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Context Repetitive joint use is a risk factor for osteoarthritis, which is a leading cause of disability. Sports requiring a racket or bat to perform repetitive high-velocity impacts may increase the risk of thumb-base osteoarthritis. However, this hypothesis remains untested. Objective To determine if a history of participation in racket or bat sports was associated with the prevalence of thumb-base osteoarthritis. Design Descriptive epidemiologic study. Setting Four US clinical sites associated with the Osteoarthritis Initiative. Patients or Other Participants We recruited 2309 men and women from the community. Eligible participants had dominant-hand radiographic readings, hand symptom assessments, and historical physical activity survey data. Main Outcome Measure(s) A history of exposure to racket or bat sports (badminton, baseball or softball, racketball or squash, table tennis [or ping pong], tennis [doubles], or tennis [singles]) was based on self-reported recall data covering 3 age ranges (12–18, 19–34, and 35–49 years). Prevalent radiographic thumb-base osteoarthritis was defined as Kellgren-Lawrence grade >2 in the first carpometacarpal joint or scaphotrapezoidal joint at the Osteoarthritis Initiative baseline visit. Symptomatic thumb-base osteoarthritis was defined as radiographic osteoarthritis and hand or finger symptoms. Results Radiographic or symptomatic thumb-base osteoarthritis was present in 355 (34%) and 56 (5%), respectively, of men (total = 1049) and 535 (42%) and 170 (13%), respectively, of women (total = 1260). After adjusting for age, race, and education level, we found no significant associations between a history of any racket or bat sport participation and thumb-base osteoarthritis (radiographic or symptomatic; odds ratios ranged from 0.82 to 1.34). Conclusions In a community-based cohort, a self-reported history of participation in racket or bat sports was not associated with increased odds of having radiographic or symptomatic thumb-base osteoarthritis in the dominant hand.

Maternal and perinatal death surveillance and response (MPDSR) is a health systems process entailing the continuous cycle of identification, notification, and review of maternal and perinatal deaths (Surveillance), followed by actions to improve service delivery and quality of care and Response. Prior to the COVID-19 pandemic, there were an estimated 4.6 million maternal and newborn deaths and stillbirths each year. During the pandemic, maternal and perinatal health outcomes have worsened, especially in low- and middle-income countries, highlighting the urgent need to galvanize MPDSR to end preventable mortality and strengthen health systems.

Background and Purpose: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). Methods: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. Results: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance ( P −9 ) and 4 novel loci at genome-wide significance ( P −8 ), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke ( P −6 ). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2 , HDAC9 , ZFHX3 , and LRCH1 . Conclusions: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.

Background and ObjectivesTo identify white matter fiber tracts that exhibit structural abnormality in patients with bottom-of-sulcus dysplasia (BOSD) and investigate their association with seizure activity.MethodsWhole-brain fixel-based analysis of diffusion MRI data was performed to identify white matter fiber tracts with significant reductions in fiber density and cross-section in patients with BOSD (n = 20) when compared to healthy control participants (n = 40). Results from whole-brain analysis were used to investigate the association of fiber tract abnormality with seizure frequency and epilepsy duration.ResultsDespite the focal nature of the dysplasia, patients with BOSD showed widespread abnormality in white matter fiber tracts, including the bilateral corticospinal, corticothalamic, and cerebellothalamic tracts, superior longitudinal fasciculi, corpus callosum (body), and the forceps major. This pattern of bilateral connectivity reduction was not related to the laterality of the lesion. Exploratory post hoc analyses showed that high seizure frequency was associated with greater reduction in fiber density at the forceps major, bilateral corticospinal, and cerebellothalamic tracts.DiscussionWe demonstrate evidence of a bilaterally distributed, specific white matter network that is vulnerable to disruption in BOSD. The degree of tract abnormality is partly related to seizure activity, but additional contributors such as the genetic background and effects of treatment or environment have not been excluded.

The ILAE Neuroimaging Task Force aims to publish educational case reports highlighting basic aspects related to neuroimaging in epilepsy consistent with the educational mission of the ILAE. Previous quantitative MRI studies have established important imaging markers of epilepsy-related pathology, including features sensitive to hippocampal cell loss and reactive astrogliosis. Here, we review the case of a female with pediatric drug-resistant epilepsy. Throughout her course of treatment, she had seven MRI investigations at several centers; the first three did not follow optimized epilepsy imaging protocols whereas the remaining four adhered to HARNESS-MRI protocols ( har monized n euroimaging of e pilepsy s tructural s equences). Visual inspection of a set of HARNESS-MR images revealed conspicuous left hippocampal hyperintensity which may have been initially overlooked on non-optimized MR images. Quantitative analysis of these multimodal imaging data along hippocampal subfields provided clear evidence of hippocampal sclerosis, with increased atrophy, increased mean diffusivity, increased T2-FLAIR signal, and lower qT1 values observed in the anterior portions of the left, compared to the right hippocampus. The patient underwent a left anterior temporal lobectomy with amygdalohippocampectomy at age 16 years. Histopathology of the resected specimen also confirmed hippocampal sclerosis with widespread gliosis and focal neuronal loss in the hippocampal subfields overlapping with regions of multimodal quantitative alterations. The patient remains seizure-free one year after surgery. Collectively, this case highlights the need for optimized data acquisition protocols early in the treatment of epilepsy and supports quantitative analysis of MRI contrasts to enhance personalized diagnosis and prognosis of drug-resistant patients with epilepsy.

