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PURPOSE: The methods currently used by English National Health Service (NHS) hospitals to manage the use of medicines were studied. METHODS: A questionnaire was mailed to directors of pharmacy at all English NHS hospitals in May 2001. RESULTS: The response rate was 57% (157/ 275). Sixty-six percent of the responding hospitals provided general acute care services, and 34% provided mental health services. About 1 responder in 5 (19%) was a specialty hospital functioning either as a freestanding institution or alongside other hospitals. The average total expenditure by the hospital trusts was pound 94 million (dollar 175 million), of which drugs accounted for pound 3.5 million (dollar 6.5 million). Many hospitals either had formularies or were constructing them (86%), and most hospitals used a process to manage the introduction of new medicines. About three fourths of the hospitals had < or = 20 pharmacist full-time equivalents. The implementation of national guidelines was variable, although some of this variation may have been due to differences in service provision. Few hospitals were actively monitoring compliance with guidelines (31%), but audits of current care were common (72%). CONCLUSION: A survey of English NHS hospitals provided information on pharmacy staffing, drug expenditures, and measures taken to ensure rational medication use. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether the capacity of remote ischemic preconditioning (IPC) against endothelial ischemia/reperfusion (I/R) injury changes across the menstrual cycle in premenopausal women and to compare IPC responses to postmenopausal women. Thirty-five women were studied (22 premenopausal/13 postmenopausal). Changes in endothelial function were determined during the early follicular vs. the late follicular phase (after positive urine ovulation test; Study 1 ), vs. the mid-luteal phase (after positive urine progesterone test; Study 2 ), and vs. estrogen-deficient postmenopausal women; Study 3). Endothelium-dependent vasodilation was assessed by the forearm blood flow (FBF) to reactive hyperemia with/without I/R injury with remote IPC (3 × 5 min cycles of upper arm ischemia). In the premenopausal women, peak FBF responses during the early follicular phase were blunted 20% ( P < 0.0001) with I/R injury (from baseline: 23.4 ± 6.2 to 19.5 ± 4.9 mL/100 mL tissue/min) compared with the late follicular/mid-luteal phases despite IPC. In postmenopausal women, peak FBF was diminished (from: 21.1 ± 5.1 to 17.2 ± 4.4 mL/100 mL tissue/min), and total FBF (area under the curve) was decreased a third (-32%; P < 0.001) with I/R injury. Protection from I/R injury was preserved during the late follicular (from baseline: 21.7 ± 5.3 to 24.8 ± 5.9 mL/100 mL tissue/min; P = 0.109) and mid-luteal phases (from: 25.1 ± 3.9 to 27.2 ± 5.7 mL/100 mL tissue/min; P = 0.267). Reduced estrogen during the early follicular phase and the rise in estrogen associated with ovulation and the mid-luteal phase may contribute to changes in IPC-mediated protection in premenopausal women and shed light on how cardioprotection may change with ovarian hormone deficiency with the menopause transition. NEW & NOTEWORTHY The capacity of remote ischemic preconditioning to protect against vascular endothelial ischemia/reperfusion injury varies widely across the phases of the menstrual cycle in healthy premenopausal women. Robust protection was afforded during the late follicular and mid-luteal phases. In contrast, weakened protection was demonstrated during the early follicular phase, with a level of impairment similar to estrogen-deficient postmenopausal women.

Microbial succession has been suggested to supplement established postmortem interval (PMI) estimation methods for human remains. Due to limitations of entomological and morphological PMI methods, microbes are an intriguing target for forensic applications as they are present at all stages of decomposition. Previous machine learning models from soil necrobiome data have produced PMI error rates from two and a half to six days; however, these models are built solely on amplicon sequencing of biomarkers (e.g., 16S, 18S rRNA genes) and do not consider environmental factors that influence the presence and abundance of microbial decomposers. This study builds upon current research by evaluating the inclusion of environmental data on microbial-based PMI estimates from decomposition soil samples. Random forest regression models were built to predict PMI using relative taxon abundances obtained from different biological markers (bacterial 16S, fungal ITS, 16S-ITS combined) and taxonomic levels (phylum, class, order, OTU), both with and without environmental predictors (ambient temperature, soil pH, soil conductivity, and enzyme activities) from 19 deceased human individuals that decomposed on the soil surface (Tennessee, USA). Model performance was evaluated by calculating the mean absolute error (MAE). MAE ranged from 804 to 997 accumulated degree hours (ADH) across all models. 16S models outperformed ITS models (p = 0.006), while combining 16S and ITS did not improve upon 16S models alone (p = 0.47). Inclusion of environmental data in PMI prediction models had varied effects on MAE depending on the biological marker and taxonomic level conserved. Specifically, inclusion of the measured environmental features reduced MAE for all ITS models, but improved 16S models at higher taxonomic levels (phylum and class). Overall, we demonstrated some level of predictability in soil microbial succession during human decomposition, however error rates were high when considering a moderate population of donors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mason et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Human decomposition in terrestrial ecosystems is a dynamic process creating localized hot spots of soil microbial activity. Longer-term (beyond a few months) impacts on decomposer microbial communities are poorly characterized and do not typically connect microbial communities to biogeochemistry, limiting our understanding of decomposer communities and their functions. We performed separate year-long human decomposition trials, one starting in spring, another in winter, integrating bacterial and fungal community structure and abundances with soil physicochemistry and biogeochemistry to identify key drivers of microbial community change. In both trials, soil acidification, elevated microbial respiration, and reduced soil oxygen concentrations occurred. Changes in soil oxygen concentrations were the primary driver of microbial succession and nitrogen transformation patterns, while fungal community diversity and abundance was related to soil pH. Relative abundance of facultative anaerobic taxa (Firmicutes and Saccharomycetes) increased during the period of reduced soil oxygen. The magnitude and timing of the decomposition responses were amplified during the spring trial relative to the winter, even when corrected for thermal inputs (accumulated degree days). Further, soil chemical parameters, microbial community structure, and fungal gene abundances remained altered at the end of 1 year, suggesting longer-term impacts on soil ecosystems beyond the initial pulse of decomposition products., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Indium (In) is a neutron absorbing additive that could feasibly be used to mitigate criticality in ceramic wasteforms containing Pu in the immobilised form, for which zirconolite (nominally CaZrTi 2 O 7 ) is a candidate host phase. Herein, the solid solutions Ca 1-x Zr 1-x In 2x Ti 2 O 7 (0.10 ≤ x ≤ 1.00; air synthesis) and Ca 1-x U x ZrTi 2-2x In 2x O 7 (x = 0.05, 0.10; air and argon synthesis) were investigated by conventional solid state sintering at a temperature of 1350 °C maintained for 20 h, with a view to characterise In 3+ substitution behaviour in the zirconolite phase across the Ca 2+ , Zr 4+ and Ti 4+ sites. When targeting Ca 1-x Zr 1-x In 2x Ti 2 O 7 , single phase zirconolite-2M was formed at In concentrations of 0.10 ≤ x ≤ 0.20; beyond x ≥ 0.20, a number of secondary In-containing phases were stabilised. Zirconolite-2M remained a constituent of the phase assemblage up to a concentration of x = 0.80, albeit at relatively low concentration beyond x ≥ 0.40. It was not possible to synthesise the In 2 Ti 2 O 7 end member compound using a solid state route. Analysis of the In K-edge XANES spectra in the single phase zirconolite-2M compounds confirmed that the In inventory was speciated as trivalent In 3+ , consistent with targeted oxidation state. However, fitting of the EXAFS region using the zirconolite-2M structural model was consistent with In 3+ cations accommodated within the Ti 4+ site, contrary to the targeted substitution scheme. When deploying U as a surrogate for immobilised Pu in the Ca 1-x U x ZrTi 2-2x In 2x O 7 solid solution, it was demonstrated that, for both x = 0.05 and 0.10, In 3+ was successfully able to stabilise zirconolite-2M when U was distributed predominantly as both U 4+ and average U 5+ , when synthesised under argon and air, respectively, determined by U L 3 -edge XANES analysis., (© 2023. The Author(s).)

