pain perception and processing., Yakov Tsepilov, Maxim Freidin et al. find that chronic musculoskeletal pain conditions at four distinct anatomical sites share a common genetic background. The authors constructed genetically independent phenotypes (GIP) from principal components analysis of the different pain phenotypes and used the GIPs to perform genome-wide association studies to identify underlying genetic factors.

The focus of the current investigation is to examine the temporal relationship of gambling onset and alcohol, tobacco, and cannabis initiation in adolescents and young adults (M age = 20.3 years) by examining the prevalence and pattern of onset for each substance and gambling pairing and the associated risk between gambling and each substance use. Data were drawn from the multiwave Missouri Family Study (n = 1,349) of African American (AA; n = 450) and White families (n = 317) enriched for risk for alcohol use disorder and includes those who were assessed for gambling behaviors and problems: AA (360 males, 390 females) and White (287 males, 312 females). Findings indicated racial differences in the overall prevalence of gambling behaviors and substance use as well as patterns of initiation-particularly within gambling/alcohol and gambling/tobacco for males. Survival models revealed some similarities as well as differences across race and gender groups in associations of gambling with initiation of substances, as well as substances with initiation of gambling. Alcohol use (AA males only) and cannabis use (AA males and White females) elevated the hazards of initiating gambling. In contrast, gambling significantly elevated the hazards of initiation alcohol across 3 of 4 groups and of cannabis use in AA males only. The results highlight some overlapping as well as distinct risk factors for both gambling and substance use initiation in this cohort enriched for vulnerability to alcohol use disorder (AUD). These findings have implications for integrating gambling prevention into existing substance use prevention and intervention efforts-particularly but not exclusively for young AA males. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Retrospective cohort study.Evaluate the effects of parity (number of births) on measures of sagittal posture in elderly women. The long-term objective of this study is to identify and mitigate factors contributing to age-related postural deformity in older adults.Adult spinal deformity is a prevalent condition that often requires costly surgical management. Females are disproportionately represented in spinal deformity surgical cases with up to 90% of patients being women. The potential contributions of pregnancy on postural degeneration have only begun to be acknowledged and require further study.Two hundred eight women with standing lateral radiographs were selected from the TwinsUK register. Parity information was extracted from questionnaires. Sagittal balance measurements (thoracic kyphosis, lumbar lordosis [LL], pelvic incidence [PI]) were collected and PI-LL mismatch was calculated. One-way analysis of variance tests were done between three separate age categories for measures of sagittal balance and parity and stepwise multivariate regression was done for PI-LL.Both age and PI-LL mismatch significantly differed between parity categories. PI-LL was on average 7.0° ± 2.5° greater in multiparous (3+ births) subjects than in nulliparous subjects (P 0.01). Parity did not have an independent relationship with lumbar disc degeneration, lumbar bone mineral density, or any of the individual sagittal balance parameters (P 0.05 for all), except for PI-LL. From a subanalysis of the effect of parity on sagittal alignment within twin pairs, we found that within pair differences in parity associate with within pair differences in thoracic kyphosis.This study established correlations between measures of spinal curvature in older women and parity for the first time. Longitudinal research is required to establish a causative relationship.4.

Summary: Background: We undertook a Grand Challenges in Global Eye Health prioritisation exercise to identify the key issues that must be addressed to improve eye health in the context of an ageing population, to eliminate persistent inequities in health-care access, and to mitigate widespread resource limitations. Methods: Drawing on methods used in previous Grand Challenges studies, we used a multi-step recruitment strategy to assemble a diverse panel of individuals from a range of disciplines relevant to global eye health from all regions globally to participate in a three-round, online, Delphi-like, prioritisation process to nominate and rank challenges in global eye health. Through this process, we developed both global and regional priority lists. Findings: Between Sept 1 and Dec 12, 2019, 470 individuals complete round 1 of the process, of whom 336 completed all three rounds (round 2 between Feb 26 and March 18, 2020, and round 3 between April 2 and April 25, 2020) 156 (46%) of 336 were women, 180 (54%) were men. The proportion of participants who worked in each region ranged from 104 (31%) in sub-Saharan Africa to 21 (6%) in central Europe, eastern Europe, and in central Asia. Of 85 unique challenges identified after round 1, 16 challenges were prioritised at the global level; six focused on detection and treatment of conditions (cataract, refractive error, glaucoma, diabetic retinopathy, services for children and screening for early detection), two focused on addressing shortages in human resource capacity, five on other health service and policy factors (including strengthening policies, integration, health information systems, and budget allocation), and three on improving access to care and promoting equity. Interpretation: This list of Grand Challenges serves as a starting point for immediate action by funders to guide investment in research and innovation in eye health. It challenges researchers, clinicians, and policy makers to build collaborations to address specific challenges. Funding: The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research Moorfields Biomedical Research Centre, Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The Seva Foundation, British Council for the Prevention of Blindness, and Christian Blind Mission. Translations: For the French, Spanish, Chinese, Portuguese, Arabic and Persian translations of the abstract see Supplementary Materials section.

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Globally, over three million women participate in rugby union, yet injury prevention and training strategies are predominantly based on androcentric data. These strategies may have limited generalisability to females, given the cervical spine is more susceptible to whiplash and less adept at resisting inertial loading. A total of 53 university rugby union players (25 female, 28 male, 20.7 ± 1.8 years) had their isometric neck strength measured. Bespoke instrumented mouthguards were used to record the magnitude of head impact events in six female and seven male competitive matches. Mean female maximal isometric neck strength was 47% lower than male. Independent samples Mann-Whitney U tests showed no significant differences for peak linear head acceleration (female: median 11.7 g, IQR 7.9 g; male: median 12.5 g, IQR 7.0 g p=0.23) or peak rotational head acceleration (female: median 800.2 rad·s-2, IQR 677.7 rad·s-2; male: median 849.4 rad·s-2, IQR 479.8 rad·s-2; p=0.76), despite the mean male body mass being 24% greater than female. Coded video analysis revealed substantial differences in head-impact mechanisms; uncontrolled whiplash dominated >50% of all recorded female impact events and

Previous research has shown that genes play a substantial role in determining a person’s susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.