There is an urgent need for models that faithfully replicate heart failure with preserved ejection fraction (HFpEF), now recognized as the most common form of heart failure in the world. In vitro approaches have several shortcomings, most notably the immature nature of stem cell‐derived human cardiomyocytes [induced pluripotent stem cells (iPSC)] and the relatively short lifespan of primary cardiomyocytes. Three‐dimensional ‘organoids’ incorporating mature iPSCs with other cell types such as endothelial cells and fibroblasts are a significant advance, but lack the complexity of true myocardium. Animal models can replicate many features of human HFpEF, and rodent models are the most common, and recent attempts to incorporate haemodynamic, metabolic, and ageing contributions are encouraging. Differences relating to species, physiology, heart rate, and heart size are major limitations for rodent models. Porcine models mitigate many of these shortcomings and approximate human physiology more closely, but cost and time considerations limit their potential for widespread use. Ex vivo analysis of failing hearts from animal models offer intriguing possibilities regarding cardiac substrate utilisation, but are ultimately subject to the same constrains as the animal models from which the hearts are obtained. Ex vivo approaches using human myocardial biopsies can uncover new insights into pathobiology leveraging myocardial energetics, substrate turnover, molecular changes, and systolic/diastolic function. In collaboration with a skilled cardiothoracic surgeon, left ventricular endomyocardial biopsies can be obtained at the time of valvular surgery in HFpEF patients. Critically, these tissues maintain their disease phenotype, preserving inter‐relationship of myocardial cells and extracellular matrix. This review highlights a novel approach, where ultra‐thin myocardial tissue slices from human HFpEF hearts can be used to assess changes in myocardial structure and function. We discuss current approaches to modelling HFpEF, describe in detail the novel tissue slice model, expand on exciting opportunities this model provides, and outline ways to improve this model further.

Balancing agricultural production with other ecosystem services is a vexing challenge. The Yahara River watershed in southern Wisconsin is a place where tensions among farmers, policymakers, and citizens at-large run high because nutrient loss from the agricultural practices of a few drive the impairment of surface waters for many. Reducing manure and fertilizer application, as well as increasing perennial grass cover have been proposed as potential solutions. Using the Agro-IBIS agroecosystem model, we examined 48 scenarios of future land management and climate for the Yahara River watershed to the year 2070. Scenarios included combinations of reduced livestock and increased perennial grassland under alternative climate trajectories. Results suggested that business as usual will lead to further environmental degradation with phosphorus-loading to waterways increasing 13, 7, and 23% under baseline, warmer and drier, and warmer and wetter climates, respectively. Watershed-wide phosphorous yield and nitrate leaching could be reduced by 50%, but only when nutrient application was reduced 50% and grassland cover was increased 50%. Furthermore, water quality improvements only materialized 50 years after modified land management practices were implemented under the most likely future climate. Our findings highlight that improving water quality under a changing climate will require long-term investment and transformative changes to current agricultural land use and land cover. Agricultural management solutions exist but are unlikely to be implemented without policies that incentivize transformative agricultural change.

In chronic infections and in cancer, persistent antigen stimulation under suboptimal conditions can lead to the induction of T-cell exhaustion. Exhausted T cells are characterized by an increased expression of inhibitory markers and a progressive and hierarchical loss of function. Although cancer-induced exhaustion in CD8 T cells has been well-characterized and identified as a therapeutic target (i.e., via checkpoint inhibition), in-depth analyses of exhaustion in other immune cell types, including CD4 T cells, is wanting. While perhaps attributable to the contextual discovery of exhaustion amidst chronic viral infection, the lack of thorough inquiry into CD4 T-cell exhaustion is particularly surprising given their important role in orchestrating immune responses through T-helper and direct cytotoxic functions. Current work suggests that CD4 T-cell exhaustion may indeed be prevalent, and as CD4 T cells have been implicated in various disease pathologies, such exhaustion is likely to be clinically relevant. Defining phenotypic exhaustion in the various CD4 T-cell subsets and how it influences immune responses and disease severity will be crucial to understanding collective immune dysfunction in a variety of pathologies. In this review, we will discuss mechanistic and clinical evidence for CD4 T-cell exhaustion in cancer. Further insight into the derivation and manifestation of exhaustive processes in CD4 T cells could reveal novel therapeutic targets to abrogate CD4 T-cell exhaustion in cancer and induce a robust antitumor immune response.

Novel targeted cancer therapies have revolutionized oncology therapies, but these treatments can have cardiovascular complications, which include heterogeneous cardiac, metabolic, and vascular sequelae. Vascular side effects have emerged as important considerations in both cancer patients undergoing active treatment and cancer survivors. Here, we provide an overview of vascular effects of cancer therapies, focusing on small-molecule kinase inhibitors and specifically inhibitors of BTK (Bruton tyrosine kinase), which have revolutionized treatment and prognosis for B-cell malignancies. Cardiovascular side effects of BTK inhibitors include atrial fibrillation, increased risk of bleeding, and hypertension, with the former 2 especially providing a treatment challenge for the clinician. Cardiovascular complications of small-molecule kinase inhibitors can occur through either on-target (targeting intended target kinase) or off-target kinase inhibition. We will review these concepts and focus on the case of BTK inhibitors, highlight the emerging data suggesting an off-target effect that may provide insights into development of arrhythmias, specifically atrial fibrillation. We believe that cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into human cardiovascular biology.

In this article we report our research into the concerns and other matters of significance for members of instructional design teams. Specifically we studied how members of a design team depicted the quality of their own motives while participating in team pursuits. This is a type of self-evaluation known as drawing distinctions of worth. Our research took the form of a case study, focusing on an instructional design team at a university in the United States. Based on interviews with team members and observations of their work, we developed an account of our research participant’s distinctions of worth organized around three themes: (a) distinctions of worth could guide their decision-making more than did the goals of the project; (b) competing distinctions of worth could be difficult for them to reconcile; and (c) their distinctions of worth could be accompanied by unanticipated costs. Overall, these themes reflect that distinctions of worth were a real aspect of our participants’ team involvement, and not merely their subjective responses to situational factors. This has implications for those managing teams or otherwise helping teams improve, which we discuss. We also discuss how research into instructional design teams that only focuses on external dynamics team members experience, and not on factors such as their distinctions of worth, cannot fully account for what it means for people to contribute towards team outcomes.