Vertebrate decomposition results in an ephemeral disturbance of the surrounding environment. Microbial decomposers are recognized as key players in the breakdown of complex organic compounds, controlling carbon and nutrient fate in the ecosystem and potentially serving as indicators of time since death for forensic applications. As a result, there has been increasing attention on documenting the microbial communities associated with vertebrate decomposition, or the 'necrobiome'. These necrobiome studies differ in the vertebrate species, microhabitats (e.g. skin vs. soil), and geographic locations studied, but many are narrowly focused on the forensic application of microbial data, missing the larger opportunity to understand the ecology of these communities. To further our understanding of microbial dynamics during vertebrate decomposition and identify knowledge gaps, there is a need to assess the current works from an ecological systems perspective. In this review, we examine recent work pertaining to microbial community dynamics and succession during vertebrate (human and other mammals) decomposition in terrestrial ecosystems, through the lens of a microbial succession ecological framework. From this perspective, we describe three major microbial microhabitats (internal, external, and soil) in terms of their unique successional trajectories and identify three major knowledge gaps that remain to be addressed., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Physician shortages across the United States will affect access to orthopaedic care for patients. Orthopaedic surgery is predicted to have one of the largest shortages among surgical subspecialties by 2025, which will disproportionally affect patients in medically underserved areas. This study examines characteristics and experiences of graduating medical students interested in orthopaedic surgery who intend to practice in underserved areas (IPUAs)., Methods: We analyzed deidentified data of AAMC Graduation Questionnaire respondents who matriculated between 2007 to 2008 and 2011 to 2012. Forty-eight thousand ninety-six (83.91%) had complete demographic, financial, and medical school elective data and were included in the study cohort. Multivariable logistic regression was performed to determine the correlation between student characteristics and intention to pursue orthopaedic surgery and IPUAs., Results: Of the 48,096 students with complete information, 2,517 (5.2%) intended to pursue a career in orthopaedic surgery. Among the orthopaedic students, men were less likely than women to report IPUAs (adjusted odds ratio [aOR], 0.6; 95% CI, 0.4-0.8). Students who identified as Black/African American (aOR, 5.0; 95% CI, 3.0-8.2) or Hispanic (aOR, 2.0; 95% CI, 1.1-3.5) were more likely than White students to report IPUAs. Medical students who intend to pursue orthopaedics and received a scholarship (aOR, 1.5; 95% CI, 1.1-2.0), participated in community research (aOR, 1.8; 95% CI, 1.4-2.3), or had a global health experience (aOR, 1.9; 95% CI, 1.5-2.5) were more likely to report IPUAs., Discussion: If orthopaedic surgeons who reported as medical students who reported IPUAs actually do so, recruiting and retaining more sex and race/ethnically diverse orthopaedic surgeons could reduce the impact of the impending shortage of orthopaedic surgeons in underserved areas. IPUA is correlated to medical school experiences related to cultural competency including global health experiences and community-based research projects., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A450)., (Copyright © 2023 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Microorganisms are key decomposers of vertebrate mortalities, breaking down body tissues and impacting decomposition progress. During human decomposition, both extrinsic environmental factors and intrinsic cadaver-related factors have the potential to impact microbial decomposers either directly or indirectly via altered physical or chemical conditions. While extrinsic factors (e.g., temperature, humidity) explain some variation in microbial response during human decomposition in terrestrial settings, recent work has noted that even under the same environmental conditions, individuals can have different decomposition patterns, highlighting the potential for intrinsic factors to impact microbial decomposers. The goal of this study was to investigate the effects of several intrinsic factors (age, sex, diseases at time of death, and body mass index [BMI]) on chemical and microbial changes in decomposition-impacted soils. In a field study conducted at the University of Tennessee Anthropology Research Facility, soils were collected from the decomposition-impacted area surrounding 19 deceased human individuals through the end of active decomposition. Soil physicochemical parameters were measured, and microbial (bacterial and fungal) communities were assessed via amplicon sequencing. BMI was shown to explain some variation in soil pH and microbial response to human decomposition. Hierarchical linear mixed (HLM) effects models revealed that BMI category significantly explained variation in pH response within decomposition-impacted soils over time (HLM F  = 9.647; P  < 0.001). Additionally, the relative abundance of soil Saccharomycetes in decomposition soils under underweight donors displayed little to no changes (mean maximum change in relative abundance, +6.6%), while all other BMI categories displayed an increased relative abundance of these organisms over time (normal, +50.6%; overweight, +64.4%; and obese, +64.6%) (HLM F  = 3.441; P  = 0.11). Together, these results reveal intrinsic factors influencing decomposition patterns, especially within the soil environment, and suggest BMI is an important factor for controlling decomposition processes. IMPORTANCE This work begins to address questions about interindividual variation in vertebrate decomposition attributed to intrinsic factors, that is, properties of the carcass or cadaver itself. Most research on factors affecting decomposition has focused on the extrinsic environment, such as temperature or humidity. While these extrinsic factors do explain some variation in decomposition patterns, interindividual variability is still observed. Understanding how intrinsic factors influence microbial decomposers will help reveal the ecological impacts of decomposition. This work also has forensic applications, as soil chemical and biological changes have been suggested as indicators of postmortem interval. We reveal factors that explain variation in the decomposition environment that should be considered in these estimates. This is particularly important as we consider the implications of variations in human populations due to diet, age, BMI, disease, toxicological loading, etc. on forensic investigations dealing with decomposing remains.