TwinsUK is the largest cohort of community-dwelling adult twins in the UK. The registry comprises over 14,000 volunteer twins (14,838 including mixed, single and triplets); it is predominantly female (82%) and middle-aged (mean age 59). In addition, over 1800 parents and siblings of twins are registered volunteers. During the last 27 years, TwinsUK has collected numerous questionnaire responses, physical/cognitive measures and biological measures on over 8500 subjects. Data were collected alongside four comprehensive phenotyping clinical visits to the Department of Twin Research and Genetic Epidemiology, King’s College London. Such collection methods have resulted in very detailed longitudinal clinical, biochemical, behavioral, dietary and socioeconomic cohort characterization; it provides a multidisciplinary platform for the study of complex disease during the adult life course, including the process of healthy aging. The major strength of TwinsUK is the availability of several ‘omic’ technologies for a range of sample types from participants, which includes genomewide scans of single-nucleotide variants, next-generation sequencing, metabolomic profiles, microbiomics, exome sequencing, epigenetic markers, gene expression arrays, RNA sequencing and telomere length measures. TwinsUK facilitates and actively encourages sharing the ‘TwinsUK’ resource with the scientific community — interested researchers may request data via the TwinsUK website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/) for their own use or future collaboration with the study team. In addition, further cohort data collection is planned via the Wellcome Open Research gateway (https://wellcomeopenresearch.org/gateways). The current article presents an up-to-date report on the application of technological advances, new study procedures in the cohort and future direction of TwinsUK.

Many people with motor-incomplete spinal cord injury (m-iSCI) experience difficulty navigating obstacles, such as curbs and stairs. The ability to relearn walking skills may be limited by proprioceptive deficits. The purpose of this study was to determine the capacity of participants to acquire a precision walking skill, and to evaluate the influence of proprioceptive deficits on the skill acquisition in individuals with m-iSCI. Sixteen individuals with m-iSCI and eight controls performed a precision walking task that required matching their foot height to a target during the swing phase. Proprioceptive deficits were quantified at the hip and knee for joint position and movement detection sense. Participants completed 600 steps of training with visual feedback. Pretraining and posttraining tests were conducted without visual feedback, along with a transfer test with an ankle weight. Posttraining and transfer tests were repeated 1 day later. Participants returned to the laboratory 1 wk later to repeat the training. Performance was calculated as the vertical distance between the target and actual foot height for each step. The posttraining and transfer performances were similar between groups. However, participants with m-iSCI had a slower rate of acquisition to achieve a similar performance level compared with controls. Acquisition rate and posttraining performance of the precision walking task were related to lower limb joint position sense among SCI participants. Although they can achieve a similar level of performance in a precision walking task, proprioceptive deficits impair the rate of learning among individuals with m-iSCI compared with able-bodied controls. NEW & NOTEWORTHY People with motor-incomplete spinal cord injuries are able to achieve the same level of performance accuracy on a precision walking task as able-bodied controls; however, the rate of learning is slower, indicating that more practice is required to stabilize performance. Our findings also show a relationship between impaired sensory function and reduced accuracy when performing a precision walking task after spinal cord injury.

Tinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E−08), rs4900545 (p = 1.8E−08) and 14:103042287_CT_C (p = 3.50E−08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases., Carolin Koss et al. show that IL-36 produced from neutrophils is a key amplifier of lung inflammation in mice by activating neutrophils, macrophages and fibroblasts in cooperation with GM-CSF and the viral mimic poly(I:C). This study suggests that targeting IL-36 may improve the treatment of neutrophilic lung diseases.

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.

Sex differences for chronic back pain (cBP) have been reported, with females usually exhibiting greater morbidity, severity, and poorer response to treatment. Genetic factors acting in an age-specific manner have been implicated but never comprehensively explored. We performed sex- and age-stratified genome-wide association study and single nucleotide polymorphism-by-sex interaction analysis for cBP defined as "Back pain for 3+ months" in 202,077 males and 237,754 females of European ancestry from UK Biobank. Two and 7 nonoverlapping genome-wide significant loci were identified for males and females, respectively. A male-specific locus on chromosome 10 near SPOCK2 gene was replicated in 4 independent cohorts. Four loci demonstrated single nucleotide polymorphism-by-sex interaction, although none of them were formally replicated. Single nucleotide polymorphism-explained heritability was higher in females (0.079 vs 0.067, P = 0.006). There was a high, although not complete, genetic correlation between the sexes (r = 0.838 ± 0.041, different from 1 with P = 7.8E-05). Genetic correlation between the sexes for cBP decreased with age (0.858 ± 0.049 in younger people vs 0.544 ± 0.157 in older people; P = 4.3E-05). There was a stronger genetic correlation of cBP with self-reported diagnosis of intervertebral disk degeneration in males than in females (0.889 vs 0.638; P = 3.7E-06). Thus, the genetic component of cBP in the UK Biobank exhibits a mild sex- and age-dependency. This provides an insight into the possible causes of sex- and age-specificity in epidemiology and pathophysiology of cBP and chronic pain at other anatomical sites.

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

BackgroundStudies on the nasal cycle can be limited by time-consuming rhinomanometric measurements. However, quantifiable subjective assessment of nasal airflow has been limited by poor correlation with rhinomanometric data, even when investigating patients with a deviated nasal septum.MethodsThirty healthy participants attended two study days for rhinomanometric and subjective assessment of nasal airflow (using the subjective ordinal scale). A nasal partitioning ratio was calculated for both measures.ResultsObjective and subjective nasal partitioning ratios were compared; strong correlations were seen, with a correlation coefficient of 0.64 (p< 0.00001) on day 1 and 0.68 (p< 0.00001) on day 2.ConclusionThe use of the subjective ordinal scale and nasal partitioning ratio provides a sensitive tool for assessing relative nasal airflow, with results that correlate strongly with rhinomanometric data. This finding strongly suggests that this combination could be used for future subjective assessment of the nasal cycle.

Studies have shown that moderate alcohol consumption is strongly associated with reduced reporting of chronic widespread pain\ud (CWP). The study designs used, however, are prone to confounding and are not able to establish the direction of causality. The\ud current study overcomes these problems using the Mendelian randomisation design to determine the effect of alcohol consumption\ud on the likelihood of reporting CWP. The UK Biobank recruited 500,000 participants aged between 40 and 69 years. Data collected\ud included questions on chronic pain and alcohol consumption, and biological samples providing genotypic information. Alcohol\ud consumption was categorised as “weekly consumption” or “nonfrequent or infrequent.” Participants were classified by genotype\ud according to alleles of the rs1229984 single-nucleotide polymorphism, either “GG” or “AA/AG.” Chronic widespread pain was\ud defined as pain all over the body for more than 3 months that interfered with activities. Associations between genotype, CWP, and\ud alcohol consumption were tested by logistic regression. Instrumental variable analysis was used to calculate the causal effect\ud of weekly alcohol consumption on CWP. Persons with “GG” genotype had an increased risk of CWP (odds ratio [OR] 1.17, 99%\ud confidence interval 1.01-1.35) and were more likely to consume alcohol weekly (OR 1.76, 1.70-1.81) compared to those with\ud “AA/AG” genotype. Weekly consumption of alcohol was associated with reduced risk of CWP (OR 0.33, 0.31-0.35), but\ud instrumental variable analysis did not show a causal effect of alcohol consumption on reducing CWP (OR 1.29, 0.96-1.74). An\ud interpretation of observational population studies as showing a protective effect of alcohol on CWP is not supported.

