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IntroductionCompared with clinical examination (CE), ultrasonography (US) provides additional and more accurate assessment of inflammation and visualization of structural damage. To better understand the effectiveness of US in metatarsophalangeal joints (MTPJs), we compared disease activity in MTPJs 2–5 assessed by CE and US, with magnetic resonance imaging (MRI) as reference standard.MethodTreatment-naïve adult patients with early RA (ACR criteria, disease duration < 2 years) were consecutively recruited. MTPJs 2–5 were assessed for swelling and tenderness, and imaged by US (Esaote MyLab70). The most symptomatic foot was imaged by peripheral MRI (1.0 Tesla). US was semiquantitatively graded for synovial thickening (ST) and power Doppler (PD) (0–3), and erosions (yes/no). MRI was semiquantitatively graded for bone marrow edema (BME), synovitis, and erosions (OMERACT). Kappa agreement, sensitivity, specificity, and predictive values were analyzed using cut-offs at ST ≥ 2, PD ≥ 1, and MRI synovitis and BME at both ≥ 1 and ≥ 2.ResultsThis study included 39 patients (85% female, mean (SD) age = 51.6 (10.3)). Using MRI synovitis and BME grade ≥ 2 as the reference, PD had superior sensitivity (82%) and kappa agreement (k = 0.43) than swollen joint count (55%, k = 0.20), but similar high specificity (88%, 83%). ST and PD were often observed in clinically asymptomatic MTPJs. US detected very few MRI erosions, but several observed erosions corresponded to grade ≥ 2 MRI erosions.ConclusionClinical swelling and PD are highly specific for active inflammation in the MTPJs. US supplemented CE by allowing observation of subclinical inflammation and structural damage.Key Points• Ultrasonography detected many subclinical synovial inflammations in metatarsophalangeal joints (MTPJs), many confirmed by MRI• Ultrasonography may best be used clinically to supplement clinical examination by assessing non-swollen joints• Ultrasonography provided quick method of visualizing bone erosions that were grade ≥ 2 on MRI

There are increasing numbers of people affected by natural disasters, disease outbreaks, and conflict. Water, sanitation, and hygiene (WASH) interventions are used in nearly all emergency responses to help reduce disease risk. However, there is a lack of summarized evidence on the efficacy and effectiveness of these interventions. We conducted a systematic review of the published and grey literature on the efficacy and effectiveness of short-term WASH interventions in emergency response in low- and middle-income countries, including: developing theory of change models; setting inclusion criteria; conducting the search; selecting evaluations for inclusion; assessing the quality of the evidence; and analysing the included evaluations. Overall, 15,026 documents were identified and 106 studies describing 114 evaluations met inclusion criteria. Interventions from 39 countries were included. Most included evaluations (77 per cent) had high risk of bias and half were from grey literature (50 per cent). For the majority of interventions, we found that WASH interventions consistently reduced both the risk of disease and transmission in emergency contexts; however, programme design and beneficiary preferences were important considerations to ensure WASH intervention efficacy and effectiveness. Critical programme design characteristics included simple interventions that were appropriately timed, community-driven, and had linkages between relief and development. Barriers and facilitators to WASH interventions in outbreak response were taste and smell of treated water, communication methods, inaccurate perception of efficacy, and trust/fear. Foundational research is needed on commonly implemented, under-researched interventions, as well as investigating the relative cost-effectiveness of emergency WASH interventions.

The common marsh snail Melampus bidentatus is an omnivore-detritivore that is typically restricted to the upper marsh zone in salt marshes of southern New England and further south. However, in Maritime Canadian salt marshes (specifically in the Northumberland Strait), M. bidentatus occurs throughout the high and low marsh zones (mean summer densities ~ 50 individuals m−2). This study determined the within-marsh distribution of M. bidentatus near its northern range limit and investigated the mechanisms responsible for this distribution. Intensive spatial and temporal sampling in 2015–2016 confirmed that all stages (adults, juveniles, and egg masses) occurred throughout the salt marsh. Investigations of snail survival (using tethering assays) and movement (using mark-recapture trials) indicated that mortality was very low and independent of marsh zone, and movement was moderate, random, and circuitous, generally maintaining snails in local areas. Thus, lack of differential survival and movement between marsh zones support an unrestricted distribution. This wide spatial distribution of M. bidentatus within salt marshes in north temperate latitudes is likely due to the species’ high physiological tolerances, absence of competition from other gastropod omnivores-detritivores, and low predation pressure in the low marsh zone. Given these findings, further research on the snails’ role in, for example, trophic dynamics would provide further insights as to latitudinal differences in the ecology of resident salt marsh fauna.

Background Parkinson’s disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been reported in PD, their functional consequences remain unclear. Herein, we addressed this question by an analysis of stool samples from the Luxembourg Parkinson’s Study ( n  = 147 typical PD cases, n  = 162 controls). Results All individuals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Stool samples from these individuals were first analysed by 16S rRNA gene sequencing. Second, we predicted the potential secretion for 129 microbial metabolites through personalised metabolic modelling using the microbiome data and genome-scale metabolic reconstructions of human gut microbes. Our key results include the following. Eight genera and seven species changed significantly in their relative abundances between PD patients and healthy controls. PD-associated microbial patterns statistically depended on sex, age, BMI, and constipation. Particularly, the relative abundances of Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging after controlling for the disease duration. Furthermore, personalised metabolic modelling of the gut microbiomes revealed PD-associated metabolic patterns in the predicted secretion potential of nine microbial metabolites in PD, including increased methionine and cysteinylglycine. The predicted microbial pantothenic acid production potential was linked to the presence of specific non-motor symptoms. Conclusion Our results suggest that PD-associated alterations of the gut microbiome can translate into substantial functional differences affecting host metabolism and disease phenotype.

