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Incorporating morphological data into modern phylogenies allows integration of fossil evidence, facilitating divergence dating and macroevolutionary inferences. Improvements in the phylogenetic utility of morphological data have been sought via Procrustes-based geometric morphometrics (GMM), but with mixed success and little clarity over what anatomical areas are most suitable. Here, we assess GMM-based phylogenetic reconstructions in a heavily sampled source of discrete characters for mammalian phylogenetics-the basicranium-in 57 species of marsupial mammals, compared with the remainder of the cranium. We show less phylogenetic signal in the basicranium compared with a 'Rest of Cranium' partition, using diverse metrics of phylogenetic signal ( K mult , phylogenetically aligned principal components analysis, comparisons of UPGMA/neighbour-joining/parsimony trees and cophenetic distances to a reference phylogeny) for scaled, Procrustes-aligned landmarks and allometry-corrected residuals. Surprisingly, a similar pattern emerged from parsimony-based analyses of discrete cranial characters. The consistent results across methods suggest that easily computed metrics such as K mult can provide good guidance on phylogenetic information in a landmarking configuration. In addition, GMM data may be less informative for intricate but conservative anatomical regions such as the basicranium, while better-but not necessarily novel-phylogenetic information can be expected for broadly characterized shapes such as entire bones. This article is part of the theme issue 'The mammalian skull: development, structure and function'.

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-β cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β cell maturation and identify sex hormones as drivers of β cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity., Competing Interests: Declaration of interests K.J.G. does consulting for Genentech and holds stock in Vertex Pharmaceuticals., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Adaptation of the islet β cell insulin-secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. β Cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates nonalcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting that LSD1 has a context-dependent role in promoting maladaptive changes in obesity. In analysis of insulin target tissues we identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD., (© 2022 by the American Diabetes Association.)

Background: The costs of quality improvement efforts in real-world settings are often unquantified. Better understanding could guide appropriate resource utilisation and drive efficiency. Immediate postpartum contraceptive care (ie, placement of an intrauterine device or contraceptive implant during hospitalisation for childbirth) represents an excellent case study for examining costs, because recommended services are largely unavailable and adoption requires significant effort. We therefore evaluated the cost of implementing immediate postpartum contraceptive services at four academic centres and one private hospital in USA., Methods: In this mixed-methods cost analysis, implementation activities were retrospectively identified using standardised data collection. Activities were categorised as preimplementation activities (infrastructure building, tool creation and stakeholder engagement) or execution activities (workforce training and process refinement). Costs were assigned based on national median salaries for the roles of individuals involved. Cross-case comparison and rapid qualitative analysis guided by the Consolidated Framework for Implementation Research were used to identify factors driving cost variation observed across sites., Results: On average, implementation activities required 204 hours (range 119-368), with this time costing $14 433.94 (range $9955.61-$23 690.49), and involving 9 (range 7-11) key team members per site. Preimplementation activities required more resources than execution activities (preimplementation: average 173 hours, $11 573.25; execution: average 31 hours, $2860.67). Sites that used lower-cost employees (eg, shifting tasks from a physician to a project manager) observed lower costs per hour for implementation activities. Implementation activities and costs were associated with local contextual factors, including stakeholder acceptance, integration of employees and infrastructure readiness for the change effort., Conclusions: Our findings provide the first estimates of health system costs for adopting recommended contraceptive care in maternity units in USA. More broadly, our findings suggest that the budget impact of improvement efforts may vary widely depending on local context., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute to signal-induced transcriptional responses, here we manipulate the signalling environment and activity of the histone demethylase LSD1 during differentiation of hESC-gut tube intermediates into pancreatic endocrine cells. We identify a transient requirement for LSD1 in endocrine cell differentiation spanning a short time-window early in pancreas development, a phenotype we reproduced in mice. Examination of enhancer and transcriptome landscapes revealed that LSD1 silences transiently active retinoic acid (RA)-induced enhancers and their target genes. Furthermore, prolonged RA exposure phenocopies LSD1 inhibition, suggesting that LSD1 regulates endocrine cell differentiation by limiting the duration of RA signalling. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited.