Background Low back pain (LBP) is the symptom of a group of syndromes with heterogeneous underlying mechanisms and molecular pathologies, making treatment selection and patient prognosis very challenging. Moreover, symptoms and prognosis of LBP are influenced by age, gender, occupation, habits, and psychological factors. LBP may be characterized by an underlying inflammatory process. Previous studies indicated a connection between inflammatory response and total plasma N-glycosylation. We wanted to identify potential changes in total plasma N-glycosylation pattern connected with chronic low back pain (CLBP), which could give an insight into the pathogenic mechanisms of the disease. Methods Plasma samples of 1128 CLBP patients and 760 healthy controls were collected in clinical centers in Italy, Belgium and Croatia and used for N-glycosylation profiling by hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) after N-glycans release, fluorescent labeling and clean-up. Observed N-glycosylation profiles have been compared with a cohort of 126 patients with acute inflammation that underwent abdominal surgery. Results We have found a statistically significant increase in the relative amount of high-branched (tri-antennary and tetra-antennary) N-glycan structures on CLBP patients' plasma glycoproteins compared to healthy controls. Furthermore, relative amounts of disialylated and trisialylated glycan structures were increased, while high-mannose and glycans containing bisecting N-acetylglucosamine decreased in CLBP. Conclusions Observed changes in CLBP on the plasma N-glycome level are consistent with N-glycosylation changes usually seen in chronic inflammation. General significance To our knowledge, this is a first large clinical study on CLBP patients and plasma N-glycome providing a new glycomics perspective on potential disease pathology.

Resolvins are omega-3 fatty acid derived potent bioactive lipids that resolve inflammation and modulate transient receptor potential channels. Exogenous administration of the resolvin precursor 17-HDHA shows a strong analgesic effect in animal models of osteoarthritis and acute inflammatory pain, but has not been studied in humans. Our aim was to assess the role of 17-HDHA and resolvins in heat pain sensitivity and in osteoarthritis pain in humans. Resolvins D1, D2, D3, D5, E1 and 17-HDHA, were measured by liquid chromatography-mass spectrometry and tested for association with heat pain thresholds in 250 healthy volunteers who had undergone quantitative sensory testing. Resolvins D1, D2 and 17-HDHA were then tested in 62 individuals affected with knee osteoarthritis and 52 age matched controls and tested for association with knee pain. Circulating levels of docosahexaenoic acid (DHA) were also measured. Levels of 17-HDHA, but not those of the other 5 resolvins tested, were associated with increased heat pain thresholds (beta = 0.075; 95% CI 0.024, 0.126; p

© 2017 by the American Society of Nephrology. Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry.We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2310-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of theminor allele at this SNP associatedwith 7%higher serum PTHconcentration. The other SNPs associatedwith serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10-17), rs219779 adjacent to CLDN14 (P=3.5310-16), rs4443100 nearRTDR1 (P=8.7310-9), and rs73186030 nearCASR(P=4.8310-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

BackgroundCommon types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203,309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK.MethodsCases in the UK Biobank were determined by a question which asked the participants if they had experienced pain in the neck or shoulder in the previous month influencing daily activities. Controls were the UK Biobank participants who reported no pain anywhere in the last month. A genome-wide association study was performed adjusting for age, sex, BMI and 9 population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication.ResultsWe identified 3 genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, havingP= 1.66 × 10-11. The second most significant locus was located in theFOXP2gene in chromosome 7 withP= 2.38 × 10-10for rs34291892. The third locus was located in theLINC01572gene in chromosome 16 withP= 4.50 × 10-8for rs62053992. In the replication stage, among 4 significant and independent genetic variants, rs2049604 in theFOXP2gene and rs62053992 in theLINC01572gene were weakly replicated in GS:SFHS (P =0.0240 andP= 0.0202, respectively). None of the single nucleotide polymorphisms (SNPs) were replicated in the TwinsUK cohort (P> 0.05).ConclusionsWe have identified 3 loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.SignificanceThis is the first genome-wide association study on neck or shoulder pain. We have identified 3 genetic loci (an intergenic region in chromosome 17, theFOXP2gene in chromosome 7, and theLINC01572gene in chromosome 16) that are associated with neck or shoulder pain using the UK Biobank cohort, among which theFOXP2gene and theLINC01572gene were weakly replicated by the Generation Scotland: Scottish Family Health Study (P< 0.05). The SNP heritability was 0.11, indicating neck or shoulder pain is a heritable trait. The tissue expression analysis suggested that neck or shoulder pain was related to multiple brain tissues, indicating the involvement of neuron function. The results will inform further research in the characterisation of the mechanisms of neck or shoulder pain.

Deep vein thrombosis and pulmonary embolism, collectively defined as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Common genetic variants conferring increased varying degrees of VTE risk have been identified by genome-wide association studies (GWAS). Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 result in perinatal lethal thrombosis in homozygotes and markedly increased VTE risk in heterozygotes. However, currently described VTE variants account for an insufficient portion of risk to be routinely used for clinical decision making. To identify new rare VTE risk variants, we performed a whole-exome study of 393 individuals with unprovoked VTE and 6114 controls. This study identified 4 genes harboring an excess number of rare damaging variants in patients with VTE: PROS1, STAB2, PROC, and SERPINC1. At STAB2, 7.8% of VTE cases and 2.4% of controls had a qualifying rare variant. In cell culture, VTE-associated variants of STAB2 had a reduced surface expression compared with reference STAB2. Common variants in STAB2 have been previously associated with plasma von Willebrand factor and coagulation factor VIII levels in GWAS, suggesting that haploinsufficiency of stabilin-2 may increase VTE risk through elevated levels of these procoagulants. In an independent cohort, we found higher von Willebrand factor levels and equivalent propeptide levels in individuals with rare STAB2 variants compared with controls. Taken together, this study demonstrates the utility of gene-based collapsing analyses to identify loci harboring an excess of rare variants with functional connections to a complex thrombotic disease.