Early diagnosis and management of prostate cancer is crucial to providing safe, high-quality care to patients. Understanding the complexities of the signs and symptoms of prostate cancer can help nurse practitioners (NPs) make timely decisions to assess a patient's complaints and consider differential diagnoses. Acting on diagnostics, NPs can guide patients through treatment strategies to ensure positive health outcomes.

Multiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait. We examined 2 dichotomous phenotypes of ideal CV health—clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical+behavioral (clinical plus: not a current smoker, body mass index <25 kg/m2)—among white participants aged 50±5 years. We performed a meta-analysis of 4 genome-wide association studies (total n=11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance (P<2.0 × 10−9). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol. A common single-nucleotide polymorphism in the APOC1/APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.

Background Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. We aimed to evaluate genome-wide associations and putative downstream functionality of genetic variants for lung function decline. Methods We conducted genome-wide association study (GWAS) analyses of decline in FEV 1 , FVC, and FEV 1 /FVC in 52,056 White ( N  = 44,988), Black ( N  = 5,788), Hispanic ( N  = 550), and Chinese American ( N  = 730) participants across seven general population cohorts. GWAS analyses were stratified by cohort, ancestry, and sex. Results were combined in cross-ancestry and ancestry-specific meta-analyses. Significant variants available in two independent COPD-enriched cohorts were tested for replication. Results We identified 361 distinct genome-wide significant ( p  < 5E-08) variants for one or more of the FEV 1 , FVC, and FEV 1 /FVC decline phenotypes, which overlapped with previously reported genetic signals for pulmonary traits. Four variants, or 10.3% of variants available for replication testing, were nominally associated ( p  < 0.05) with at least one decline phenotype in COPD-enriched cohorts. Gene-level analysis of GWAS results implicated 38 genes, many with consistent associations across ancestries or decline phenotypes. Annotation class analysis revealed enrichment of regulatory processes for corticosteroid biosynthesis and metabolism. Drug repurposing analysis identified 43 approved compounds targeting eight implicated genes. Conclusions Our GWAS meta-analyses identified numerous genetic loci associated with lung function decline. These findings contribute knowledge to the genetic architecture of lung function decline, provide evidence for a role of corticosteroids in the etiology of lung function decline, and identify drug targets meriting further study for potential repurposing to slow lung function decline and mitigate lung disease.

Water, sanitation, and hygiene (WASH) interventions are key to reducing the burden of disease associated with outbreaks, and are commonly implemented in emergency response. However, there is a lack of summarized evidence on the efficacy and effectiveness of these interventions. We conducted a systematic review of published and grey literature by developing theory of change models, developing inclusion criteria, conducting the search, selecting evaluations for inclusion, assessing the quality of the evidence, and analysing the included evaluations. Overall, 15,026 documents were identified and 51 evaluations from 47 studies met inclusion criteria. Interventions from 19 countries were included, primarily in response to cholera (86 per cent). Most included evaluations (70 per cent) were at high risk of bias and nearly half were from grey literature (49 per cent). We found that WASH interventions consistently reduced both the risk of disease and the risk of transmission in outbreak contexts; however, programme design and beneficiary preferences were important considerations to ensure WASH intervention effectiveness. Critical programme design characteristics included simple interventions that were appropriately timed, community-driven, and had linkages between relief and development. Beneficiary preferences, barriers, and facilitators to WASH interventions in outbreak response were taste and smell of water treatment, communication methods, inaccurate perception of efficacy, and trust/fear. Research on commonly implemented but severely under-researched WASH interventions is recommended. It is also recommended that responders implement interventions that are: efficacious, simple, well-timed, community-driven, link relief and development, and address barriers and facilitators to use with communities.

Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

PurposeNewly diagnosed breast cancer patients face substantial stress and uncertainty that may undermine their quality of life (QoL). The purpose of the present study was to examine the associations between health-related fitness (HRF) and QoL in newly diagnosed breast cancer patients from the Alberta Moving Beyond Breast Cancer Study.MethodsNewly diagnosed breast cancer patients with early-stage disease (n = 1458) were recruited between 2012 and 2019 in Edmonton and Calgary, Canada to complete baseline HRF and QoL assessments within 90 days of diagnosis. HRF assessments included cardiorespiratory fitness (VO2peak treadmill test), muscular fitness (upper and lower body strength and endurance tests), and body composition (dual x-ray absorptiometry). QoL was assessed by the Medical Outcomes Study Short Form 36 (SF-36) version 2. We used logistic regression analyses to examine the associations between quartiles of HRF and poor/fair QoL (bottom 20%) after adjusting for key covariates.ResultsIn multivariable analysis, the least fit groups compared to the most fit groups for relative upper body strength (OR = 3.19; 95% CI = 1.98–5.14), lean mass percentage (OR = 2.31; 95% CI = 1.37–3.89), and relative VO2peak (OR = 2.08; 95% CI = 1.21–3.57) were independently at a significantly higher risk of poor/fair physical QoL. No meaningful associations were found for mental QoL.ConclusionsThe three main components of HRF (muscular fitness, cardiorespiratory fitness, and body composition) were independently associated with physical QoL in newly diagnosed breast cancer patients. Exercise interventions designed to improve these components of HRF may optimize physical QoL and help newly diagnosed breast cancer patients better prepare for treatments and recovery.