Objectives: In humans, neuronal processes related to brain development elevate the metabolic rate of brain tissue relative to the body during early childhood. This phenomenon has been hypothesized to contribute to slow somatic growth in preadolescent Homo sapiens. The uncoupling of the brain's metabolic rate from brain size during development complicates the study of the evolutionary emergence of these traits in the fossil record. Here, we extend a method previously developed to predict interspecific differences in cerebral blood flow (a correlate of cerebral glucose use) to predict ontogenetic changes in human brain metabolism., Materials and Methods: Radii of the carotid foramen from an ontogenetic series of modern human crania were used to predict blood flow rates through the internal carotid arteries (ICA), which were compared to empirically measured ICA flow and brain metabolism values., Results: Predictions of both absolute ICA blood flow rates and perfusion (ICA blood flow rates relative to brain size) generally match measured values in infancy and childhood. Maximum predicted ICA blood flow rates and perfusion were found to occur between ages 5 and 8, which roughly correspond to the age of maximum measured ICA blood flow rate and absolute and brain mass-specific rate of whole brain glucose uptake., Discussion: These findings suggest that, during human growth and development, the size of the carotid foramen corresponds well to blood flow requirements through the ICA, and the method tested here may provide new opportunities for studying developmental changes in brain metabolism using osteological samples, including fossil hominins., (© 2019 Wiley Periodicals, Inc.)

Supplying the central nervous system with oxygen and glucose for metabolic activities is a critical function for all animals at physiologic, anatomical, and behavioral levels. A relatively proximate challenge to nourishing the brain is maintaining adequate blood flow. Euarchontans (primates, dermopterans and treeshrews) display a diversity of solutions to this challenge. Although the vertebral artery is a major encephalic vessel, previous research has questioned its importance for irrigating the cerebrum. This presents a puzzling scenario for certain strepsirrhine primates (non-cheirogaleid lemuriforms) that have reduced promontorial branches of the internal carotid artery and no apparent alternative encephalic vascular route except for the vertebral artery. Here, we present results of phylogenetic comparative analyses of data on the cross-sectional area of bony canals that transmit the vertebral artery (transverse foramina). These results show that, across primates (and within major primate subgroups), variation in the transverse foramina helps significantly to explain variation in forebrain mass even when variation in promontorial canal cross-sectional areas are also considered. Furthermore, non-cheirogaleid lemuriforms have larger transverse foramina for their endocranial volume than other euarchontans, suggesting that the vertebral arteries compensate for reduced promontorial artery size. We also find that, among internal carotid-reliant euarchontans, species that are more encephalized tend to have a promontorial canal that is larger relative to the transverse foramina. Tentatively, we consider the correlation between arterial canal diameters (as a proxy for blood flow) and brain metabolic demands. The results of this analysis imply that human investment in brain metabolism (∼27% of basal metabolic rate) may not be exceptional among euarchontans., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To describe pharmacy-supported transition-of-care (TOC) interventions and determine their effect on 30-day all-cause readmissions., Data Sources: MEDLINE/PubMed, EMBASE, International Pharmaceutical Abstracts, ABI Inform Complete, PsychINFO, Web of Science, Academic Search Complete, CINHAL, Cochrane library, OIASTER, ProQuest Dissertations & Theses, ClinicalTrials.gov , and relevant websites were searched from January 1, 1995, to December 31, 2015., Study Selection and Data Extraction: PICOS+E criteria were utilized. Eligible studies reported pharmacy-supported TOC interventions compared with usual care in adult patients discharged to home within the United States. Studies were required to evaluate postdischarge outcomes (eg, rate of readmissions, hospital utilization). Randomized controlled trials, cohort studies, or controlled before-and-after studies were included. Two reviewers independently extracted data and evaluated study quality., Data Synthesis: A total of 56 articles were included in the systematic review (n = 61 858), of which 32 reported 30-day all-cause readmissions and were included in the meta-analysis. A taxonomy was developed to categorize targeted patients, intervention types, and pharmacy personnel as sole intervener. The meta-analysis demonstrated about a 32% reduction in the odds of readmission (odds ratio [OR] = 0.68; 95% CI = 0.61 to 0.75) observed for pharmacy-supported TOC interventions compared with usual care. Heterogeneity was identified ( I 2 = 55%; P < 0.001). A stratified meta-analysis showed that interventions with patient-centered follow-up reduced 30-day readmissions relative to studies without follow-up (OR = 0.70; CI = 0.63 to 0.78)., Conclusions: Pharmacy-supported TOC programs were associated with a significant reduction in the odds of 30-day readmissions.

