Mapping trabecular disconnection "hotspots" in aged human spine and hip

Trabecular bone disconnection is an independent factor in age-related skeletal failure where real termini (ReTm; rare in youth) may cause weakness disproportionate to tissue loss, yet their structural contribution at vulnerable locations remains uncertain. ReTm (previously recorded at the iliac crest) were mapped in "normal" aged vertebral bodies (T11-L5 autopsy; 20 females, 10 males) and corresponding proximal femora (autopsy; 10 females). Results were compared with biomechanically failed femora from orthopaedic subjects aged >. 58. yr (osteoporosis OP, 10 females; osteoarthritis OA, 10 females). A novel direct 2D/3D histological method was applied to large, thick (300. μm) slices superficially silver-stained to separate ReTm (unstained) from apparent termini (planar artefacts, brown). Light microscope field co-ordinates enabled ReTm mapping and statistical testing relative to i) sex, ii) tissue sector and iii) slicing plane. In men ReTm populations were small and random while in women they were large and sector-specific. In vertebrae they clustered anterior/superior being rare posterior/inferior; in the femoral head they concentrated distal/superior and also near the fovea, being fewer distal/inferior. A distribution polarity was evident with 100% more ReTm observed transversely (i.e., on tensile-related cross struts) than longitudinally (i.e., on compression-related vertical struts). Their numbers rose in OP (BV/TV. . 14%), remaining polarised and sector-specific in OP only. Comparative experimentation by marrow elution of an OP animal model demonstrated "floating segments" as a possible outcome. Conclusions were supported statistically that trabecular disconnection "hotspots" at vulnerable locations are sex- and sector-specific, mainly transaxial, and subject to disease modulation

Development of a longitudinal integrated clerkship at an academic medical center

In 2005, medical educators at the University of California, San Francisco (UCSF), began developing the Parnassus Integrated Student Clinical Experiences (PISCES) program, a year-long longitudinal integrated clerkship at its academic medical center. The principles guiding this new clerkship were continuity with faculty preceptors, patients, and peers; a developmentally progressive curriculum with an emphasis on interdisciplinary teaching; and exposure to undiagnosed illness in acute and chronic care settings. Innovative elements included quarterly student evaluation sessions with all preceptors together, peer-to-peer evaluation, and oversight advising with an assigned faculty member. PISCES launched with eight medical students for the 2007/2008 academic year and expanded to 15 students for 2008/2009. Compared to UCSF's traditional core clerkships, evaluations from PISCES indicated significantly higher student satisfaction with faculty teaching, formal didactics, direct observation of clinical skills, and feedback. Student performance on discipline-specific examinations and United States Medical Licensing Examination step 2 CK was equivalent to and on standardized patient examinations was slightly superior to that of traditional peers. Participants' career interests ranged from primary care to surgical subspecialties. These results demonstrate that a longitudinal integrated clerkship can be implemented successfully at a tertiary care academic medical center

Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves

<p>Abstract</p> <p>Background</p> <p>The results of Randomized Controlled Trials (RCTs) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio. These do not constitute the sufficient statistics required for meta-analysis or cost-effectiveness analysis, and their use in secondary analyses requires strong assumptions that may not have been adequately tested. In order to enhance the quality of secondary data analyses, we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated.</p> <p>Methods</p> <p>We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations, using where available information on number of events and numbers at risk. The reproducibility and accuracy of survival probabilities, median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics (survival probabilities, medians and hazard ratios) with statistics based on repeated reconstructions by multiple observers.</p> <p>Results</p> <p>The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics. Accuracy was excellent for survival probabilities and medians, for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported.</p> <p>Conclusion</p> <p>The algorithm is a reliable tool for meta-analysis and cost-effectiveness analyses of RCTs reporting time-to-event data. It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves.</p

Measuring the health-related Sustainable Development Goals in 188 countries : a baseline analysis from the Global Burden of Disease Study 2015

Background In September, 2015, the UN General Assembly established the Sustainable Development Goals (SDGs). The SDGs specify 17 universal goals, 169 targets, and 230 indicators leading up to 2030. We provide an analysis of 33 health-related SDG indicators based on the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015). Methods We applied statistical methods to systematically compiled data to estimate the performance of 33 health-related SDG indicators for 188 countries from 1990 to 2015. We rescaled each indicator on a scale from 0 (worst observed value between 1990 and 2015) to 100 (best observed). Indices representing all 33 health-related SDG indicators (health-related SDG index), health-related SDG indicators included in the Millennium Development Goals (MDG index), and health-related indicators not included in the MDGs (non-MDG index) were computed as the geometric mean of the rescaled indicators by SDG target. We used spline regressions to examine the relations between the Socio-demographic Index (SDI, a summary measure based on average income per person, educational attainment, and total fertility rate) and each of the health-related SDG indicators and indices. Findings In 2015, the median health-related SDG index was 59.3 (95% uncertainty interval 56.8-61.8) and varied widely by country, ranging from 85.5 (84.2-86.5) in Iceland to 20.4 (15.4-24.9) in Central African Republic. SDI was a good predictor of the health-related SDG index (r(2) = 0.88) and the MDG index (r(2) = 0.2), whereas the non-MDG index had a weaker relation with SDI (r(2) = 0.79). Between 2000 and 2015, the health-related SDG index improved by a median of 7.9 (IQR 5.0-10.4), and gains on the MDG index (a median change of 10.0 [6.7-13.1]) exceeded that of the non-MDG index (a median change of 5.5 [2.1-8.9]). Since 2000, pronounced progress occurred for indicators such as met need with modern contraception, under-5 mortality, and neonatal mortality, as well as the indicator for universal health coverage tracer interventions. Moderate improvements were found for indicators such as HIV and tuberculosis incidence, minimal changes for hepatitis B incidence took place, and childhood overweight considerably worsened. Interpretation GBD provides an independent, comparable avenue for monitoring progress towards the health-related SDGs. Our analysis not only highlights the importance of income, education, and fertility as drivers of health improvement but also emphasises that investments in these areas alone will not be sufficient. Although considerable progress on the health-related MDG indicators has been made, these gains will need to be sustained and, in many cases, accelerated to achieve the ambitious SDG targets. The minimal improvement in or worsening of health-related indicators beyond the MDGs highlight the need for additional resources to effectively address the expanded scope of the health-related SDGs.Peer reviewe