This cross-sectional study applied the intergroup contact theory in the context of transgender prejudice and examined the relationships between quality and quantity of contact and explicit and implicit anti-transgender prejudice. Additionally, the study assessed the possible mediating role of intergroup anxiety in the relationship between intergroup contact and anti-transgender prejudice. Structural equation modeling was used to examine the proposed relationships, controlling for gender, religiosity, and political conservatism. Data were collected from an online sample of 354 participants (males: n = 168; females: n = 186). As hypothesized, greater quantity of contact was uniquely related to less implicit anti-transgender prejudice, whereas greater quality of contact was uniquely related to less explicit and implicit anti-transgender prejudice. Intergroup anxiety mediated the relationships between quality of contact and implicit and explicit anti-transgender prejudice but did not mediate the relationship between quantity of contact and implicit anti-transgender prejudice.

STUDY DESIGN A longitudinal cotwin control study of the Vietnam Era Twin Registry. OBJECTIVE The aim of this study was to examine the association of post-traumatic stress disorder (PTSD) symptoms with incident chronic back pain (CBP), while controlling for genetic factors and early family environment. SUMMARY OF BACKGROUND DATA It is unknown whether PTSD symptoms are associated with an increased incidence of CBP. METHODS In 2010 to 2012, a baseline survey was undertaken as part of a large-scale study of PTSD. Study participants completed the PTSD Symptom Checklist (PCL) and a self-report measure of CBP. In 2015 to 2017, a follow-up survey was sent to all 171 monozygotic (MZ) twin pairs (342 individuals) where both cotwins had no history of CBP at baseline, but only one cotwin in the pair met criteria for having current PTSD symptoms (one twin with PCL

International audience; Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2 clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our indepth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.

Objective: 10–50% of college students meet the diagnostic criteria for one or more mental illnesses; unfortunately, less than half seek treatment. This study assessed the predictive power of specif...

BACKGROUND There is some evidence that upper-body training modalities can improve not only aerobic capacity but also seated balance in people with spinal cord injury (SCI), even in those classified with motor-complete paralysis above T6. Here, we evaluated the effect of arm crank ergometry (ACE) "spin" training on trunk muscle recruitment and its effects on seated balance and aerobic capacity. METHODS Eight individuals with high-level complete and 6 with either a low-level complete or a motor-incomplete SCI participated in this study. Participants completed 5 weeks of a group ACE "spin" training protocol which featured modulations in cadence and resistance as well as back-supported and unsupported bouts. Surface electromyography was used to confirm trunk muscle recruitment during unsupported ACE. Changes in aerobic capacity (peak oxygen consumption) and seated balance control (center of pressure parameters) were assessed at pre- and post-intervention. RESULTS Unsupported ACE was effective for eliciting trunk muscle activity (P

Introduction There is a dearth of research on the impact of pre-treatment assessment effort and symptom exaggeration on the treatment outcomes of Veterans engaging in trauma-focused therapy, handicapping therapists providing these treatments. Research suggests a multi-method approach for assessing symptom exaggeration in Veterans with posttraumatic stress disorder (PTSD), which includes effort and symptom validity tests, is preferable. Symptom exaggeration has also been considered a “cry for help,” associated with increased PTSD and depressive symptoms. Recently, research has identified resilience as a moderator of PTSD and depressive symptom severity and an important predictor of treatment response among individuals with PTSD. Thus, it is important to examine the intersection of symptom exaggeration, resilience, and treatment outcome to determine whether assessment effort and symptom exaggeration compromise treatment response. Materials and Methods We recruited Veterans, aged 18–50 who served during the Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) era, from mental health clinics and fliers posted in a large Veterans Affairs Medical Center. Veterans met inclusion criteria if they were diagnosed with PTSD via a clinician-administered assessment. Sixty-one Veterans consented to participate and self-selected into a cognitive processing therapy (CPT) group or treatment-as-usual. We offered self-selection because low recruitment rates delayed treatment start dates and were consistent with a Veteran-centered care philosophy. Veterans were assessed before and after treatment to determine the impact of assessment effort and symptom exaggeration scores on measures of PTSD and depressive symptoms and resilience. This study examined whether assessment effort failure and symptom exaggeration were associated with compromised psychotherapy outcomes in Veterans with PTSD undergoing CPT group. We hypothesized that a pattern of responding consistent with both effort and symptom exaggeration would result in higher (ie, more severe) pre- and post-treatment scores on PTSD and depressive symptom outcome measures and lower resiliency when compared to Veterans providing good effort and genuine responding. Hypotheses were evaluated using bivariate correlation analyses, analysis of variance, and chi-square analyses. Results Pre-treatment scores on measures of PTSD and depressive symptoms were higher among Veterans whose pattern of responding was consistent with poor assessment effort and symptom exaggeration; these Veterans also scored lower on a measure of resiliency. At post-treatment, there were no differences between Veterans displaying good and failed effort testing on measures of PTSD and depressive symptoms or in whether they completed treatment. Post-treatment resiliency scores remained significantly lower in those with failed effort testing. Conclusion These results suggest that Veterans with PTSD whose validity testing scores are indicative of poor effort and symptom exaggeration may be less resilient but may still complete a CPT group treatment and benefit from treatment at a rate comparable to Veterans who evidence good assessment effort and genuine symptom reporting pre-treatment. These findings also challenge the assumption that pre-treatment assessment effort failure and symptom exaggeration accurately predict poor effort in trauma-focused psychotherapy.

Back pain (BP) is a common condition of major social importance and poorly understood pathogenesis. Combining data from the UK Biobank and CHARGE consortium cohorts allowed us to perform a very large GWAS (total N = 509,070) and examine the genetic correlation and pleiotropy between BP and its clinical and psychosocial risk factors. We identified and replicated three BP associated loci, including one novel region implicating SPOCK2/CHST3 genes. We provide evidence for pleiotropic effects of genetic factors underlying BP, height, and intervertebral disc problems. We also identified independent genetic correlations between BP and depression symptoms, neuroticism, sleep disturbance, overweight, and smoking. A significant enrichment for genes involved in central nervous system and skeletal tissue development was observed. The study of pleiotropy and genetic correlations, supported by the pathway analysis, suggests at least two strong molecular axes of BP genesis, one related to structural/anatomic factors such as intervertebral disk problems and anthropometrics; and another related to the psychological component of pain perception and pain processing. These findings corroborate with the current biopsychosocial model as a paradigm for BP. Overall, the results demonstrate BP to have an extremely complex genetic architecture that overlaps with the genetic predisposition to its biopsychosocial risk factors. The work sheds light on pathways of relevance in the prevention and management of LBP.