Socioeconomic demand for natural capital is causing catastrophic losses of biodiversity and ecosystem functionality, most notably in regions where socioeconomic-and eco-systems compete for natural capital, e.g., energy (animal or plant matter). However, a poor quantitative understanding of what natural capital is needed to support biodiversity in ecosystems, while at the same time satisfy human development needs-those associated with human development within socioeconomic systems-undermines our ability to sustainably manage global stocks of natural capital. Here we describe a novel concept and accompanying methodology (relating the adult body mass of terrestrial species to their requirements for land area, water, and energy) to quantify the natural capital needed to support terrestrial species within ecosystems, analogous to how natural capital use by humans is quantified in a socioeconomic context. We apply this methodology to quantify the amount of natural capital needed to support species observed using a specific surveyed site in Scotland. We find that the site can support a larger assemblage of species than those observed using the site; a primary aim of the rewilding project taking place there. This method conceptualises, for the first time, a comprehensive "dual-system" approach: modelling natural capital use in socioeconomic-and eco-systems simultaneously. It can facilitate the management of natural capital at the global scale, and in both the conservation and creation (e.g., rewilding) of biodiversity within managed ecosystems, representing an advancement in determining what socioeconomic trade-offs are needed to achieve contemporary conservation targets alongside ongoing human development., Competing Interests: The authors declare no competing financial interests., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Zirconolite is considered to be a suitable wasteform material for the immobilization of Pu and other minor actinide species produced through advanced nuclear separations. Here, we present a comprehensive investigation of Dy 3+ incorporation within the self-charge balancing zirconolite Ca 1- x Zr 1- x Dy 2 x Ti 2 O 7 solid solution, with the view to simulate trivalent minor actinide immobilization. Compositions in the substitution range 0.10 ≤ x ≤ 1.00 (Δ x = 0.10) were fabricated by a conventional mixed oxide synthesis, with a two-step sintering regime at 1400 °C in air for 48 h. Three distinct coexisting phase fields were identified, with single-phase zirconolite-2M identified only for x = 0.10. A structural transformation from zirconolite-2M to zirconolite-4M occurred in the range 0.20 ≤ x ≤ 0.30, while a mixed-phase assemblage of zirconolite-4M and cubic pyrochlore was evident at Dy concentrations 0.40 ≤ x ≤ 0.50. Compositions for which x ≥ 0.60 were consistent with single-phase pyrochlore. The formation of zirconolite-4M and pyrochlore polytype phases, with increasing Dy content, was confirmed by high-resolution transmission electron microscopy, coupled with selected area electron diffraction. Analysis of the Dy L 3 -edge XANES region confirmed that Dy was present uniformly as Dy 3+ , remaining analogous to Am 3+ . Fitting of the EXAFS region was consistent with Dy 3+ cations distributed across both Ca 2+ and Zr 4+ sites in both zirconolite-2M and 4M, in agreement with the targeted self-compensating substitution scheme, whereas Dy 3+ was 8-fold coordinated in the pyrochlore structure. The observed phase fields were contextualized within the existing literature, demonstrating that phase transitions in CaZrTi 2 O 7 -REE 3+ Ti 2 O 7 binary solid solutions are fundamentally controlled by the ratio of ionic radius of REE 3+ cations.