ObjectiveTo determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD).MethodsWe reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG.ResultsThirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0–14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8–9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication.ConclusionBOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping.Classification of EvidenceThis study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures.

Not all agriculture based on perennial plants is ecologically sound or socially just. But an agroecological concept of perennial agriculture must be. We suggest three key elements of an agroecologi...

Business-state relations literature on developing countries focuses on the characteristics of an industry to determine its influence on the state but pays minimal attention to the process associate...

Public safety personnel (PSP) are at risk of developing posttraumatic stress injury (PTSI) due to exposure to traumatic experiences and accidents. Rehabilitation programs are available, but their success varies. We studied: (1) characteristics of PSP undergoing PTSI rehabilitation in comparison to non-PSP workers; and (2) predictive value of various factors for return to work. Methods A population-based cohort study was conducted using data on injured workers undergoing PTSI rehabilitation. Of the 488 workers included, 131 were PSP. Outcome measures were: (1) return to pre-accident work at rehabilitation discharge; (2) days receiving wage replacement benefits in the year following rehabilitation. Results PSP were mainly employed (90.8%), male (59.5%), paramedics/ambulance workers (58.0%); a minority (43.5%) returned to pre-accident work after rehabilitation. Compared to non-PSP workers, PSP were more likely to initially be diagnosed with psychological injuries (94.7% versus 59.4%, p < 0.001) rather than musculoskeletal injuries. Return to pre-accident work was predicted by shorter injury duration, having a primary mental health diagnosis, working at time of admission, and not having symptoms requiring treatment in a complex rehabilitation program. PSPs were slower to experience full recovery in the year after rehabilitation. Factors predicting fewer benefit days included not having a secondary psychological injury, being employed, and working at time of admission. Conclusions Most PSP did not return to work in full after PTSI rehabilitation. Outcomes are likely to improve by starting treatment earlier and maintaining connections with the workplace.

OBJECTIVE The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores assess the insulinemic and inflammatory potentials of habitual dietary patterns, irrespective of the macronutrient content, and are based on plasma insulin response or inflammatory biomarkers, respectively. The glycemic index (GI) and glycemic load (GL) assess postprandial glycemic potential based on dietary carbohydrate content. We tested the hypothesis that dietary patterns promoting hyperinsulinemia, chronic inflammation, or hyperglycemia may influence type 2 diabetes risk. RESEARCH DESIGN AND METHODS We calculated dietary scores from baseline (1993–1998) food frequency questionnaires among 73,495 postmenopausal women in the Women’s Health Initiative, followed through March 2019. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes risk. We also estimated multivariable-adjusted absolute risk of type 2 diabetes. RESULTS During a median 13.3 years of follow-up, 11,009 incident cases of type 2 diabetes were diagnosed. Participants consuming the most hyperinsulinemic or proinflammatory dietary patterns experienced greater risk of type 2 diabetes; HRs (95% CI) comparing highest to lowest dietary index quintiles were EDIH 1.49 (1.32–1.68; Ptrend < 0.0001) and EDIP 1.45 (1.29–1.63; Ptrend < 0.0001). The absolute excess incidence for the same comparison was 220 (EDIH) and 271 (EDIP) cases per 100,000 person-years. GI and GL were not associated with type 2 diabetes risk: GI 0.99 (0.88–1.12; Ptrend = 0.46) and GL 1.01 (0.89–1.16; Ptrend = 0.30). CONCLUSIONS Our findings in this diverse cohort of postmenopausal women suggest that lowering the insulinemic and inflammatory potentials of the diet may be more effective in preventing type 2 diabetes than focusing on glycemic foods.

ObjectiveTo determine the health economic burden of epilepsy for Australians of working age by using life table modeling and to model whether improved seizure control may result in substantial health economic benefits.MethodsLife table modeling was used for working age Australians aged 15–69 years with epilepsy and the cohort was followed until age 70 years. Published 2017 population and epilepsy-related data regarding epilepsy prevalence, mortality, and productivity were used. This model was then re-simulated, assuming the cohort no longer had epilepsy. Differences in outcomes between these cohorts were attributed to epilepsy. Scenarios were also simulated in which the proportion of seizure-free patients increased from baseline 70% up to 75% and 80%.ResultsIn 2017, Australians of working age with epilepsy followed until age 70 years were predicted to experience over 14,000 excess deaths, more than 78,000 years of life lost, and over 146,000 productivity-adjusted life years lost due to epilepsy. This resulted in lost gross domestic product (GDP) of US $22.1 billion. Increasing seizure freedom by 5% and 10% would reduce health care costs, save years of life, and translate to US $2.6 billion and US $5.3 billion GDP retained for seizure freedom rates of 75% and 80%, respectively.ConclusionsOur study highlights the considerable societal and economic burden of epilepsy. Relatively modest improvements in overall seizure control could bring substantial economic benefits.

