Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that ...fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1
). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1
FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.
Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 ...correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.
Objective
To assess whether the presence of structural osteoarthritis (OA) features over as many as 4 years prior to incident radiographic OA increases the risk of radiographic OA in a nested, ...case–control design.
Methods
We studied 355 knees from the Osteoarthritis Initiative cohort that developed radiographic OA before the 48‐month visit. They were matched one‐to‐one by sex, age, and contralateral knee radiographic status with a control knee. Magnetic resonance images (MRIs) were read for bone marrow lesions (BMLs), cartilage damage, meniscal damage (including tears and extrusion), Hoffa synovitis, and effusion synovitis. Conditional logistic regression was applied to assess the risk of radiographic OA with regard to the presence of BMLs (score ≥2), cartilage lesions (score ≥1.1), meniscal damage (any) and extrusion of ≥3 mm ± (score ≥2), and Hoffa and effusion synovitis (any). Time points were defined as incident radiographic OA visit (P0), 1 year prior to the detection of radiographic OA (P −1), 2 years prior to the detection of radiographic OA (P −2), etc.
Results
The presence of Hoffa synovitis (hazard ratio HR 1.76 95% confidence interval (95% CI) 1.18–2.64), effusion synovitis (HR 1.81 95% CI 1.18–2.78), and medial meniscal damage (HR 1.83 95% CI 1.17–2.89) at P −2 predicted radiographic OA incidence. At P −1, all features but meniscal extrusion predicted radiographic OA, with highest odds for medial BMLs (HR 6.50 95% CI 2.27–18.62) and effusion synovitis (HR 2.50 95% CI 1.76–3.54). The findings at P −3 and P −4 did not reach statistical significance.
Conclusion
Our findings indicate that the presence of specific structural features of MRI‐detected joint damage 2 years prior to incident radiographic OA increases the risk of incident radiographic OA. However, 1 year prior to radiographic OA, the presence of almost any abnormal morphologic feature increases the risk of radiographic OA in the subsequent year.
Age-associated conditions are increasingly common among persons living with human immunodeficiency virus (HIV) (PLWH). A longitudinal investigation of their accrual is needed given their implications ...on clinical care complexity. We examined trends in the co-occurrence of age-associated conditions among PLWH receiving clinical care, and differences in their prevalence by demographic subgroup.
This cohort study was nested within the North American AIDS Cohort Collaboration on Research and Design. Participants from HIV outpatient clinics were antiretroviral therapy-exposed PLWH receiving clinical care (ie, ≥1 CD4 count) in the United States during 2000-2009. Multimorbidity was irreversible, defined as having ≥2: hypertension, diabetes mellitus, chronic kidney disease, hypercholesterolemia, end-stage liver disease, or non-AIDS-related cancer. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) comparing demographic subgroups were obtained by Poisson regression with robust error variance, using generalized estimating equations for repeated measures.
Among 22969 adults, 79% were male, 36% were black, and the median baseline age was 40 years (interquartile range, 34-46 years). Between 2000 and 2009, multimorbidity prevalence increased from 8.2% to 22.4% (Ptrend < .001). Adjusting for age, this trend was still significant (P < .001). There was no difference by sex, but blacks were less likely than whites to have multimorbidity (aPR, 0.87; 95% CI, .77-.99). Multimorbidity was the highest among heterosexuals, relative to men who have sex with men (aPR, 1.16; 95% CI, 1.01-1.34). Hypertension and hypercholesterolemia most commonly co-occurred.
Multimorbidity prevalence has increased among PLWH. Comorbidity prevention and multisubspecialty management of increasingly complex healthcare needs will be vital to ensuring that they receive needed care.
Background
Environmental DNA (eDNA) analysis is increasingly being used to detect the presence and relative abundance of rare species, especially invasive or imperiled aquatic species. The rapid ...progress in the eDNA field has resulted in numerous studies impacting conservation and management actions. However, standardization of eDNA methods and reporting across the field is yet to be fully established, with one area being the calculation and interpretation of assay limit of detection (LOD) and limit of quantification (LOQ).
Aims
Here, we propose establishing consistent methods for determining and reporting of LOD and LOQ for single‐species quantitative PCR (qPCR) eDNA studies.
Materials & Methods/ Results
We utilize datasets from multiple cooperating laboratories to demonstrate both a discrete threshold approach and a curve‐fitting modeling approach for determining LODs and LOQs for eDNA qPCR assays. We also provide details of an R script developed and applied for the modeling method.
Discussion/Conclusions
Ultimately, standardization of how LOD and LOQ are determined, interpreted, and reported for eDNA assays will allow for more informed interpretation of assay results, more meaningful interlaboratory comparisons of experiments, and enhanced capacity for assessing the relative technical quality and performance of different eDNA qPCR assays.