Objective: To compare the yield of epileptiform abnormalities on 30-minute recordings with those greater than 45 minutes. Methods: We performed a prospective observational cross-sectional study of all outpatient routine EEGs comparing the rate of interictal epileptiform discharges (IEDs) and clinical events during the initial 30 minutes (routine) with those occurring in the remaining 30–60 minutes (extended). A relative increase of 10% was considered clinically significant. Results: EEGs from 1,803 patients were included; overall EEG duration was 59.4 minutes (SD ±6.5). Of 426 patients with IEDs at any time during the EEG, 81 (19.1%, 95% confidence interval 15.6–23) occurred only after the initial 30 minutes. The rate of late IEDs was not associated with age, indication, IED type, or sleep deprivation. Longer recording times also increased event capture rate by approximately 30%. Conclusions: The yield of IED and event detection is increased in extended outpatient EEGs compared to 30-minute studies.

Objective: The primary aim of this study was to determine the feasibility of delivering an exoskeleton-assisted walking intervention targeting lower urinary tract function in people with motor-complete spinal cord injury. Secondary aims were to deter-mine if exoskeleton walking activates the pelvic floor muscles, and compare 2 exoskeleton programmes regarding lower urinary tract function. Design: Randomized pilot trial. Subjects: Adults with motor-complete spinal cord injury at or above T10. Methods: Participants were randomized to receive Ekso or Lokomat training. Feasibility outcomes included recruitment rate, adherence, and adverse events. Pelvic floor muscle electromyography was recorded during walking. Urodynamic studies, 3-day bladder diary, and Qualiveen-30 were administered pre- and post-training. Results: Twelve people were screened and 6 people enrolled in the study. Two subjects withdrew from unrelated reasons. There was one adverse event. Pelvic floor muscle activity was greater in the Ekso group. Lower urinary tract function did not clearly change in either group. Conclusion: This pilot study demonstrates the feasibility of delivering an exoskeleton training programme targeting lower urinary tract function. Ekso-walking elicits pelvic floor muscle activity, but it remains unclear how locomotor training impacts lower urinary tract function. Lay abstract Some studies in people with spinal cord injury have report-ed improvements in urinary bladder health after gait therapy, but the mechanisms behind this are unclear. Strong pelvic floor muscles are crucial to urinary bladder health, and these muscles are normally active during walking. It is possible that the pelvic floor muscles are similarly engaged during exoskeleton-walking in people with spinal cord injury, and this could improve urinary bladder health. This study demonstrates that delivering an exoskeleton intervention to people with spinal cord injury for urinary bladder health is feasible. Participants were successfully recruited to a training programme, and any dropouts were because of issues unrelated to the study. Furthermore, the study showed that the pelvic floor muscles are active while walking in 1 type of exoskeleton, but it remains unclear how exoskeleton-walking may help improve urinary bladder outcomes. Further research is needed to explore how exoskeleton interventions may engage the pelvic floor muscles and improve urinary bladder health outcomes for those with spinal cord injury.

In 1978, the World Health Organization defined primary health care as the cornerstone of global health. In recent years, the usual causes of mortality (infections, deficiency diseases) now include chronic and degenerative diseases. It is now possible to provide tertiary care to patients without adequate resources for their survival after discharge. The health system has not been able to adapt to such change and has maintained a fragmented, reactive, disease-centered model. "Selective primary care" is useful to redirect primary care bases according to the characteristics of the population. A set of specific measures, targeted at a population with specific vulnerabilities, leverages the power of primary health care. Here we describe the "Outpatient Pediatric Special Care" model of care implemented at the Center for Health and Community Action no. 5, in the Autonomous City of Buenos Aires.En 1978, la Organización Mundial de la Salud definió la atención primaria de la salud como pilar fundamental de la salud global. En los últimos años, a las causas habituales de mortalidad (infecciosas, carenciales) se sumaron las provocadas por enfermedades crónicas y degenerativas. Es posible brindar atención de alta complejidad a pacientes sin recursos adecuados para su supervivencia luego del egreso. El sistema de salud no supo adaptarse a este cambio y mantuvo un modelo fragmentado, reactivo y centrado en la enfermedad. La “atención primaria selectiva” permite reorientar las bases de la atención primaria según las características de la población. Un grupo de acciones específicas, dirigidas a una población con vulnerabilidades particulares, potencia las virtudes de la atención primaria de la salud. Se describe el modelo de atención “Cuidados Especiales Ambulatorios Pediátricos” implementado en el Centro de Salud y Acción Comunitaria N.º 5 de la Ciudad de Buenos Aires.

Genetically modified mice are commonly generated by the microinjection of pluripotent embryonic stem (ES) cells into wild-type host blastocysts1, producing chimeric progeny that require breeding for germline transmission and homozygosity of modified alleles. As an alternative approach and to facilitate studies of the immune system, we previously developed RAG2-deficient blastocyst complementation2. Because RAG2-deficient mice cannot undergo V(D)J recombination, they do not develop B or T lineage cells beyond the progenitor stage2: injecting RAG2-sufficient donor ES cells into RAG2-deficient blastocysts generates somatic chimaeras in which all mature lymphocytes derive from donor ES cells. This enables analysis, in mature lymphocytes, of the functions of genes that are required more generally for mouse development3. Blastocyst complementation has been extended to pancreas organogenesis4, and used to generate several other tissues or organs(5–10), but an equivalent approach for brain organogenesis has not yet been achieved. Here we describe neural blastocyst complementation (NBC), which can be used to study the development and function of specific forebrain regions. NBC involves targeted ablation, mediated by diphtheria toxin subunit A, of host-derived dorsal telencephalic progenitors during development. This ablation creates a vacant forebrain niche in host embryos that results in agenesis of the cerebral cortex and hippocampus. Injection of donor ES cells into blastocysts with forebrain-specific targeting of diphtheria toxin subunit A enables donor-derived dorsal telencephalic progenitors to populate the vacant niche in the host embryos, giving rise to neocortices and hippocampi that are morphologically and neurologically normal with respect to learning and memory formation. Moreover, doublecortin-deficient ES cells-generated via a CRISPR-Cas9 approach-produced NBC chimaeras that faithfully recapitulated the phenotype of conventional, germline doublecortin-deficient mice. We conclude that NBC is a rapid and efficient approach to generate complex mouse models for studying forebrain functions; this approach could more broadly facilitate organogenesis based on blastocyst complementation.