BACKGROUND Prostate cancer (PC) risk increases with African ancestry and a history of sexually transmitted infections (STIs). Also, single-nucleotide polymorphisms (SNPs) in toll-like receptor (TLR) genes influence PC risk. This pilot study explores interactions between STIs and TLR-related SNPs in relation to PC risk among Jamaican men. METHODS This case-control study evaluates two TLR related SNPs in 356 Jamaican men (194 controls and 162 cases) with or without history of STIs using stepwise penalized logistic regression in multivariable analyses. RESULTS Age (odds ratio [OR] = 1.08; 95% confidence interval [CI]: 1.04-1>.12; p

The 2019 novel coronavirus disease (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread and worsen in many parts of the world. As the pandemic grows, it is especially important to understand how the virus and the pandemic are affecting pregnant women and infants. While early data suggested that being infected with the virus did not increase the risk of adverse pregnancy or infant outcomes, as more information has emerged, it has become clear that risks for some adverse pregnancy and infant outcomes are increased (e.g., preterm birth, cesarean section, respiratory distress, and hospitalization). The Healthy Outcomes of Pregnancy for Everyone in the time of novel coronavirus disease-19 (HOPE COVID-19) study is a multi-year, prospective investigation designed to better understand how the SARS-CoV-2 virus and COVID-19 impact adverse pregnancy and infant outcomes. The study also examines how the pandemic exacerbates existing hardships such as social isolation, economic destabilization, job loss, housing instability, and/or family member sickness or death among minoritized and marginalized communities. Specifically, the study examines how pandemic-related hardships impact clinical outcomes and characterizes the experiences of Black, Latinx and low-income groups compared to those in other race/ethnicity and socioeconomic stratum. The study includes two nested cohorts. The survey only cohort will enroll 7500 women over a two-year period. The survey+testing cohort will enroll 2500 women over this same time period. Participants in both cohorts complete short surveys daily using a mobile phone application about COVID-19-related symptoms (e.g., fever and cough) and complete longer surveys once during each trimester and at 6–8 weeks and 6, 12 and 18 months after delivery that focus on the health and well-being of mothers and, after birth, of infants. Participants in the survey+testing cohort also have testing for SARS-CoV-2 and related antibodies during pregnancy and after birth as well as testing that looks at inflammation and for the presence of other infections like Influenza and Rhinovirus. Study results are expected to be reported on a rolling basis and will include quarterly reporting for participants and public health partners as well as more traditional scientific reporting.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now a pandemic with devastating implications for populations, healthcare systems, and economies globally. Many healthcare workers (HCWs), including those in primary and community care settings, may be at increased risk of COVID-19 infection.1 COVID-19 is known to have three modes of transmission: contact (direct or via a fomite, that is, a contaminated surface or object), droplets (from the respiratory tract of an infected individual during coughing or sneezing transmitted onto a mucosal surface or conjunctiva of a susceptible individual), and aerosols (microbes within droplets that remain suspended in air for long periods).2,3 Personal protective equipment (PPE) reduces the transference of droplets or other body fluids onto HCWs’ skin and clothing or directly onto the mucous membranes of the eye or nasopharynx. PPE can also include respiratory protective equipment to protect against aerosol inhalation. Concerns have, however, been raised about PPE provision for preventing COVID-19 in primary and community care staff.4 This is a particularly pressing concern given the anxiety and stress of working in conditions that may pose a threat to health and which can negatively impact the productivity and care provided by HCWs.5 In this article we present findings from rapid reviews conducted regarding PPE for frontline primary care and community care staff, and what circumstances may potentially put HCWs at risk of contagion. Most guidance on PPE appears skewed to secondary care settings (emergency department or inpatient) and focuses mainly on ‘high-risk’ scenarios, for which full aerosol, droplet, and contact PPE (that is, disposable gloves, gown, eye protection, and respirator masks) are recommended. The highest number of contacts in many healthcare settings, however, will be within primary and community environments, including not just general practices but …

Summary Background While the COVID-19 pandemic will increase mortality due to the virus, it is also likely to increase mortality indirectly. In this study, we estimate the additional maternal and under-5 child deaths resulting from the potential disruption of health systems and decreased access to food. Methods We modelled three scenarios in which the coverage of essential maternal and child health interventions is reduced by 9·8–51·9% and the prevalence of wasting is increased by 10–50%. Although our scenarios are hypothetical, we sought to reflect real-world possibilities, given emerging reports of the supply-side and demand-side effects of the pandemic. We used the Lives Saved Tool to estimate the additional maternal and under-5 child deaths under each scenario, in 118 low-income and middle-income countries. We estimated additional deaths for a single month and extrapolated for 3 months, 6 months, and 12 months. Findings Our least severe scenario (coverage reductions of 9·8–18·5% and wasting increase of 10%) over 6 months would result in 253 500 additional child deaths and 12 200 additional maternal deaths. Our most severe scenario (coverage reductions of 39·3–51·9% and wasting increase of 50%) over 6 months would result in 1 157 000 additional child deaths and 56 700 additional maternal deaths. These additional deaths would represent an increase of 9·8–44·7% in under-5 child deaths per month, and an 8·3–38·6% increase in maternal deaths per month, across the 118 countries. Across our three scenarios, the reduced coverage of four childbirth interventions (parenteral administration of uterotonics, antibiotics, and anticonvulsants, and clean birth environments) would account for approximately 60% of additional maternal deaths. The increase in wasting prevalence would account for 18–23% of additional child deaths and reduced coverage of antibiotics for pneumonia and neonatal sepsis and of oral rehydration solution for diarrhoea would together account for around 41% of additional child deaths. Interpretation Our estimates are based on tentative assumptions and represent a wide range of outcomes. Nonetheless, they show that, if routine health care is disrupted and access to food is decreased (as a result of unavoidable shocks, health system collapse, or intentional choices made in responding to the pandemic), the increase in child and maternal deaths will be devastating. We hope these numbers add context as policy makers establish guidelines and allocate resources in the days and months to come. Funding Bill & Melinda Gates Foundation, Global Affairs Canada.