The immobilisation and disposal of fissile materials from civil and defence nuclear programmes requires compatible, passively safe and proliferation resistant wasteforms. In this study, we demonstrate the application of an albite glass-zirconolite ceramic material for immobilisation of chloride contaminated plutonium oxide residues in the United Kingdom. The chlorine solubility limit in the albite glass phase was determined to be 1.0 ± 0.1 wt%, above the maximum envisaged chorine inventory of 0.5 wt%, attainable at a 20 wt% PuO 2 incorporation rate within the ceramic. Cl K-edge of X-ray Absorption Near Edge Spectroscopy (XANES) was exploited to confirm partitioning of Cl to the glass phase, speciated as the chloride anion, with exsolution of crystalline NaCl above the chlorine solubility limit. Combinatorial fitting of Cl XANES data, utilising a library of chemically plausible reference spectra, demonstrated the association of Cl with Na and Ca modifier cations, with environments characteristic of the aluminosilicate chloride minerals eudialyte, sodalite, chlorellestadite and afghanite. Adventitious incorporation of Ca, Zr and Ti within the albite glass phase apparently assists chlorine solubility, by templating a local chemical environment characteristic of the mineral reference compounds. The partitioning of Ce, as a Pu analogue, within the glass-ceramic was not adversely impacted by incorporation of Cl. The significance of this research is in demonstrating the compatibility of the glass-ceramic wasteform toward Cl solubility at the expected incorporation rate, below the determined solubility limit. Thus, an upstream heat treatment facility to remove chloride contamination, as specified in the current conceptual flowsheet, would not be required from the perspective of wasteform compatibility, thus providing scope to de-risk the technology roadmap and reduce the projected capital and operational plant costs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: In England, rises in healthcare expenditure consistently outpace growth in both GDP and total public expenditure. To ensure the National Health Service (NHS) remains financially sustainable, relevant data on healthcare expenditure are needed to inform decisions about which services should be delivered, by whom and in which settings., Methods: We analyse routine data on NHS expenditure in England over 9 years (2008/09 to 2016/17). To quantify the relative contribution of the different care settings to overall healthcare expenditure, we analyse trends in 14 healthcare settings under three broad categories: Hospital Based Care (HBC), Diagnostics and Therapeutics (D&T) and Community Care (CC). We exclude primary care and community mental health services settings due to a lack of consistent data. We employ a set of indices to aggregate diverse outputs and to disentangle growth in healthcare expenditure that is driven by activity from that due to cost pressures. We identify potential drivers of the observed trends from published studies., Results: Over the 9-year study period, combined NHS expenditure on HBC, D&T and CC rose by 50.2%. Expenditure on HBC rose by 54.1%, corresponding to increases in both activity (29.2%) and cost (15.7%). Rises in expenditure in inpatient (38.5%), outpatient (57.2%), and A&E (59.5%) settings were driven predominately by higher activity. Emergency admissions rose for both short-stay (45.6%) and long-stay cases (26.2%). There was a switch away from inpatient elective care (which fell by 5.1%) and towards day case care (34.8% rise), likely reflecting financial incentives for same-day discharges. Growth in expenditure on D&T (155.2%) was driven by rises in the volume of high cost drugs (270.5%) and chemotherapy (110.2%). Community prescribing grew by 45.2%, with costs falling by 24.4%. Evidence on the relationship between new technologies and healthcare expenditure is mixed, but the fall in drug costs could reflect low generic prices, and the use of health technology assessment or commercial arrangements to inform pricing of new medicines., Conclusions: Aggregate trends in HCE mask enormous variation across healthcare settings. Understanding variation in activity and cost across settings is an important initial step towards ensuring the long-term sustainability of the NHS.

This study investigated the sensitivity, specificity, and accuracy of physical examination compared with high resolution sonography for the detection of the palmaris longus tendon in 136 wrists. The incidence of tendon absence was 10% by sonography and 14% by physical examination. The sensitivity of the physical examination was 94% and the specificity 86% compared with sonography as the reference standard. Accurate identification of the palmaris longus tendon through physical examination was not influenced by body mass index or wrist circumference. Upon review of the sonography images, none of the palmaris longus tendons missed on physical examination were considered to be adequate for grafting based on expert opinion. While physical exam was 93% accurate for detection of the palmaris longus tendon compared with ultrasound, our study suggests that it is sufficient for detection of those tendons that can be used as donors clinically.

Deficient progranulin levels cause dose-dependent neurological syndromes: haploinsufficiency leads to frontotemporal lobar degeneration (FTLD) and nullizygosity produces adult-onset neuronal ceroid lipofuscinosis. Mechanisms controlling progranulin levels are largely unknown. To better understand progranulin regulation, we performed a genome-wide RNAi screen using an ELISA-based platform to discover genes that regulate progranulin levels in neurons. We identified 830 genes that raise or lower progranulin levels by at least 1.5-fold in Neuro2a cells. When inhibited by siRNA or some by submicromolar concentrations of small-molecule inhibitors, 33 genes of the druggable genome increased progranulin levels in mouse primary cortical neurons; several of these also raised progranulin levels in FTLD model mouse neurons. "Hit" genes regulated progranulin by transcriptional or posttranscriptional mechanisms. Pathway analysis revealed enrichment of hit genes from the autophagy-lysosome pathway (ALP), suggesting a key role for this pathway in regulating progranulin levels. Progranulin itself regulates lysosome function. We found progranulin deficiency in neurons increased autophagy and caused abnormally enlarged lysosomes and boosting progranulin levels restored autophagy and lysosome size to control levels. Our data link the ALP to neuronal progranulin: progranulin levels are regulated by autophagy and, in turn, progranulin regulates the ALP. Restoring progranulin levels by targeting genetic modifiers reversed FTLD functional deficits, opening up potential opportunities for future therapeutics development. SIGNIFICANCE STATEMENT Progranulin regulates neuron and immune functions and is implicated in aging. Loss of one functional allele causes haploinsufficiency and leads to frontotemporal lobar degeneration (FTLD), the second leading cause of dementia. Progranulin gene polymorphisms are linked to Alzheimer's disease (AD) and complete loss of function causes neuronal ceroid lipofuscinosis. Despite the critical role of progranulin levels in neurodegenerative disease risk, almost nothing is known about their regulation. We performed an unbiased screen and identified specific pathways controlling progranulin levels in neurons. Modulation of these pathways restored levels in progranulin-deficient neurons and reversed FTLD phenotypes. We provide a new comprehensive understanding of the genetic regulation of progranulin levels and identify potential targets to treat FTLD and other neurodegenerative diseases, including AD., (Copyright © 2019 the authors.)