Objectives: Three dental topography measurements: Dirichlet Normal Energy (DNE), Relief Index (RFI), and Orientation Patch Count Rotated (OPCR) are examined for their interaction with measures of wear, within and between upper and lower molars in Alouatta palliata. Potential inferences of the "dental sculpting" phenomenon are explored., Materials and Methods: Fifteen occluding pairs of howling monkey first molars (15 upper, 15 lower) opportunistically collected from La Pacifica, Costa Rica, were selected to sample wear stages ranging from unworn to heavily worn as measured by the Dentine Exposure Ratio (DER). DNE, RFI, and OPCR were measured from three-dimensional surface reconstructions (PLY files) derived from high-resolution CT scans. Relationships among the variables were tested with regression analyses., Results: Upper molars have more cutting edges, exhibiting significantly higher DNE, but have significantly lower RFI values. However, the relationships among the measures are concordant across both sets of molars. DER and EDJL are curvilinearly related. DER is positively correlated with DNE, negatively correlated with RFI, and uncorrelated with OPCR. EDJL is not correlated with DNE, or RFI, but is positively correlated with OPCR among lower molars only., Discussion: The relationships among these metrics suggest that howling monkey teeth adaptively engage macrowear. DNE increases with wear in this sample presumably improving food breakdown. RFI is initially high but declines with wear, suggesting that the initially high RFI safeguards against dental senescence. OPCR values in howling monkey teeth do not show a clear relationship with wear changes., (© 2016 Wiley Periodicals, Inc.)

Well-preserved crania of notharctine adapiforms from the Eocene of North America provide the best direct evidence available for inferring neuroanatomy and encephalization in early euprimates (crown primates). Virtual endocasts of the notharctines Notharctus tenebrosus (n = 3) and Smilodectes gracilis (n = 4) from the middle Eocene Bridger formation of Wyoming, and the late Eocene European adapid adapiform Adapis parisiensis (n = 1), were reconstructed from high-resolution X-ray computed tomography (CT) data. While the three species share many neuroanatomical similarities differentiating them from plesiadapiforms (stem primates) and extant euprimates, our sample of N. tenebrosus displays more variation than that of S. gracilis, possibly related to differences in the patterns of cranial sexual dimorphism or within-lineage evolution. Body masses predicted from associated teeth suggest that N. tenebrosus was larger and had a lower encephalization quotient (EQ) than S. gracilis, despite their close relationship and similar inferred ecologies. Meanwhile, body masses predicted from cranial length of the same specimens suggest that the two species were more similar, with overlapping body mass and EQ, although S. gracilis exhibits a range of EQs shifted upwards relative to that of N. tenebrosus. While associated data from other parts of the skeleton are mostly lacking for specimens included in this study, measurements for unassociated postcrania attributed to these species yield body mass and EQ estimates that are also more similar to each other than those based on teeth. Regardless of the body mass prediction method used, results suggest that the average EQ of adapiforms was similar to that of plesiadapiforms, only overlapped the lower quadrant for the range of extant strepsirrhines, and did not overlap with the range of extant haplorhines. However, structural changes evident in these endocasts suggest that early euprimates relied more on vision than olfaction relative to plesiadapiforms, despite having relatively small endocranial volumes compared to extant taxa., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

New World monkeys (platyrrhines) are a diverse part of modern tropical ecosystems in North and South America, yet their early evolutionary history in the tropics is largely unknown. Molecular divergence estimates suggest that primates arrived in tropical Central America, the southern-most extent of the North American landmass, with several dispersals from South America starting with the emergence of the Isthmus of Panama 3-4 million years ago (Ma). The complete absence of primate fossils from Central America has, however, limited our understanding of their history in the New World. Here we present the first description of a fossil monkey recovered from the North American landmass, the oldest known crown platyrrhine, from a precisely dated 20.9-Ma layer in the Las Cascadas Formation in the Panama Canal Basin, Panama. This discovery suggests that family-level diversification of extant New World monkeys occurred in the tropics, with new divergence estimates for Cebidae between 22 and 25 Ma, and provides the oldest fossil evidence for mammalian interchange between South and North America. The timing is consistent with recent tectonic reconstructions of a relatively narrow Central American Seaway in the early Miocene epoch, coincident with over-water dispersals inferred for many other groups of animals and plants. Discovery of an early Miocene primate in Panama provides evidence for a circum-Caribbean tropical distribution of New World monkeys by this time, with ocean barriers not wholly restricting their northward movements, requiring a complex set of ecological factors to explain their absence in well-sampled similarly aged localities at higher latitudes of North America.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral T antigens and exhibited apoptotic death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following T antigen-triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.