The blood-brain barrier (BBB) is a dynamic component of the brain-vascular interface that maintains brain homeostasis and regulates solute permeability into brain tissue. The expression of tight junction proteins between adjacent endothelial cells and the presence of efflux proteins prevents entry of foreign substances into the brain parenchyma. BBB dysfunction, however, is evident in many neurological disorders including ischemic stroke, trauma, and chronic neurodegenerative diseases. Currently, major contributors to BBB dysfunction are not well understood. Here, we employed a multicellular 3D neurovascular unit organoid containing human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes and neurons to model the effects of hypoxia and neuroinflammation on BBB function. Organoids were cultured in hypoxic chamber with 0.1% O2 for 24 hours. Organoids cultured under this hypoxic condition showed increased permeability, pro-inflammatory cytokine production, and increased oxidative stress. The anti-inflammatory agents, secoisolariciresinol diglucoside and 2-arachidonoyl glycerol, demonstrated protection by reducing inflammatory cytokine levels in the organoids under hypoxic conditions. Through the assessment of a free radical scavenger and an anti-inflammatory endocannabinoid, we hereby report the utility of the model in drug development for drug candidates that may reduce the effects of ROS and inflammation under disease conditions. This 3D organoid model recapitulates characteristics of BBB dysfunction under hypoxic physiological conditions and when exposed to exogenous neuroinflammatory mediators and hence may have potential in disease modeling and therapeutic development.

Background Recent clinical trials have evaluated angiotensin-converting enzyme (ACE) inhibitors (ACEis), angiotensin receptor blockers (ARBs), and beta blockers (BBs) in relation to cardiotoxicity in patients with cancer, typically defined by ejection fraction declines. However, these trials have not examined long-term, hard clinical endpoints. Within a prospective study, we examined the risk of heart failure (HF) and coronary heart disease (CHD) events in relation to use of commonly used antihypertensive medications, including ACEis/ARBs, BBs, calcium channel blockers (CCB), and diuretics, comparing women with and without cancer. Materials and Methods In a cohort of 56,997 Women's Health Initiative study participants free of cardiovascular disease who received antihypertensive treatment, we used multivariable-adjusted Cox regression models to calculate the hazard ratios (HRs) of developing CHD, HF, and a composite outcome of cardiac events (combining CHD and HF) in relation to use of ACEis/ARBs, CCBs, or diuretics versus BBs, separately in women with and without cancer. Results Whereas there was no difference in risk of cardiac events comparing ACEi/ARB with BB use among cancer-free women (HR = 0.99 [0.88–1.12]), among cancer survivors ACEi/ARB users were at a 2.24-fold risk of total cardiac events (1.18–4.24); p-interaction = .06). When investigated in relation to CHD only, an increased risk was similarly observed in ACEi/ARB versus BB use for cancer survivors (HR = 1.87 [0.88–3.95]) but not in cancer-free women (HR = 0.91 [0.79–1.06]; p-interaction = .04). A similar pattern was also seen in relation to HF but did not reach statistical significance (p-interaction = .23). Conclusion These results from this observational study suggest differing risks of cardiac events in relation to antihypertensive medications depending on history of cancer. Although these results require replication before becoming actionable in a clinical setting, they suggest the need for more rigorous examination of the effect of antihypertensive choice on long-term cardiac outcomes in cancer survivors. Implications for Practice Although additional research is needed to replicate these findings, these data from a large, nationally representative sample of postmenopausal women indicate that beta blockers are favorable to angiotensin-converting enzyme inhibitors in reducing the risk of cardiac events among cancer survivors. This differs from the patterns observed in a noncancer cohort, which largely mirrors what is found in the randomized clinical trials in the general population.

Both natural and engineered networks are often modular. Whether a network node interacts with only nodes from its own module or nodes from multiple modules provides insight into its functional role. The participation coefficient (PC) is typically used to measure this attribute, although its value also depends on the size and connectedness of the module it belongs to and may lead to nonintuitive identification of highly connected nodes. Here, we develop a normalized PC that reduces the influence of intramodular connectivity compared with the conventional PC. Using brain, C. elegans, airport, and simulated networks, we show that our measure of participation is not influenced by the size or connectedness of modules, while preserving conceptual and mathematical properties, of the classic formulation of PC. Unlike the conventional PC, we identify London and New York as high participators in the air traffic network and demonstrate stronger associations with working memory in human brain networks, yielding new insights into nodal participation across network modules., Author Summary It is challenging to reliably quantify how single elements (i.e., nodes) in a network are connected to different subcomponents (i.e., modules) of a network; this is important as intermodular connectivity contribute to efficient and distributed information processing. Participation coefficient (PC) calculates how distributed nodes are across modules. But PC is influenced by modularity algorithms that tend to favor large modules with strong intramodule connectivity, that in turn generate low PC values, even if a node has strong intermodule connectivity. We use a network randomization approach and show that by reducing the influence of intramodular connectivity, we obtain node participation results unaffected by size and connectedness of modules. This provides network scientists with new insights into the intermodular connectivity configurations of complex networks.

Funder: National Institute for Health Research (NIHR) GOSH BRC, OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.

We present an illustrative case to address anterior temporal lobe atrophy with poor delineation of the temporopolar gray-white matter interface based on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in patients with temporal lobe epilepsy associated with hippocampal sclerosis (TLE-HS). A 52-year-old woman with pharmacoresistant seizures since the age of six months underwent a previous MRI scan using a suboptimal protocol which was reported as unremarkable. MRI performed according to an epilepsy protocol showed classic signs of left HS and ipsilateral temporal polar atrophy with blurring of the gray-white matter boundary on FLAIR images. She underwent a left amygdalohippocampectomy and anterior temporal resection and remains seizure-free after 24 months. Histopathological analyses showed HS and no signs of focal cortical dysplasia (FCD). Blurring and atrophy of the ipsilateral temporal pole are common in TLE-HS and often misinterpreted as FCD. This relates to delayed myelination in patients with seizures before the age of two, is more pronounced on FLAIR sequences, and gives a false impression of cortical thickening. However, the T1-weighted images show a relatively well-demarcated cortical-subcortical transition and normal cortical thickness. By contrast, the cortical thickening in FCD is observed on both T1-weighted and FLAIR images. Since FCD also occurs in temporal lobe regions, it is important to differentiate the extra-hippocampal MRI abnormalities in TLE-HS from those likely to be FCD. This case highlights the importance of evaluation based on detailed imaging, which should always be conducted considering the EEG, seizure semiology, and other clinical information.