Individuals with a spinal cord injury (SCI) ≥T6 level exhibit impaired cardiovascular responses to exercise that can limit exercise capacity.1 The burgeoning field of neuromodulation has recently demonstrated that epidural spinal cord stimulation (ESCS), configured to facilitate motor function in humans with SCI, can also modulate cardiovascular function (i.e., increasing or maintaining arterial blood pressure at rest or in response to an orthostatic challenge, respectively).2–4 Here we present a unique application of ESCS to improve upper body exercise capacity in an individual with SCI, via the modulation of cardiovascular and respiratory function.

Summary Background Internationally, chest radiography is the standard investigation for identifying rib fractures in suspected physical abuse in infants. Several small observation studies in children have found that chest CT can provide greater accuracy than radiography for fracture detection, potentially aiding medicolegal proceedings in abuse cases; however, to our knowledge, this greater accuracy has not been comprehensively evaluated. We aimed to determine differences in rib fracture detection rates between post-mortem chest radiographs and chest CT images, using forensic autopsy as the reference standard. Methods In this retrospective diagnostic accuracy study, we searched the Great Ormond Street Hospital (London, UK) radiology information system for all children aged 0–16 years who had a post-mortem skeletal survey (ie, full-body radiography), CT, and full autopsy between Jan 1, 2012, and Jan 1, 2017, for a purpose of death investigation. Cases were excluded if the imaging was done for a reason other than a forensic investigation or if image quality was suboptimal. Radiologists were recruited as reporters on a voluntary basis via membership databases from international radiology and post-mortem imaging societies with no specific inclusion or exclusion criteria. Reporters were sent a set of chest radiographs on a password protected and encrypted USB flash drive or via a secure filesharing website and independently reported on the presence of rib fractures, fracture location, and the confidence level of their interpretation. They were masked to the clinical information of the images. 1 month later, the same reporters were sent CTs for the same cases in a random order and asked to report on the same features. The primary objective was to compare the accuracy of detection of rib fractures by use of post-mortem chest radiographs and CTs, with autopsy data as reference standard. Accuracy was assessed by comparison of diagnostic statistics, calculated using random-intercept multilevel logistic models with reporter and patient included as cross-classified random-effects. Findings 25 cases of children (aged 1 month to 7 years), with 136 rib fractures at autopsy with paired post-mortem chest radiographs and CTs, were selected for analysis. 38 radiologists were recruited as reporters from 23 international centres; 12 (32%) were consultants, median experience of 14·5 years (range 6–27), and 26 (68%) were registrars, median experience of 4 years (range 2–9). Across all radiologists, three times as many rib fractures were correctly detected by use of chest CTs compared with chest radiography (sensitivity 44·9% [95% CI 31·7–58·9] vs 13·5% [8·1–21·5]; difference 31·4% [23·3–37·8; p

STUDY DESIGN: Longitudinal study of spine magnetic resonance imaging (MRI) in a large-scale population-based study.OBJECTIVE: To determine the order of appearance of degenerative change in vertebral bodies and intervertebral discs. We also sought to define the influence of endplate defect on low back pain (LBP) and to determine whether there is a genetic influence on endplate defect.SUMMARY OF BACKGROUND DATA: Endplate defect is a magnetic resonance imaging trait, found to be associated with intervertebral disc degeneration. There is a lack of understanding regarding the mechanism underlying lumbar disc degeneration (LDD). Recent attention has shifted to vertebral endplate defects and their role in spine degeneration pathology.METHODS: Individuals from the TwinsUK spine study having longitudinal T2-weighted lumbar MR scans at baseline (n = 996) and a decade later (n = 438) were included. LDD, vertebral endplate defect by calculating a total endplate (TEP) score and Modic change (MC) were assessed using standard techniques. Mixed-effects models were used to determine the association between the features of spine pathology, adjusted for covariates. Endplate defect heritability was estimated using variance component analysis.RESULTS: Significant association was found between endplate defect, LDD, MRI features of LDD and MC was observed. Endplate defect was associated with severe disabling LBP (p ≤ 0.013) in multivariate analysis. An association between disc degeneration (DD) at baseline and MC at follow-up was shown at upper lumbar levels. TEP score was heritable with estimated additive genetic component A = 55.3% (95% CI 43.0-65.4).CONCLUSION: Endplate defect, LDD and MC are all independent risk factors for episodes of severe and disabling LBP. Longitudinal analysis showed DD is followed by MC. Endplate defect has significant heritability of 55%. However, whether endplate defect triggers DD or these pathological changes occur concurrently could not be conclusively determined.LEVEL OF EVIDENCE: 2.

An “omics” investigation of chronic widespread pain in 2 population samples reveals a genetic variant in CYP3A5 as underlying steroid hormone abnormalities seen in CWP., Chronic widespread musculoskeletal pain (CWP) is common, having a population prevalence of 10%. This study aimed to define the biological basis of the CWP/body mass association by using a systems biology approach. Adult female twins (n = 2444) from the TwinsUK registry who had extensive clinical, anthropometric, and “omic” data were included. Nontargeted metabolomics screening including 324 metabolites was carried out for CWP and body composition using dual-energy X-ray absorptiometry. The biological basis of these associations was explored through a genome-wide association study and replicated in an independent population sample (Cooperative Health Research in the Region of Augsburg [KORA] study, n = 2483). A causal role for the genetic variants identified was sought in CWP using a Mendelian randomisation study design. Fat mass/height2 was the body composition variable most strongly associated with CWP (TwinsUK: P = 2.4 × 10−15 and KORA: P = 1.59 × 10−10). Of 324 metabolites examined, epiandrosterone sulfate (EAS) was highly associated with both CWP (P = 1.05 × 10−09 in TwinsUK and P = 3.70 × 10−06 in KORA) and fat mass/height2. Genome-wide association study of EAS identified imputed single nucleotide polymorphism rs1581492 at 7q22.1 to be strikingly associated with EAS levels (P ≤ 2.49 × 10−78), and this result was replicated in KORA (P = 2.12 × 10−9). Mendelian randomization by rs1581492 genotype showed that EAS is unlikely to be causally related to CWP. Using an agnostic omics approach to focus on the association of CWP with body mass index, we have confirmed a steroid hormone association and identified a genetic variant upstream of the CYP genes, which likely controls this response. This study suggests that steroid hormone abnormalities result from pain rather than causing it, and EAS may provide a biomarker that identifies subgroups at risk of CWP.