Background: Identifying clinical scenarios that maximize the cost-effectiveness of biological treatments can lead to optimized health care cost-saving and clinical effectiveness from a society's perspective., Methods: Published articles between January 1995 and June 2012 were searched in PubMed, EMBASE, ABI/INFORM, Tuft's Cost-Effectiveness Analysis Registry Database, Cochrane National Health Service Economic Evaluation Database, International Pharmaceutical Abstracts, Web of Science, and Google Scholar. Studies of interest included the following: (1) cost studies, (2) economic evaluations, or (3) narrative or systematic reviews related to economic evaluations of biological treatments for moderate-to-severe Crohn's disease (CD). The primary outcomes of interest included costs associated with biological treatments and cost-effectiveness measures, including incremental cost-effectiveness ratios. A threshold of $100,000/quality-adjusted life year (£60,000/quality-adjusted life year) gained was used for treatment cost-effectiveness., Results: Thirty-eight studies were identified, including 15 economic evaluations and 23 cost studies or reviews of economic evaluations. Economic evaluations found that infliximab and adalimumab were more cost-effective than standard therapy for luminal CD when provided as an induction therapy followed by episodic therapy over 5 or more years. The cost-effectiveness of infliximab and adalimumab versus standard therapy for luminal CD was less certain when used as 1-year maintenance treatment with or without previous induction therapy. Cost studies revealed that infliximab therapy reduced health care resource utilization and cost. Older reviews were inconclusive about the cost-effectiveness of biological treatments used for CD., Conclusions: Current evidence suggests that biological treatments may be cost-effective for CD under certain clinical scenarios. Future studies evaluating all biological treatments are needed to compare their respective benefits and costs.

Objectives: To develop a mouse model for multispectral fluorescence imaging of the pancreas and pancreatic microenvironment., Methods: Cre/loxP technology was used to develop this model. We crossed mT/mG indicator mice, engineered to constitutively express a conditional tdTomato transgene that converts to green fluorescent protein (GFP) expression after exposure to Cre recombinase, with Pdx1-Cre transgenic mice. To characterize this model for studies of pancreas biology, we performed bright light and fluorescence imaging of body cavities and intact organs and confocal microscopy of pancreata from offspring of Pdx1-Cre and mT/mG crosses., Results: Pdx1-Cre-mT/mG mice demonstrated bright GFP expression within the pancreas and duodenum and intense tdTomato expression in all other organs. Green fluorescent protein expression was mosaic in Pdx1-Cre-mT/mG pancreata, with most showing extensive conversion from tdTomato to GFP expression within the epithelial-derived elements of the pancreatic parenchyma. Because both GFP and tdTomato are membrane targeted, individual cell borders were clearly outlined in confocal images of mT/mG pancreata., Conclusions: This mouse model enables multispectral fluorescence imaging of individual cells and cell processes at the microscopic level of the pancreatic microenvironment; it should prove valuable for a variety of fluorescence imaging studies, ranging from pancreatic development to pancreatic cancer biology.