Decomposing vertebrates, including humans, result in pronounced changes in surrounding soil biogeochemistry, particularly nitrogen (N) and carbon (C) availability, and alter soil micro- and macrofauna. However, the impacts of subsurface human decomposition, where oxygen becomes limited and microbial biomass is generally lower, are far less understood. The goals of this study were to evaluate the impact of human decomposition in a multi-individual, shallow (~70 cm depth) grave on soil biogeochemistry and soil microbial and nematode communities. Three individuals were interred and allowed to decay for four years. Soils were collected from two depths (0‒5 and 30‒35 cm) along linear transects radiating from the grave as well as from within and below (85‒90 cm depth) the grave during excavation to assess how decomposition affects soil properties. Along radiating surface transects, several extracellular enzymes rates and nematode richness increased with increasing distance from the grave, and likely reflect physical site disruption due to grave excavation and infill. There was no evidence of carcass-sourced C and N lateral migration from the grave, at least at 30‒35 cm depth. Within the grave, soils exhibited significant N-enrichment (e.g., ammonium, dissolved organic N), elevated electrical conductivity, and elevated respiration rates with depth. Soil biogeochemistry within the grave, particularly in the middle (30‒35 cm) and base (70‒75 cm depth), was significantly altered by human decomposition. Mean microbial gene abundances changed with depth in the grave, demonstrating increased microbial presence in response to ongoing decomposition. Human-associated Bacteroides were only detected at the base of the grave where anoxic conditions prevailed. Nematode community abundance and richness were reduced at 70‒75 cm and not detectable below 85‒90 cm. Further, we identified certain Plectus spp. as potential indicators of enrichment due to decomposition. Here we demonstrate that human decomposition influences soil biogeochemistry, microbes, and microfauna up to four years after burial., Competing Interests: The affiliation of JD with Bode Cellmark does not alter our adherence to PLOS ONE policies on sharing data and materials.

Progranulin (PGRN), a secreted growth factor, is a key regulator of inflammation and is genetically linked to two common and devastating neurodegenerative diseases. Haploinsufficiency mutations in GRN , the gene encoding PGRN, cause frontotemporal dementia (FTD), and a GRN SNP confers significantly increased risk for Alzheimer's disease (AD). Because cellular and animal data indicate that increasing PGRN can reverse phenotypes of both FTD and AD, modulating PGRN level has been proposed as a therapeutic strategy for both diseases. However, little is known about the regulation of PGRN levels. In this study, we performed an siRNA-based screen of the kinome to identify genetic regulators of PGRN levels in a rodent cell-based model system. We found that knocking down receptor-interacting serine/threonine protein kinase 1 ( Ripk1 ) increased both intracellular and extracellular PGRN protein levels by increasing the translation rate of PGRN without affecting mRNA levels. We observed this effect in Neuro2a cells, wild-type primary mouse neurons, and Grn -haploinsufficient primary neurons from an FTD mouse model. We found that the effect of RIPK1 on PGRN is independent of the kinase activity of RIPK1 and occurs through a novel signaling pathway. These data suggest that targeting RIPK1 may be a therapeutic strategy in both AD and FTD., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Prospective payment arrangements are now the main form of hospital funding in most developed countries. An essential component of such arrangements is the classification system used to differentiate patients according to their expected resource requirements. In this article we describe the evolution and structure of Healthcare Resource Groups (HRGs) in England and the way in which costs are calculated for patients allocated to each HRG. We then describe how payments are made, how policy has evolved to incentivise improvements in quality, and how prospective payment is being applied outside hospital settings.

Background: The Quality and Outcomes Framework (QOF) incentivises general practices in England to provide proactive care for people with serious mental illness (SMI) including schizophrenia, bipolar disorder and other psychoses. Better proactive primary care may reduce the risk of psychiatric admissions to hospital, but this has never been tested empirically., Methods: The QOF data set included 8234 general practices in England from 2006/2007 to 2010/2011. Rates of hospital admissions with primary diagnoses of SMI or bipolar disorder were estimated from national routine hospital data and aggregated to practice level. Poisson regression was used to analyse associations., Results: Practices with higher achievement on the annual review for SMI patients (MH9), or that performed better on either of the two lithium indicators for bipolar patients (MH4 or MH5), had more psychiatric admissions. An additional 1% in achievement rates for MH9 was associated with an average increase in the annual practice admission rate of 0.19% (95% CI 0.10% to 0.28%) or 0.007 patients (95% CI 0.003 to 0.01)., Conclusions: The positive association was contrary to expectation, but there are several possible explanations: better quality primary care may identify unmet need for secondary care; higher QOF achievement may not prevent the need for secondary care; individuals may receive their QOF checks postdischarge rather than prior to admission; individuals with more severe SMI may be more likely to be registered with practices with better QOF performance; and QOF may be a poor measure of the quality of care for people with SMI., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: To test the impact of a UK pay-for-performance indicator, the Quality and Outcomes Framework (QOF) dementia review, on three types of hospital admission for people with dementia: emergency admissions where dementia was the primary diagnosis; emergency admissions for ambulatory care sensitive conditions (ACSCs); and elective admissions for cataract, hip replacement, hernia, prostate disease, or hearing loss., Methods: Count data regression analyses of hospital admissions from 8,304 English general practices from 2006/7 to 2010/11. We identified relevant admissions from national Hospital Episode Statistics and aggregated them to practice level. We merged these with practice-level data on the QOF dementia review. In the base case, the exposure measure was the reported QOF register. As dementia is commonly under-diagnosed, we tested a predicted practice register based on consensus estimates. We adjusted for practice characteristics including measures of deprivation and uptake of a social benefit to purchase care services (Attendance Allowance)., Results: In the base case analysis, higher QOF achievement had no significant effect on any type of hospital admission. However, when the predicted register was used to account for under-diagnosis, a one-percentage point improvement in QOF achievement was associated with a small reduction in emergency admissions for both dementia (-0.1%; P=0.011) and ACSCs (-0.1%; P=0.001). In areas of greater deprivation, uptake of Attendance Allowance was consistently associated with significantly lower emergency admissions. In all analyses, practices with a higher proportion of nursing home patients had significantly lower admission rates for elective and emergency care., Conclusion: In one of three analyses at practice level, the QOF review for dementia was associated with a small but significant reduction in unplanned hospital admissions. Given the rising prevalence of dementia, increasing pressures on acute hospital beds and poor outcomes associated with hospital stays for this patient group, this small change may be clinically and economically relevant.