IL-33 Drives Augmented Responses to Ozone in Obese Mice

Background: Ozone increases IL-33 in the lungs, and obesity augments the pulmonary effects of acute ozone exposure. Objectives: We assessed the role of IL-33 in the augmented effects of ozone observed in obese mice. Methods: Lean wildtype and obese db/db mice were pretreated with antibodies blocking the IL-33 receptor, ST2, and then exposed to ozone (2 ppm for 3 hr). Airway responsiveness was assessed, bronchoalveolar lavage (BAL) was performed, and lung cells harvested for flow cytometry 24 hr later. Effects of ozone were also assessed in obese and lean mice deficient in γδ T cells and their wildtype controls. Results: and Discussion: Ozone caused greater increases in BAL IL-33, neutrophils, and airway responsiveness in obese than lean mice. Anti-ST2 reduced ozone-induced airway hyperresponsiveness and inflammation in obese mice but had no effect in lean mice. Obesity also augmented ozone-induced increases in BAL CXCL1 and IL-6, and in BAL type 2 cytokines, whereas anti-ST2 treatment reduced these cytokines. In obese mice, ozone increased lung IL-13+ innate lymphoid cells type 2 (ILC2) and IL-13+ γδ T cells. Ozone increased ST2+ γδ T cells, indicating that these cells can be targets of IL-33, and γδ T cell deficiency reduced obesity-related increases in the response to ozone, including increases in type 2 cytokines. Conclusions: Our data indicate that IL-33 contributes to augmented responses to ozone in obese mice. Obesity and ozone also interacted to promote type 2 cytokine production in γδ T cells and ILC2 in the lungs, which may contribute to the observed effects of IL-33. Citation: Mathews JA, Krishnamoorthy N, Kasahara DI, Cho Y, Wurmbrand AP, Ribeiro L, Smith D, Umetsu D, Levy BD, Shore SA. 2017. IL-33 drives augmented responses to ozone in obese mice. Environ Health Perspect 125:246–253; http://dx.doi.org/10.1289/EHP27

Identification of the identical human mutation in ACVR1 in 2 cats with fibrodysplasia ossificans progressiva

Two domestic shorthair cats, 1 intact female and 1 intact male, presented with progressive limb lameness and digital deformities at4 and 6 months of age. Stiffness and swelling of the distal thoracic and pelvic limb joints progressed to involve hip and shoulderjoints, resulting in reduced mobility. Radiographs in both cats and computed tomography of the male cat revealed ankylosing,polyarticular deposits of extracortical heterotopic bone spanning multiple axial and appendicular joints, extending into adjacentmusculotendinous tissues. All findings supported fibrodysplasia ossificans progressiva (FOP), a disorder characterized by toemalformations and progressive heterotopic ossification in humans. In both cats, molecular analyses revealed the same hetero-zygous mutation in the activin A receptor type I (ACVR1) gene that occurs in humans with FOP. Several reports of heterotopicossification in cats exist, but this is the first one to identify clinical FOP in 2 cats with the identical mutation that occurs in >95% ofhumans with F

Neurological symptoms in individuals with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP), a rare, disabling condition caused by gain-of-function mutations of a bone morphogenetic protein (BMP) type I receptor, leads to episodes of heterotopic ossification and resultant immobility. Neurological problems have not been associated with FOP, but neurological symptoms are commonly reported by FOP patients. To determine the prevalence of neurological symptoms and their characteristics in individuals with FOP, we conducted a survey of the 470 patient members of the International FOP Association (IFOPA) using a questionnaire about neurological symptoms. There were 168 responses (105 females, 63 males; age 1.5-68 years) from 30 countries representing 36 % of IFOPA members. Chronic neurological symptoms were reported by 86 (51 %). Prevalence of neuropathic pain (NP) was significantly increased (P &lt; 0.001) compared to the general population, and tenfold more common in females (15 %) than males (1.6 %). Of those with NP, 94 % reported other sensory abnormalities. Prevalence of recurrent severe headaches (HA) (26 %) was similar to that in the general population, but prevalence in females with FOP (36 %) was almost fourfold greater than in males. Prevalence of NP, HA, and other sensory abnormalities was substantially higher in post-pubertal females; 33 % reported symptoms worsened during menstrual periods. Worsening of neurological symptoms during FOP flare-ups was reported by 23 %. Three patients with FOP (1.8 %) reported myoclonus, a prevalence much greater than reported in the general population (P &lt; 0.001). Our worldwide survey indicates that neurological symptoms are common in FOP. We speculate that these symptoms are related to effects of dysregulated BMP signaling on the central and/or peripheral nervous systems