Background: Direct-to-consumer advertisement (DTCA) of prescription medications has become an important informational source for health care consumers. As future health care professionals on the front line of potential communication and dispensing of products emerging from DTCA, it is important to elicit the attitudes of student-pharmacists., Objectives: This study aims to (1) evaluate the validity of the DTCA attitudinal questionnaire using Rasch rating scale analysis and (2) investigate the attitudes of pharmacy students toward DTCA and determine whether these attitudes were associated with years of pharmacy education and demographic characteristics., Methods: This investigation used a cross-sectional print-based questionnaire to evaluate the attitudes of pharmacy students toward DTCA of prescription medications. The 16-item questionnaire included items addressing the attitudes of pharmacy students toward DTCA with respect to patients' knowledge of medications, pharmacists' interaction with patients, and overall consumer judgment of medical prescriptions. Analyses included Rasch analysis and a multiple linear regression., Results: A total of 243 students submitted usable questionnaires (85% response rate). Item response categories were collapsed from 5 categories to 3, and 4 items were removed to achieve acceptable Rasch model fit. Pharmacy students demonstrated little difficulty in agreeing with the statements suggesting that DTCA helps patients take a more active role in health care and had the most difficulty in agreeing with items suggesting that DTCA may lead to inappropriate prescribing to satisfy patient requests. Students' overall support for DTCA was the only variable that predicted the questionnaire score (P<.001)., Conclusions: In conclusion, the Rasch analysis evaluated the psychometric properties of the instrument and identified the necessity to adapt the questionnaire from previous iterations to adequately fit the student population. Future research should examine factors that contribute to the variance in attitudes toward DTCA among a larger and more heterogeneous population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background and Purpose: To estimate the cost-effectiveness of stroke prevention in patients with nonvalvular atrial fibrillation by using novel oral anticoagulants apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg compared with warfarin., Methods: A Markov decision-analysis model was constructed using data from clinical trials to evaluate lifetime costs and quality-adjusted life-years of novel oral anticoagulants compared with warfarin. The modeled population was a hypothetical cohort of 70-year-old patients with nonvalvular atrial fibrillation, increased risk for stroke (CHADS2 ≥ 1), renal creatinine clearance ≥ 50 mL/min, and no previous contraindications to anticoagulation. The willingness-to-pay threshold was $50 000/quality-adjusted life-years gained., Results: In the base case, warfarin had the lowest cost of $77 813 (SD, $2223), followed by rivaroxaban 20 mg ($78 738 ± $1852), dabigatran 150 mg ($82 719 ± $1959), and apixaban 5 mg ($85 326 ± $1512). Apixaban 5 mg had the highest quality-adjusted life-years estimate at 8.47 (SD, 0.06), followed by dabigatran 150 mg (8.41 ± 0.07), rivaroxaban 20 mg (8.26 ± 0.06), and warfarin (7.97 ± 0.04). In a Monte Carlo probabilistic sensitivity analysis, apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg, and warfarin were cost-effective in 45.1%, 40%, 14.9%, 0% of the simulations, respectively., Conclusions: In patients with nonvalvular atrial fibrillation and an increased risk of stroke prophylaxis, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were all cost-effective alternatives to warfarin. The cost-effectiveness of novel oral anticoagulantss was dependent on therapy pricing in the United States and neurological events associated with rivaroxaban 20 mg.

Objective: To evaluate the presence of pulmonary abnormalities in rheumatoid arthritis (RA)-related autoantibody-positive subjects without inflammatory arthritis., Methods: Forty-two subjects who did not have inflammatory arthritis but were positive for anti-cyclic citrullinated peptide antibodies and/or ≥2 rheumatoid factor isotypes (a profile that is 96% specific for RA), 15 autoantibody-negative controls, and 12 patients with established seropositive early RA (<1-year duration) underwent spirometry and high-resolution computed tomography (HRCT) lung imaging., Results: The median age of autoantibody-positive subjects was 54 years, 52% were female, and 38% were ever-smokers; these characteristics were not significantly different from those of autoantibody-negative control subjects. No autoantibody-positive subject had inflammatory arthritis based on joint examination. HRCT revealed that 76% of autoantibody-positive subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities, and air trapping, compared with 33% of autoantibody-negative controls (P = 0.005). The prevalence and type of lung abnormalities among autoantibody-positive subjects were similar to those among patients with early RA. In 2 autoantibody-positive subjects with airways disease, inflammatory arthritis classifiable as articular RA developed ∼13 months after the lung evaluation., Conclusion: Airways abnormalities that are consistent with inflammation are common in autoantibody-positive subjects without inflammatory arthritis and are similar to airways abnormalities seen in patients with early RA. These findings suggest that the lung may be an early site of autoimmune-related injury and potentially a site of generation of RA-related autoimmunity. Further studies are needed to define the mechanistic role of lung inflammation in the development of RA., (Copyright © 2012 by the American College of Rheumatology.)