We propose establishing consistent methods for determining and reporting of LOD and LOQ for single‐species quantitative PCR (qPCR) eDNA studies. We demonstrate the use of both a discrete threshold approach and a curve‐fitting modeling approach for determining LODs and LOQs for these assays. Ultimately, standardization of how LOD and LOQ are determined, interpreted, and reported for eDNA assays will allow for more informed interpretation of assay results, more meaningful interlaboratory comparisons of experiments, and enhanced capacity for assessing the relative technical quality and performance of different eDNA qPCR assays.
Medication adherence plays an important role in optimizing the outcomes of many treatment and preventive regimens in chronic illness. Self-report is the most common method for assessing adherence ...behavior in research and clinical care, but there are questions about its validity and precision. The NIH Adherence Network assembled a panel of adherence research experts working across various chronic illnesses to review self-report medication adherence measures and research on their validity. Self-report medication adherence measures vary substantially in their question phrasing, recall periods, and response items. Self-reports tend to overestimate adherence behavior compared with other assessment methods and generally have high specificity but low sensitivity. Most evidence indicates that self-report adherence measures show moderate correspondence to other adherence measures and can significantly predict clinical outcomes. The quality of self-report adherence measures may be enhanced through efforts to use validated scales, assess the proper construct, improve estimation, facilitate recall, reduce social desirability bias, and employ technologic delivery. Self-report medication adherence measures can provide actionable information despite their limitations. They are preferred when speed, efficiency, and low-cost measures are required, as is often the case in clinical care.
The management of patients after anterior cruciate ligament reconstruction should be evidence based. Since our original published guidelines in 1996, successful outcomes have been consistently ...achieved with the rehabilitation principles of early weight bearing, using a combination of weight-bearing and non-weight-bearing exercise focused on quadriceps and lower extremity strength, and meeting specific objective requirements for return to activity. As rehabilitative evidence and surgical technology and procedures have progressed, the original guidelines should be revisited to ensure that the most up-to-date evidence is guiding rehabilitative care. Emerging evidence on rehabilitative interventions and advancements in concomitant surgeries, including those addressing chondral and meniscal injuries, continues to grow and greatly affect the rehabilitative care of patients with anterior cruciate ligament reconstruction. The aim of this article is to update previously published rehabilitation guidelines, using the most recent research to reflect the most current evidence for management of patients after anterior cruciate ligament reconstruction. The focus will be on current concepts in rehabilitation interventions and modifications needed for concomitant surgery and pathology.
Therapy, level 5.
Trained birth attendants at delivery are important for preventing both maternal and newborn deaths. West Java is one of the provinces on Java Island, Indonesia, where many women still deliver at home ...and without the assistance of trained birth attendants. This study aims to explore the perspectives of community members and health workers about the use of delivery care services in six villages of West Java Province.
A qualitative study using focus group discussions (FGDs) and in-depth interviews was conducted in six villages of three districts in West Java Province from March to July 2009. Twenty FGDs and 165 in-depth interviews were conducted involving a total of 295 participants representing mothers, fathers, health care providers, traditional birth attendants and community leaders. The FGD and in-depth interview guidelines included reasons for using a trained or a traditional birth attendant and reasons for having a home or an institutional delivery.
The use of traditional birth attendants and home delivery were preferable for some community members despite the availability of the village midwife in the village. Physical distance and financial limitations were two major constraints that prevented community members from accessing and using trained attendants and institutional deliveries. A number of respondents reported that trained delivery attendants or an institutional delivery were only aimed at women who experienced obstetric complications. The limited availability of health care providers was reported by residents in remote areas. In these settings the village midwife, who was sometimes the only health care provider, frequently travelled out of the village. The community perceived the role of both village midwives and traditional birth attendants as essential for providing maternal and health care services.
A comprehensive strategy to increase the availability, accessibility, and affordability of delivery care services should be considered in these West Java areas. Health education strategies are required to increase community awareness about the importance of health services along with the existing financing mechanisms for the poor communities. Public health strategies involving traditional birth attendants will be beneficial particularly in remote areas where their services are highly utilized.
The inactivation of starch branching IIb (SBEIIb) in rice is traditionally associated with elevated apparent amylose content, increased peak gelatinization temperature, and a decreased proportion of ...short amylopectin branches. To elucidate further the structural and functional role of this enzyme, the phenotypic effects of down-regulating SBEIIb expression in rice endosperm were characterized by artificial microRNA (amiRNA) and hairpin RNA (hp-RNA) gene silencing. The results showed that RNA silencing of SBEIIb expression in rice grains did not affect the expression of other major isoforms of starch branching enzymes or starch synthases. Structural analyses of debranched starch showed that the doubling of apparent amylose content was not due to an increase in the relative proportion of amylose chains but instead was due to significantly elevated levels of long amylopectin and intermediate chains. Rices altered by the amiRNA technique produced a more extreme starch phenotype than those modified using the hp-RNA technique, with a greater increase in the proportion of long amylopectin and intermediate chains. The more pronounced starch structural modifications produced in the amiRNA lines led to more severe alterations in starch granule morphology and crystallinity as well as digestibility of freshly cooked grains. The potential role of attenuating SBEIIb expression in generating starch with elevated levels of resistant starch and lower glycaemic index is discussed.
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