Corticosteroid insensitivity in asthma limits the ability to effectively manage severe asthma, which is characterized by persistent airway inflammation, airway hyperresponsiveness (AHR), and airflow obstruction despite corticosteroid treatment. Recent reports indicate that corticosteroid insensitivity is associated with increased interferon-γ (IFN-γ) levels and T-helper (Th) 1 lymphocyte infiltration in severe asthma. Signal transducer and activator of transcription 1 (STAT1) activation by IFN-γ is a key signaling pathway in Th1 inflammation; however, its role in the context of severe allergic airway inflammation and corticosteroid sensitivity remains unclear. In this study, we challenged wild-type (WT) and Stat1−/− mice with mixed allergens (MA) augmented with c-di-GMP [bis-(3′-5′)-cyclic dimeric guanosine monophosphate], an inducer of Th1 cell infiltration with increased eosinophils, neutrophils, Th1, Th2, and Th17 cells. Compared with WT mice, S tat1−/− had reduced neutrophils, Th1, and Th17 cell infiltration. To evaluate corticosteroid sensitivity, mice were treated with either vehicle, 1 or 3 mg/kg fluticasone propionate (FP). Corticosteroids significantly reduced eosinophil infiltration and cytokine levels in both c-di-GMP + MA-challenged WT and Stat1−/− mice. However, histological and functional analyses show that corticosteroids did not reduce airway inflammation, epithelial mucous cell abundance, airway smooth muscle mass, and AHR in c-di-GMP + MA-challenged WT or Stat1−/− mice. Collectively, our data suggest that increased Th1 inflammation is associated with a decrease in corticosteroid sensitivity. However, increased airway pathology and AHR persist in the absence of STAT1 indicate corticosteroid insensitivity in structural airway cells is a STAT1 independent process.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-genetic signatures could guide diagnosis, and ultimately, tailor therapeutic approaches to specific epilepsy syndromes.

Background and ObjectiveTo test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD).MethodsWe used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2–55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity.ResultsOverall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls.DiscussionThis first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy.Classification of EvidenceThis study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

This case reminded us that not every moist, erythematous, crusting eruption is purely infectious.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Mode-locked mid-infrared (MIR) fiber laser research has been dominated by the generation of pulses in the picosecond regime using saturable absorbers (SAs) and more recently frequency shifted feedback (FSF). Despite the significant emphasis placed on the development of materials to serve as the SAs for the MIR, published pulse durations have been substantially longer than what has been reported in the near-infrared (NIR). In this report we present experimental data supporting the view that the majority of demonstrations involving SAs and FSF have been limited by the presence of molecular gas absorption in the free-space sections of their cavities. We show that the pulse duration is directly linked to the width of an absorption-free region of the gaseous absorption profile and that the resulting optical spectrum is nearly always bounded by strong absorption features.

The ongoing research on mid-infrared lasers is motivated by their numerous applications, which include sensing, surgical procedures, and spectroscopy [1] . Current advancements in fluoride fiber-based radiation sources showcases their ability to provide extremely wide (exceeding 500 nm) tuning capabilities [2] , and generation of few-cycle pulses [3] . In the last years, frequency-shifted feedback mechanism has played a significant role in the development of short-pulse mid-infrared fiber lasers. It is a recently rediscovered approach to picosecond pulse generation that was successfully adapted to the ~3 µm spectral range, where availability of real saturable absorbers commonly used in near-infrared fiber lasers is still limited.

A machine learning approach to accelerate convergence of the nonlinear solver in multiphase flow problems is presented here. The approach dynamically controls an acceleration method based on numerical relaxation. It is demonstrated in a Picard iterative solver but is applicable to other types of nonlinear solvers. The aim of the machine learning acceleration is to reduce the computational cost of the nonlinear solver by adjusting to the complexity/physics of the system. Using dimensionless parameters to train and control the machine learning enables the use of a simple two-dimensional layered reservoir for training, while also exploring a wide range of the parameter space. Hence, the training process is simplified and it does not need to be rerun when the machine learning acceleration is applied to other reservoir models. We show that the method can significantly reduce the number of nonlinear iterations without compromising the simulation results, including models that are considerably more complex than the training case.

Isolated intrainferior vena cava (IVC) recurrence of renal cell carcinoma (RCC) is a rare presentation. In this investigator-initiated intervention, we present our novel experience, with f...

Smoke from wildfires results in air pollution that can impact the performance of solar photovoltaic plants. Production is impacted by factors including the proximity of the fire to a site of interest, the extent of the wildfire, wind direction, and ambient weather conditions. We construct a model that quantifies the relationships among weather, wildfire-induced pollution, and PV production for utility-scale and distributed generation sites located in the western United States. The regression model identified a 9.4%-37.8% reduction in solar PV production on smokey days. This model can be used to determine expected production losses at impacted sites. We also present an analysis of factors that contribute to solar photovoltaic energy production impacts from wildfires. This work will inform anticipated production changes for more accurate grid planning and operational considerations.