Objectives: To evaluate changes in medical, pharmacy, and nurse practitioner students' drug-drug interaction (DDI) knowledge after attending an educational program., Design: A DDI knowledge assessment containing 15 different drug pairs was administered to participants before and after a 45-minute educational session., Evaluation: Pharmacy, medical, and nursing students scored significantly higher on the posttest assessment for DDI recognition (median change 3, 9, and 8, respectively) and management strategy (median change 5, 9, 8, respectively), indicating a significant improvement in DDI knowledge as a result of the educational session. Pharmacy students scored significantly higher on the pretest; however, no difference was observed between the students' posttest scores. Posttest scores for all student groups were significantly greater than their respective pretest scores (p < 0.001)., Conclusions: Significant improvement in healthcare professional students' DDI knowledge was observed following participation in the educational session.

Objective: To examine perinatal depression in north and northeast Omaha, NE., Methods: The records of a sample of 119 randomly selected clients from Omaha Healthy Start (OHS) were reviewed. Three screening instruments were employed to identify women with depression: they were asked whether they were depressed (DQ); they received the Edinburgh Postpartum Depression Scale (EPDS) and/or the Beck Depression Inventory (BDI)., Results: The number of women with depressive symptoms identified by each technique varied from: DQ (16.8%), EPDS (16%) and BDI (7.6%). The three methods identified three subpopulations of women with different maternal and child health risk profiles reflected by their responses on an OHS-developed Maternal and Child Health Risk Assessment Tool., Conclusion: In combination, these simple techniques identified depressed women with different risk profiles who would have been missed using a single approach exclusively.

Coronary thrombosis and the risk of clinical adverse events remains high despite considerable advances in the management of acute coronary syndromes (ACS) with the combined use of aspirin, heparin, fibrinolytic therapy, and percutaneous coronary intervention (PCI). Platelet aggregation and thrombosis play a key role in the pathogenesis of unstable coronary syndromes. Over the past several years, multiple placebo-controlled trials involving more than 50,000 ACS patients have shown that blockade of the platelet receptor glycoprotein (GP) IIb/IIIa, the final pathway in platelet aggregation, reduces the incidence of ischemic complications among patients with ACS. Three agents (abciximab, eptifibatide, and tirofiban) are currently approved for use with aspirin and heparin in the management of ACS or during percutaneous coronary intervention. They have consistently been shown to reduce the incidence of death or myocardial infarction in the ACS population including the patients not routinely scheduled for early revascularization. They provide an augmented treatment effect among high-risk ACS patients, particularly those who have a baseline troponin-t-positive status. Recently published practice guidelines have recommended their use in high-risk patients with ACS and all those undergoing PCI.

Patients with end-stage renal failure develop osteodystrophy in part due to defective production of 1,25-dihydroxycholecalciferol by the kidney. We treated eight adults with chronic renal failure and osteodystrophy with 1,25-dihydroxycholecalciferol (calcitriol) for 30-44 months. Seven of these patients were also symptomatic with bone pain and/or muscle weakness. Striking amelioration of muscle weakness occurred, and bone pain was considered to be significantly improved in four of seven patients. Hypercalcemia was noted in all the patients, necessitating a reduction in the daily dose of calcitriol to a range of 0.125 to 0.5 microgram/day. While serum alkaline phosphatase fell during therapy, serum iPTH did not show any significant change. Bone mineral content improved in four patients, though it still remained below normal. Radiographic changes of osteodystrophy showed definite improvement in only three.

Association of membranous glomerulonephropathy with crescentic glomerulonephritis is apparently extremely rare. We report three patients who had this combination. One patient had biopsy-proven membranous glomerulonephropathy thirteen months prior to sudden and rapid decline in renal function necessitating hemodialysis. A repeat renal biopsy showed a superimposed crescentic nephritis and antiglomerular (GBM) antibodies were demonstrable in the serum. A second patient had proteinuria of unknown duration and then developed renal failure. Renal biopsy showed crescentic nephritis with a fine granular glomerular immunofluorescence for IgG typical of membranous glomerulonephropathy. Anti-GBM antibodies were present in this patient's serum. The third patient presented with acute renal failure of moderate severity. A renal biopsy revealed crescentic nephritis, granular deposits of immunoglobulins, and epimembranous electron-dense deposits typical of membranous glomerulonephropathy. Although his creatinine clearance improved spontaneously, nephrotic syndrome has persisted and a repeat renal biopsy showed a progression of the membranous glomerulonephropathy with the disappearance of the crescentic lesions. The reason for this peculiar association of membranous glomerulonephropathy and crescentic glomerulonephritis is unclear. It is possible that deposition of immune-complexes along glomerular basement membrane may render the glomerulus more susceptible to additional injury from a variety of other agents. Alternatively, depostis formed in one disease could initiate release of normal or altered basement membrane material and lead to formation of anti-GBM antibodies and subsequent development.