Background: Chronic plaque psoriasis is the most common type of psoriasis and is characterized by redness, thickness and scaling. First-line management is with topical treatments., Objectives: Our objective was to establish the effectiveness, tolerability and safety of topical treatments for people with chronic plaque psoriasis of the scalp, assessing placebo-controlled trials of all treatments and head-to-head trials that assessed vitamin D analogues., Methods: As part of a Cochrane review of topical treatments for psoriasis, we systematically searched electronic databases for randomized controlled trials. The review included 26 randomized controlled trials of treatments for psoriasis of the scalp with 8020 participants. Trials used several measures to assess changes in psoriasis severity: these were combined using the standardized mean difference metric and interpreted by reporting as a six-point global improvement score., Results: On effectiveness grounds, very potent or potent steroid treatments should be preferred to vitamin D3 analogue with approximately an average 10% additional improvement on a six-point scale. Vitamin D3 analogue combined with potent steroid appears slightly more effective than potent steroid monotherapy (3% additional improvement on a six-point scale). Rates of withdrawal from treatment and adverse events in trials were generally low and similar to those for placebo. There remains uncertainty about the atrophic potential of corticosteroid treatments for scalp psoriasis., Conclusions: Corticosteroids are more effective than vitamin D analogues and similarly tolerated. However, further research is needed to inform long-term maintenance treatment and provide appropriate safety data., (© 2013 The Authors BJD © 2013 British Association of Dermatologists.)

Importance: Azathioprine hypersensitivity syndrome can present clinically and histopathologically like Sweet syndrome. Shared clinical features include fever, constitutional symptoms, prompt response to systemic corticosteroid therapy, neutrophilia, and abrupt onset of erythematous cutaneous lesions. Histologically, both azathioprine hypersensitivity syndrome and Sweet syndrome are rich in neutrophils., Observations: An 81-year-old woman with Crohn disease presented with fever and an acute eruption of plaques on her extremities within 2 weeks of starting treatment with azathioprine. Laboratory evaluation was notable for leukocytosis and neutrophilia. Skin biopsy of an erythematous plaque on the thigh demonstrated a suppurative folliculitis. Azathioprine treatment was discontinued resulting in resolution of the clinical lesions within 5 days. Our case was compared with 18 cases with similar clinical features., Conclusions and Relevance: We report a case of azathioprine hypersensitivity syndrome and review the literature on azathioprine-induced eruptions with features of Sweet syndrome. Our patient's distribution of lesions on the extremities and the finding of suppurative folliculitis on histopathology were not classical for Sweet syndrome. Azathioprine hypersensitivity syndrome seems to be a neutrophil-driven dermatosis; therefore, many overlapping features with Sweet syndrome are not surprising. Due to the potential for anaphylaxis with azathioprine rechallenge, a better term for a Sweetlike presentation in the setting of azathioprine administration is azathioprine hypersensitivity syndrome.