Kidney disease is a major medical problem globally. Chronic kidney disease (CKD) is a progressive loss of kidney function. It causes accumulation of waste and fluid in the body, eventually resulting in kidney failure as well as damaging other organs. Although dialysis and kidney transplantation have been used as primary treatments for renal disease, dialysis does not restore full renal function, and there is a shortage of donor kidneys for transplantation. Recent advances in cell-based therapies have offered a means to augment and restore renal function. Various types of cells have been tested to evaluate their therapeutic effects on injured kidneys. Among various types of cells, amniotic fluid stem cells (AFSCs) share advantages of both embryonic and adult stem cells, such as pluripotent activity, remarkable plasticity, and immunomodulatory effects, which may allow their future therapeutic use as an “off-the-shelf” cell source. AFSC presents advantages of both conventional pluripotent and adult stem cells, such as pluripotent activity, remarkable plasticity, and immunomodulatory effects. This study demonstrates that administration of human-derived AFSC facilitates functional and structural improvement in a rat model of CKD, and suggests that cell therapy with AFSC has potential as a therapeutic strategy to recover renal function in patients with CKD. IMPACT STATEMENT: Patients with chronic kidney disease (CKD) have limited treatment options, and renal transplantation is the only definitive treatment method that restores kidney function. However, challenges associated with transplantation, including donor organ shortage, rejection, and life-long immunosuppression, remain a problem. Recently, stem cell-based therapies have been proposed as an alternative approach to augment and restore renal function. In this study, we used human-derived amniotic fluid stem cells (AFSCs) to treat CKD in a rat model and demonstrated that AFSC treatment facilitated positive effects in terms of improvements of renal function.

Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. Approximately 50% of individuals over the age of 50 report an experience of knee pain within the past 12 months. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and seek supporting evidence in cohorts from 23andMe, the Osteoarthritis Initiative, and the Johnston County Osteoarthritis Project. We identified two loci that reached genome-wide significance in the UK Biobank: rs143384, located in GDF5 (P = 1.32 × 10−12), a gene previously implicated in osteoarthritis; and rs2808772, located near COL27A1 (P = 1.49 × 10−8). These findings were supported in cohorts with self-reported osteoarthritis/radiographic knee osteoarthritis without pain information. In this report on genome-wide association of knee pain, we identified two loci in or near GDF5 and COL27A1 that are associated with knee pain., Weihua Meng, Mark Adams et al. report a genome-wide association study of knee pain in the UK Biobank, identifying two loci near GDF5 and COL27A1 as significantly associated. These findings are supported by association data in additional cohorts, using self-reported osteoarthritis or radiographic knee osteoarthritis as a proxy for knee pain.

Organic livestock production in the U.S. requires that a significant amount of feed comes from grazed pasture. While principles of grazing management for temperate grasslands are well known, organic livestock production may result in unique plant-soil dynamics with ramifications for farmer decision-making and management. We reviewed the literature for direct or indirect evidence that organic pasture management results in altered plant-soil dynamics and assessed whether organic management might necessitate modifications or additions to managed grazing principles. The literature directly addressing these questions is sparse. We found some evidence that organic management can stimulate soil biota but no evidence for grassland yield, soil stocks, or soil transformation rate differences between organic and non-organic pastures. Given the constraint on fertilizer and herbicide inputs in organic management, established principles of managed grazing – rotating livestock frequently through paddocks such that plants are uniformly grazed but left with significant residual biomass and time for regrowth – are critical for maintaining dense, productive swards in organic pasture management.

Objectives Disability prevention strategies are more achievable before osteoarthritis disease drives impairment. It is critical to identify high-risk groups, for strategy implementation and trial eligibility. An established measure, gait speed is associated with disability and mortality. We sought to develop and validate risk stratification trees for incident slow gait in persons at high risk for knee osteoarthritis, feasible in community and clinical settings. Methods Osteoarthritis Initiative (derivation cohort) and Multicenter Osteoarthritis Study (validation cohort) participants at high risk for knee osteoarthritis were included. Outcome was incident slow gait over up to 10-year follow-up. Derivation cohort classification and regression tree analysis identified predictors from easily assessed variables and developed risk stratification models, then applied to the validation cohort. Logistic regression compared risk group predictive values; area under the receiver operating characteristic curves (AUCs) summarised discrimination ability. Results 1870 (derivation) and 1279 (validation) persons were included. The most parsimonious tree identified three risk groups, from stratification based on age and WOMAC Function. A 7-risk-group tree also included education, strenuous sport/recreational activity, obesity and depressive symptoms; outcome occurred in 11%, varying 0%–29 % (derivation) and 2%–23 % (validation) depending on risk group. AUCs were comparable in the two cohorts (7-risk-group tree, 0.75, 95% CI 0.72 to 0.78 (derivation); 0.72, 95% CI 0.68 to 0.76 (validation)). Conclusions In persons at high risk for knee osteoarthritis, easily acquired data can be used to identify those at high risk of incident functional impairment. Outcome risk varied greatly depending on tree-based risk group membership. These trees can inform individual awareness of risk for impaired function and define eligibility for prevention trials.

ObjectiveTo identify brain regions underlying interictal generalized paroxysmal fast activity (GPFA), and their causal interactions, in children and adults with Lennox-Gastaut syndrome (LGS).MethodsConcurrent scalp EEG-fMRI was performed in 2 separately analyzed patient groups with LGS: 10 children (mean age 8.9 years) scanned under isoflurane-remifentanil anesthesia and 15 older patients (mean age 31.7 years) scanned without anesthesia. Whole-brain event-related analysis determined GPFA-related activation in each group. Results were used as priors in a dynamic causal modeling (DCM) analysis comparing evidence for different neuronal hypotheses describing initiation and propagation of GPFA between cortex, thalamus, and brainstem.ResultsA total of 1,045 GPFA events were analyzed (cumulative duration 1,433 seconds). In both pediatric and older groups, activation occurred in distributed association cortical areas, as well as the thalamus and brainstem (p < 0.05, corrected for family-wise error). Activation was similar across individual patients with structural, genetic, and unknown etiologies of epilepsy, particularly in frontoparietal cortex. In both groups, DCM revealed that GPFA was most likely driven by prefrontal cortex, with propagation occurring first to the brainstem and then from brainstem to thalamus.ConclusionsWe show reproducible evidence of a cortically driven process within the epileptic network of LGS. This network is present early (in children) and late (in older patients) in the course of the syndrome and across diverse etiologies of epilepsy, suggesting that LGS reflects shared “secondary network” involvement. A cortical-to-subcortical hierarchy is postulated whereby GPFA rapidly propagates from prefrontal cortex to the brainstem via extrapyramidal corticoreticular pathways, whereas the thalamus is engaged secondarily.