Two patients with hypodipsia and hypernatremia are described. The first patient, whose hypodipsia was of unknown cause, developed hypernatremia unless large volumes of fluid were urged upon him; upon treatment with chlorpropamide normal serum sodium levels were achieved with spontaneous fluid intake. The second patient had hypodipsia and diabetes insipidus resulting from a craniopharyngioma. Treatment with vasopressin and a prescribed daily water intake resulted in frequent hyper- and hyponatremia, but treatment with chlorpropramide yielded serum sodium values which were more often normal and less variable. In neither patient could the improved water regulation be attributed to an effect of chlorpropamide on renal water excretion. Possible mechanisms for the effect of chlorpropamide on thirst are discussed.

Fourteen maintenance hemodialysis patients volunteered to participate in a 6-month program of exercise training. The exercise was performed on a stationary bicycle during the hemodialysis treatment. Six maintenance hemodialysis patients served as control without exercise training. Exercising patients participated in 91% of all possible exercise sessions. The exercise group showed a significant (23%) increase in maximal oxygen consumption over the 6 months. No change in exercise capacity resulted in the control group. Five of eight hypertensive patients in the exercise group decreased or discontinued antihypertensive medications. No changes occurred in hematocrit or lipid profiles in either group. We conclude that exercise training during the hemodialysis treatment is technically feasible and safe for appropriately screened patients and will increase exercise capacity, and in some patients improve blood pressure control. Exercise during dialysis also improves compliance to regular exercise and facilitates supervised exercise sessions, which are desirable in this patient group.

In order to determine whether or not antidiuretic hormone (ADH) is essential to the inhibition of an acute water diuresis in adrenal insufficiency, the response to oral water loads was tested in rats with hereditary hypothalamic diabetes insipidus (DI) which lack ADH. It was found that 60 min after water loads of 3 or 5% of body weight urine flow was significantly lower and urine osmolality significantly higher in adrenalectomized DI rats than in the same DI rats before removal of their adrenal glands. The efficacy of gluco- and mineralocorticoids in reversing the inhibition was then determined in the same adrenalectomized DI rats. Prednisolone alone, administered either acutely or chronically, restored the response in urine flow to that seen in the same rats before adrenalectomy, but failed to correct the defect in urinary dilution. Aldosterone when given alone tended to correct the diluting ability but not the response in urine flow. When these two adrenal cortical hormones were given simultaneously, both the urine flow and urine osmolality were nearly identical to what they had been in the same DI rats before adrenalectomy. These studies strongly suggest (a) that ADH is not essential to the inhibition of an acute water diuresis in adrenal insufficiency, although it may abet the inhibition in individuals without diabetes insipidus, which can elaborate ADH; and (b) that both gluco- and mineralocorticoids are required in adrenal insufficiency in order to fully restore the water diuresis as judged by the dual criteria of urine flow and urine osmolality.

This study utilized rates with hereditary hypothalamic diabetes insipidus (D.I.) in order to explore possible mechanisms which prevent full urinary concentration after acute administration of vasopressin in hypothalamic D.I. and which correct this concentrating defect with prolonged therapy.IT WAS FOUND: (a) that the concentrating defect persisted even when the urinary osmolal excretion of D. I. rats was reduced to that of normal animals; (b) that the defect was not corrected more rapidly if larger doses of vasopressin were given; (c) that it persisted even when the D.I. rats were deprived of drinking water after vasopressin was given; (d) that there was osmotic equilibration between urine and renal papilla at a time when the concentrating defect was still evident; and (e) that the correction of the defect was associated with progressive and significant rise of the papillary osmolality. These studies appear to rule out osmotic diuresis, accumulation of exogenous vasopressin, persistent primary polydipsia, or delay in the induction of membrane permeability as causes for the concentrating defect. Rather, subnormal osmolality of the renal papilla, which can be corrected only gradually, accounts for the initial concentrating defect and the long time required for its correction. Reduction of water content and increase of urea content are primarily responsible for restoration of papillary osmolality to normal.