Background: Chronic plaque psoriasis is the most common type of psoriasis, and it is characterised by redness, thickness, and scaling. First-line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar-based preparations, dithranol, salicylic acid, and topical retinoids., Objectives: To compare the effectiveness, tolerability, and safety of topical treatments for chronic plaque psoriasis, relative to placebo, and to similarly compare vitamin D analogues (used alone or in combination) with other topical treatments., Search Methods: We updated our searches of the following databases to February 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2011, Issue 2), MEDLINE (from 1948), EMBASE (from 1980), Science Citation Index (from 2008), Conference Proceedings Citation Index - Science (from 2008), BIOSIS (from 1993), Dissertation Abstracts via DialogClassic (all publication years), and Inside Conferences (all publication years).We identified ongoing and unpublished studies from the UK Clinical Research Network Study Portfolio and the metaRegister of Controlled Trials. We checked the bibliographies of published studies and reviews for further references to relevant trials, and we contacted trialists and companies for information about newly published studies.A separate search for adverse effects was undertaken in February 2011 using MEDLINE and EMBASE (from 2005).Final update searches for both RCTs and adverse effects were undertaken in August 2012. Although it has not been possible to incorporate RCTs and adverse effects studies identified through these final searches within this review, we will incorporate these into the next update., Selection Criteria: Randomised trials comparing active topical treatments against placebo or against vitamin D analogues (used alone or in combination) in people with chronic plaque psoriasis., Data Collection and Analysis: One author extracted study data and assessed study quality. A second author checked these data. We routinely contacted trialists and companies for missing data. We also extracted data on withdrawals and on local and systemic adverse events. We defined long-term trials as those with a duration of at least 24 weeks., Main Results: This update added 48 trials and provided evidence on 7 new active treatments. In total, the review included 177 randomised controlled trials, with 34,808 participants, including 26 trials of scalp psoriasis and 6 trials of inverse psoriasis, facial psoriasis, or both. The number of included studies counted by Review Manager (RevMan) is higher than these figures (190) because we entered each study reporting a placebo and an active comparison into the 'Characteristics of included studies' table as 2 studies.When used on the body, most vitamin D analogues were significantly more effective than placebo, with the standardised mean difference (SMD) ranging from -0.67 (95% CI -1.04 to -0.30; 1 study, 119 participants) for twice-daily becocalcidiol to SMD -1.66 (95% CI -2.66 to -0.67; 1 study, 11 participants) for once-daily paricalcitol. On a 6-point global improvement scale, these effects translate into 0.8 and 1.9 points, respectively. Most corticosteroids also performed better than placebo; potent corticosteroids (SMD -0.89; 95% CI -1.06 to -0.72; I² statistic = 65.1%; 14 studies, 2011 participants) had smaller benefits than very potent corticosteroids (SMD -1.56; 95% CI -1.87 to -1.26); I² statistic = 81.7%; 10 studies, 1264 participants). On a 6-point improvement scale, these benefits equate to 1.0 and 1.8 points, respectively. Dithranol, combined treatment with vitamin D/corticosteroid, and tazarotene all performed significantly better than placebo.Head-to-head comparisons of vitamin D for psoriasis of the body against potent or very potent corticosteroids had mixed findings. For both body and scalp psoriasis, combined treatment with vitamin D and corticosteroid performed significantly better than vitamin D alone or corticosteroid alone. Vitamin D generally performed better than coal tar, but findings relative to dithranol were mixed. When applied to psoriasis of the scalp, vitamin D was significantly less effective than both potent corticosteroids and very potent corticosteroids. Indirect evidence from placebo-controlled trials supported these findings.For both body and scalp psoriasis, potent corticosteroids were less likely than vitamin D to cause local adverse events, such as burning or irritation. Combined treatment with vitamin D/corticosteroid on either the body or the scalp was tolerated as well as potent corticosteroids, and significantly better than vitamin D alone. Only 25 trials assessed clinical cutaneous dermal atrophy; few cases were detected, but trials reported insufficient information to determine whether assessment methods were robust. Clinical measurements of dermal atrophy are insensitive and detect only the most severe cases. No comparison of topical agents found a significant difference in systemic adverse effects., Authors' Conclusions: Corticosteroids perform at least as well as vitamin D analogues, and they are associated with a lower incidence of local adverse events. However, for people with chronic plaque psoriasis receiving long-term treatment with corticosteroids, there remains a lack of evidence about the risk of skin dermal atrophy. Further research is required to inform long-term maintenance treatment and provide appropriate safety data.

Background: Patients with heart failure often receive little supportive or palliative care. 'Better Together' was a 2-year pilot study of a palliative care service for patients with advanced congestive heart failure (CHF)., Objective: To determine if the intervention made it more likely that patients would be cared for and die in their place of choice, and to investigate its cost-effectiveness., Methods: This pragmatic non-randomised pilot evaluation was set in two English primary care trusts (Bradford and Poole). Prospective patient-level data on outcomes and costs were compared with data from a historical control group of clinically comparable patients. Outcomes included death in preferred place of care (available only for the intervention group) and 'hospital admissions averted'. Costs included medical procedures, inpatient care and the direct cost of providing the intervention., Results: 99 patients were referred. Median survival from referral was 48 days in Bradford and 31 days in Poole. Most patients who died did so in their preferred place of death (Bradford 70%, Poole 77%). An estimated 14 and 18 hospital admissions for heart failure were averted in Bradford and Poole, respectively. The average cost-per-heart failure admission averted was £1529 in Bradford, but the intervention was cost saving in Poole. However, there was considerable uncertainty around these cost-effectiveness estimates., Conclusions: This pilot study provides tentative evidence that a collaborative home-based palliative care service for patients with advanced CHF may increase the likelihood of death in place of choice and reduce inpatient admissions. These findings require confirmation using a more robust methodological framework.

A learning healthcare system has emerged as a means of addressing the need to move evidence to the bedside in a manner that is meaningful and efficacious. The advent of electronic healthcare records has translated to massive quantities of clinical data; a learning healthcare system coupled with locally derived clinical rules will push practice-based evidence to the point of care where its application will mean improved quality and patient outcomes.

Background: Mutation in the folliculin gene in Birt-Hogg-Dubé (BHD) syndrome leads to a spectrum of benign tumors of the hair follicle, classically including both fibrofolliculoma and trichodiscoma. In addition, lesions clinically indistinguishable from fibrofolliculoma/ trichodiscoma may show histopathologic findings of perifollicular fibroma or angiofibroma. Although some consider perifollicular fibroma to be a variant of angiofibroma, the specific histopathologic findings of perifollicular fibroma are uncommon., Methods: This is a case series., Results: In 4 patients with multiple facial lesions, recognizing perifollicular fibroma would have been helpful in leading to the diagnosis of BHD syndrome., Conclusion: Perifollicular fibroma is on a spectrum with fibrofolliculoma and trichodiscoma; in a patient with multiple lesions, the diagnosis of perifollicular fibroma is suggestive of BHD syndrome., (Copyright © 2012 John Wiley & Sons A/S.)