Objective To report the surgical treatment and outcome of a non-ambulatory calf with cervical vertebral ostoeomyelitis. Study design Clinical report. Sample population One 3.5-month-old female mixed-breed calf with tetraparesis of 3 months duration. Methods After computed tomography-guided bone biopsy, a bacterial osteolytic lesion within the body of the fourth cervical vertebrae (C4) and resultant pathologic compression fracture clinically resulting in full tetraparesis was diagnosed in the calf. Culture results from the lesion within C4 confirmed a diagnosis of Trueperella pyogenes. Results Poor response to medical management justified surgical debridment of the lesion in C4 and subsequent stabilization of the cervical vertebral column. A three-part procedure was performed including (1) debridement of the C4, (2) bilateral ventral vertebral stabilization from C3 to C5, and (3) placement of ampicillin-impregnated plaster of Paris beads within the body of C4. With postoperative physical rehabilitation, the calf regained full ambulatory function. At 1-month follow-up, the calf remained ambulatory with mild proprioceptive ataxia and no evidence of implant failure. At annual recheck, the calf had gained 208 kg and remained fully ambulatory with no residual neurologic deficits. Conclusion Surgical intervention and use of antibiotic-impregnated implants offered a viable alternative to long-term medical management of vertebral osteomyelitis in the calf reported here. Clinical significance This case identifies surgical intervention as a potential means for improving outcomes in a historically fatal condition of production animals.

Introduction Excessive alcohol consumption continues to be a significant concern to overall military readiness; each year, it results in non-deployable active duty service members and service members separated from service. In 2009, The Community Preventive Services Task Force recommended limiting the hours of alcohol sales as an evidence-based and effective intervention to reduce alcohol-related harms. In June 2014, partnerships at an Army Installation in the Midwestern United States implemented a policy to reduce excessive alcohol consumption and associated alcohol-related harms. Although community-based interventions have been shown to successfully reduce alcohol-related negative consequences, little research has explored the effects of these interventions in military communities. Materials and Methods The intervention reduced the retail sale of alcoholic beverages by eight hours daily (11:01 pm to 6:59 am) within the installation community. The U.S. Army Public Health Review Board approved this study as public health practice. The quantitative assessment from a mixed-methods evaluation implemented an interrupted time series design to assess changes in the community resulting from the intervention. Revenue and crime data were collected 11 months and 12 months prior to and after the onset of the intervention, respectively, to quantify the adherence to and effectiveness of the policy. The outcome variables measured in the evaluation were Serious Incident Reports (SIRs) and Driving Under the Influence/Driving While Intoxicated (DUI/DWI) citations. A Wilcoxon Signed-Rank Test of significance was used to measure changes in crime outcomes post-policy. Results The results indicated that pre-policy rates of overall DUI/DWI citations, and DUI/DWI citations on-post were significantly higher than post-policy DUI/DWI citations (p < 0.05). The results also indicated that pre-policy rates of overall SIRS, alcohol-related SIRs, and SIRs occurring at night were not statistically higher than post-policy rates (p ≥ 0.05). The pre-policy DUI/DWI citations occurring off-post and DUI/DWI citations occurring at night did not reach statistical significance (p > 0.05). Policy adherence was good and total alcohol sales revenue remained stable before and after policy implementation. Conclusions This was the first known evaluation within a military community to report improvements in crime statistics following an eight hour reduction in daily retail sale hours of alcohol. The reduction in alcohol-related harms presented in this evaluation are typical for small communities implementing alcohol-related policies; however, the effect sizes reported here are larger than those reported in the current literature, suggesting that the policy positively impacted the installation community in decreasing alcohol-related harms. Evaluation data did not show statistically significant reductions in DUI/DWI citations and SIRs occurring during night hours. Further, the evaluation design disallows the ability to draw a causal relationship between the intervention and measured outcomes. Additional installations should consider implementing similar policies to determine if observed effects are replicable. Future studies should include a longitudinal design that would allow for long-lasting changes to be observed within the population, measurement of additional proximal outcomes (e.g., reported alcohol consumption), and investigating social and health outcomes both inside and outside the confines of the installation community.

Introduction The prevalence of erectile dysfunction (ED) is substantial and continues to rise. Current therapeutics for ED consist of oral medications, intracavernosal injections, vacuum erection devices, and penile implants. While such options may manage the disease state, none of these modalities, however, restore function. Stem cell therapy has been evaluated for erectile restoration in animal models. These cells have been derived from multiple tissues, have varied potential, and may function via local engraftment or paracrine signaling. Bone marrow-derived stem cells (BMSC) and adipose-derived stem cells (ASC) have both been used in these models with noteworthy effects. Aim Herein, we will review the pathophysiology of ED, animal models, current and novel stem-cell based therapeutics, clinical trials and areas for future research. Methods The relevant literature and contemporary data using keywords, “stem cells and erectile dysfunction” was reviewed. Main outcome measure Examination of evidence supporting the association between erectile dysfunction and adipose derived stem cells, bone marrow derived stem cells, placental stem cells, urine stem cells and stem cell therapy respectively. Results Placental-derived stem cells and urine-derived stem cells possess many similar properties as BMSC and ASC, but the methods of acquisition are favorable. Human clinical trials have already demonstrated successful use of stem cells for improvement of erectile function. Conclusion The future of stem cell research is constantly being evaluated, although, the evidence suggests a place for stem cells in erectile dysfunction therapeutics. Matz EL, Terlecki R, Zhang Y, et al. Stem Cell Therapy for Erectile Dysfunction. Sex Med Rev 2019;7:321–328.