The milestone publication by Slick, Sherman, and Iverson (1999) of criteria for determining malingered neurocognitive dysfunction led to extensive research on validity testing. Position statements by the National Academy of Neuropsychology and the American Academy of Clinical Neuropsychology (AACN) recommended routine validity testing in neuropsychological evaluations. Despite this widespread scientific and professional support, the Social Security Administration (SSA) continued to discourage validity testing, a stance that led to a congressional initiative for SSA to reevaluate their position. In response, SSA commissioned the Institute of Medicine (IOM) to evaluate the science concerning the validation of psychological testing. The IOM concluded that validity assessment was necessary in psychological and neuropsychological examinations (IOM, 2015 ).The AACN sought to provide independent expert guidance and recommendations concerning the use of validity testing in disability determinations.A panel of contributors to the science of validity testing and its application to the disability process was charged with describing why the disability process for SSA needs improvement, and indicating the necessity for validity testing in disability exams.This work showed how the determination of malingering is a probability proposition, described how different types of validity tests are appropriate, provided evidence concerning non-credible findings in children and low-functioning individuals, and discussed the appropriate evaluation of pain disorders typically seen outside of mental consultations.A scientific plan for validity assessment that additionally protects test security is needed in disability determinations and in research on classification accuracy of disability decisions.

Age-related hearing impairment (ARHI) is a common condition with complex etiology but a recognized genetic component. Heritability estimates for pure tone audiogram-determined hearing ability lie in the range 26–75%. The speech-in-noise (SIN) auditory test, however, may be better at encapsulating ARHI symptoms, particularly the diminished ability to segregate environmental sounds into comprehendible auditory streams. As heritability of SIN has not previously been reported, we explored the genetic and environmental contributions to ARHI determined by SIN in 2,076 twins (87.8% female) aged 18–87 (mean age 54.4). SIN was found to be significantly heritable (A, unadjusted for age = 40%; 95% confidence intervals, CI = 32%–47%). With age adjustment, heritability fell (A= 25%; 95% CI = 16–33%), and a relatively strong influence of environmental exposure unshared within twin siblings was identified (E= 75%). To explore the environmental aspects further, we assessed the influence of diet (through the Food Frequency Questionnaire, FFQ), smoking (through self-report and cotinine metabolite levels) and alcohol intake (through the FFQ). A negative influence of high cholesterol diet was observed after adjustment (p= .037). A protective effect of raised serum high-density lipoprotein (HDL) cholesterol levels was observed after adjustment (p= .004). This study is the first assessment of the genetic and environmental influence on SIN perception. The findings suggest SIN is less heritable than pure tone audiogram (PTA) ability and highly influenced by the environment unique to each twin. Furthermore, a possible role of dietary fat in the etiology of ARHI is highlighted.

Supplemental Digital Content is Available in the Text. The prevalence of neuropathic pain within chronic widespread pain is 16%. Neuropathic pain is 37% heritable and shares underlying genetic factors with chronic widespread pain., Chronic widespread pain (CWP) has complex aetiology and forms part of the fibromyalgia syndrome. Recent evidence suggests a higher frequency of neuropathic pain features in those with CWP than previously thought. The aim of this study was to determine the prevalence of neuropathic pain features in individuals with CWP and to estimate the influence of genetic and environmental factors on neuropathic pain in CWP. Validated questionnaires (the London Fibromyalgia Screening Study questionnaire and PainDETECT questionnaire) were used to classify twins as having CWP and neuropathic pain, respectively. The prevalence of CWP was 14.7% (n = 4324), and of the 1357 twins invited to complete neuropathic pain screening, 15.9% of those having CWP demonstrated features of neuropathic pain. Neuropathic pain was found to be heritable (A = 37%; 95% confidence interval [CI]: 23%-50%) with unique environmental factors accounting for 63% (95% CI: 49%-79%) of the variance. Heritability of neuropathic pain and CWP were found to be correlated, 0.54 (95% CI: 0.42-0.65). Increasing age, raised body mass index, female gender, and smoking were all risk factors for neuropathic pain (P < 0.05), and CWP (P < 0.05). High socioeconomic status showed negative correlation with neuropathic pain (P = 0.003) and CWP (P = 0.001). Bivariate analysis of the 2 pain traits revealed that genetic predisposition to neuropathic pain is shared with that for CWP. This is the first study to provide formal heritability estimates for neuropathic pain in CWP. The findings suggest that at least some of the genetic factors underlying the development of neuropathic pain and CWP are the same.

The Behavioral and Emotional Screening System (BESS) is a relatively new method for identifying behavior and emotional risk (BER) in children and adolescents. Psychometric evidence regarding this instrument is important for researchers and practitioners considering the use of the BESS for identifying BER in students. Previous psychometric research specifically regarding the BESS Student Form involved the use of samples of elementary and middle school-age children. This study adds to the psychometric evidence for scores on the BESS Student Form by using samples of high school aged students to assess both the factor structure reported by Dowdy, Twyford et al. (2011) and the measurement invariance of the BESS items with regard to ethnicity, English language proficiency, and socioeconomic status. The results indicate that while the proposed 4-factor structure of the BESS Student Form is appropriate, lower than preferred reliabilities for some of the factors indicates that reporting the overall risk T score is more appropriate than reporting factor scores for risk classification purposes. Additionally, the BESS Student Form items did not exhibit measurement bias when comparing across ethnicities, language proficiency classification, or socioeconomic status (via free/reduced lunch classification).

BackgroundRheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may also be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease discordant monozygotic twin pairs.MethodsGenome-wide DNA methylation was assessed in 79 monozygotic twin pairs discordant for rheumatoid arthritis using the HumanMethylation450 BeadChip array (Illumina). Discordant twins were tested for both differential DNA methylation and methylation variability between RA and healthy twins. The methylation variability signature was then compared with methylation variants from studies of other autoimmune diseases and with an independent healthy population.ResultsWe have identified a differentially variable DNA methylation signature, that suggests multiple stress response pathways may be involved in the aetiology of the disease. This methylation variability signature also highlighted potential epigenetic disruption of multiple RUNX3 transcription factor binding sites as being associated with disease development. Comparison with previously performed epigenome-wide association studies of rheumatoid arthritis and type 1 diabetes identified shared pathways for autoimmune disorders, suggesting that epigenetics plays a role in autoimmunity and offering the possibility of identifying new targets for intervention.ConclusionsThrough genome-wide analysis of DNA methylation in disease discordant monozygotic twins, we have identified a differentially variable DNA methylation signature, in the absence of differential methylation in rheumatoid arthritis. This finding supports the importance of epigenetic variability as an emerging component in autoimmune disorders.

STUDY DESIGN: Cross-sectional study of spine MR in a population, predominantly female, sample.OBJECTIVE: To determine the relationship between vertebral endplate defect and intervertebral disc degeneration (DD) in general population.SUMMARY OF BACKGROUND DATA: Precise understanding of the mechanisms leading to DD development is lacking. In a degenerating disc, mechanical and structural changes lead to further worsening of disc integrity. Increasing attention has been paid to vertebral endplate defects as having a possible role in the etiopathogenesis of DD.METHODS: The study population comprised 831 twin volunteers from TwinsUK (mean age 54 ± 8 years, 95.8% female). Lumbar T2-weighted magnetic resonance images were coded for endplate defects from 8310 endplates into six grades. Total endplate score (TEP score) was achieved by summing both endplate defect grades from the same disc level. DD was evaluated using two different classifications; Pfirrmann grading, and a quantitative trait for DD based on a 4-point grading systems. Multivariable regression analysis was used to determine relationships between the traits of interest and the known risk factors for DD, age and body mass index (BMI). A receiver operator curve for TEP score predicting DD was generated, and survival analysis paired with Cox proportional hazards models analysis performed.RESULTS: There was statistically significant association between DD and age and BMI. These associations lost significance when TEP score was included as predictor in multivariable model. TEP score was strongly and independently associated at every lumbar disc level with DD (Pfirmann p≤0.001; 4-point grading systems p CONCLUSIONS: Our large, population-based study has shown that endplate defect was strongly and independently associated with DD at every lumbar disc level. These results provide a mechanism by which increasing age and BMI predispose to DD.LEVEL OF EVIDENCE: 2.

SummaryObjectives: To determine if regional variations in strain patterns occur within the suspensory ligament under tensile load. Local increases in strain may put certain regions of the suspensory ligament at risk and may explain the poor healing and high recurrence rates associated with suspensory branch injuries.Methods: The suspensory ligament and its bone attachments were isolated from each of 10 adult equine cadaveric forelimbs and radiodense reference beads were inserted throughout the length of the ligament. Specimens were attached to a custom fixture secured to a materials testing system. Radio-graphs were acquired at 50, 445, 1112, and 2224 N of applied tensile load. Changes in distances between the beads in each region of the suspensory ligament were measured and the regional strain was calculated. Significant differences were determined using a repeated-measures analysis of variance.Results: The suspensory ligament exhibited significant differences in regional strain (p Clinical significance: The equine suspensory ligament demonstrates a heterogeneous strain pattern during tensile loading, with the distal regions exhibiting significantly more strain than the proximal region. The nonhomogenous strain pattern could explain the regional difference in injury and re-injury rates.

Background Trauma exposure has been linked to risky sexual behavior (RSB), but few studies have examined the impact of distinct trauma types on RSB in one model or how the association with trauma and RSB may differ across race. Purpose The objective of the current study was to examine the contribution of trauma exposure types to RSB—substance-related RSB and partner-related RSB identified through factor analysis—in young Black and White adult women. Methods We investigated the associations of multiple trauma types and RSB factor scores in participants from a general population sample of young adult female twins (n = 2,948). We examined the independent relationship between specific traumas and RSB, adjusting for substance use, psychopathology, and familial covariates. All pertinent constructs were coded positive only if they occurred before sexual debut. Results In Black women, sexual abuse was significantly associated with substance-related and partner-related RSB, but retained significance only for partner-related RSB in a fully adjusted model. For White women, sexual abuse and physical abuse were associated with both RSB factors in the base and fully adjusted models. Witnessing injury or death was only associated with RSBs in base models. For both groups, initiating alcohol (for Black women), alcohol, or cannabis (for White women) before sexual debut (i.e., early exposure) was associated with the greatest increased odds of RSB. Conclusions Data highlight the contribution of prior sexual abuse to RSBs for both White and Black women, and of prior physical abuse to RSBs for White women. Findings have implications for intervention after physical and sexual abuse exposure to prevent RSB, and thus, potentially reduce sexually transmitted infection/human immunodeficiency virus infection and unintended pregnancy in young women.

Supplemental Digital Content is Available in the Text. We analysed epigenome-wide methylation in blood DNA in Caucasian female twins. Bioinformatics analyses of the associated methylation signals showed enrichment for neurological pathways in CWP., Chronic widespread musculoskeletal pain (CWP), has a considerable heritable component, which remains to be explained. Epigenetic factors may contribute to and account for some of the heritability estimate. We analysed epigenome-wide methylation using MeDIPseq in whole blood DNA from 1708 monozygotic and dizygotic Caucasian twins having CWP prevalence of 19.9%. Longitudinally stable methylation bins (lsBINs), were established by testing repeated measurements conducted ≥3 years apart, n = 292. DNA methylation variation at lsBINs was tested for association with CWP in a discovery set of 50 monozygotic twin pairs discordant for CWP, and in an independent dataset (n = 1608 twins), and the results from the 2 samples were combined using Fisher method. Functional interpretation of the most associated signals was based on functional genomic annotations, gene ontology, and pathway analyses. Of 723,029 signals identified as lsBINs, 26,399 lsBINs demonstrated the same direction of association in both discovery and replication datasets at nominal significance (P ≤ 0.05). In the combined analysis across 1708 individuals, whereas no lsBINs showed genome-wide significance (P < 10-8), 24 signals reached p≤9E-5, and these included association signals mapping in or near to IL17A, ADIPOR2, and TNFRSF13B. Bioinformatics analyses of the associated methylation bins showed enrichment for neurological pathways in CWP. We estimate that the variance explained by epigenetic factors in CWP is 6%. This, the largest study to date of DNA methylation in CWP, points towards epigenetic modification of neurological pathways in CWP and provides proof of principle of this method in teasing apart the complex risk factors for CWP.