The objective of the study was to catalog hair shaft abnormalities in individuals with ectodermal dysplasia (ED) syndromes using light microscopy and to compare findings with those in unaffected controls. Light microscopy was performed in a nonblinded manner on hair shafts from 65 participants with seven types of ED (hypohidrotic ED, ED-ectrodactyly-cleft lip or palate, ankyloblepharon-ectodermal defects-cleft lip and palate, Clouston syndrome, Goltz syndrome, Schopf-Schulz Passarge syndrome, and oculodentodigital dysplasia) and 41 unaffected controls. Hair donations were collected at the 28th Annual National Family Conference held by the National Foundation for Ectodermal Dysplasia. Control participants were recruited from a private dermatology practice and an academic children's hospital outpatient dermatology clinic. Sixty-five affected participants and 41 unaffected controls were included in the analysis. We assessed the hair shafts of ED and control participants for abnormalities visible using LM. Light microscopy identified various pathologic hair shaft abnormalities in each type of ED, although none of the findings were statistically significantly different from those of the control group. Light microscopy is a poor adjuvant tool in the diagnosis of ED syndromes. Most findings are nonspecific and not sufficiently sensitive., (© 2011 Wiley Periodicals, Inc.)

The objective of this paper is to examine how well the QALY captures the health gains generated by cancer treatments, with particular focus on the methods for constructing QALYs preferred by the UK National Institute for Health and Clinical Excellence (NICE). Data were obtained using a keyword search of the MEDLINE database and a hand search of articles written by leading researchers in the subject area (with follow up of the references in these articles). Key arguments were discussed and developed at an oncology workshop in September 2009 at the Office of Health Economics. Three key issues emerged. First, the EQ-5D, NICE's preferred measure of health-related quality of life (QOL) in adults, has been found to be relatively insensitive to changes in health status of cancer patients. Second, the time trade-off, NICE's preferred technique for estimating the values of health states, involves making assumptions that are likely to be violated in end-of-life scenarios. Third, the practice of using valuations of members of the general population, as recommended by NICE, is problematic because such individuals typically display a misunderstanding of what it is really like for patients to live with cancer. Because of the way in which it is constructed, the QALY shows important limitations in terms of its ability to accurately capture the value of the health gains deemed important by cancer patients. A research agenda for addressing these limitations is proposed.

Melanocytic nevi can have a wide range of histologic appearances. Within the spectrum of nevi, there exists a group that presents in certain anatomic locations with histologically worrisome features but nonetheless benign behavior. This group of nevi has been broadly categorized as nevi of special sites. The anatomic locations affected by this group include the embryonic milkline (breast, axillae, umbilicus, genitalia), flexural areas, acral surfaces, ear, and scalp. Nevi in these locations may be mistaken for melanomas because of their histologic appearance, resulting in inappropriate overtreatment of patients. In this article, the authors review the histologic features of these special site nevi and discuss the criteria that help distinguish them from melanoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The key elements of the evaluation process of an evidence-based practice (EBP) program and the infrastructure needed as identified by a large health care organization. The EBP evaluation program has 2 major elements for measuring success. The first component for evaluation is the impact on the clinical outcomes of care and the second is the fiscal implications of implementing the EBP. This article focuses on the fiscal evaluation component and describes a process to calculate the cost of care compared to before and after implementation of the EBP. The literature to support the care calculations is examined and a cost algorithm is described.

Background: The Quality and Outcomes Framework (QOF) is a pioneering attempt to improve the quality of primary care in the UK through the use of financial rewards. Despite its achievements, there are concerns that the QOF may offer poor value for money., Aim: To assess the cost-effectiveness of QOF payments., Design of Study: Economic analysis., Setting: England, UK., Method: Cost-effectiveness evidence was identified for a subset of nine QOF indicators with a direct therapeutic impact. These data were then applied to an analytic framework to determine the conditions under which QOF payments would be cost-effective. This framework was constructed to assess the cost-effectiveness of QOF payments by modelling the incentive structure using cost-effectiveness thresholds of 20 000 and 30 000 UK pounds per quality-adjusted life year (QALY) gained, to represent good value to the NHS. It used 2004/2005 data on the QOF performance of all English primary care practices., Results: Average indicator payments ranged from 0.63 to 40.61 UK pounds per patient, and the percentage of eligible patients treated ranged from 63% to 90%. The proportional changes required for QOF payments to be cost-effective varied widely between the indicators. Although most indicators required only a fraction of a 1% change to be cost-effective, for some indicators improvements in performance of around 20% were needed., Conclusion: For most indicators that can be assessed, QOF incentive payments are likely to be a cost-effective use of resources for a high proportion of primary care practices, even if the QOF achieves only modest improvements in care. However, only a small subset of the indicators has been considered, and no account has been taken of the costs of administering the QOF scheme.

Like other diseases of the follicular occlusion tetrad, acne conglobata can be difficult to treat. We describe the successful use of modern external beam radiation for acne conglobata in the case of a 53-year-old man with long-standing and disfiguring acne conglobata and hidradenitis suppurativa. For patients with severe acne conglobata resistant to more accepted therapies, modern external beam radiation may be a viable alternative on the therapeutic ladder., (Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Melanocytic nevi can have a wide range of histologic appearances. Within the spectrum of nevi, there exists a group that presents in certain anatomic locations with histologically worrisome features but nonetheless benign behavior. This group of nevi has been broadly categorized as nevi of special sites. The anatomic locations affected by this group include the embryonic milkline (breast, axillae, umbilicus, genitalia), flexural areas, acral surfaces, ear, and scalp. Nevi in these locations may be mistaken for melanomas because of their histologic appearance, resulting in inappropriate overtreatment of patients. In this article, the authors review the histologic features of these special site nevi and discuss the criteria that help distinguish them from melanoma., (Copyright © 2009. Published by Elsevier Inc.)

Background: Decision-making processes that determine cancer drug availability vary internationally. The National Institute for Health and Clinical Excellence (NICE) assesses clinical and cost-effectiveness, but recent restrictions on the availability of cancer drugs suggest that NICE may be getting tougher., Objectives: To determine whether NICE is rejecting a higher proportion of cancer drugs and whether the reasons for restricting technologies have changed., Methods: NICE decisions on cancer drugs from May 2000 to October 2008 were classified as 'positive', 'restricted' or 'negative', and decisions taken before and after a change in NICE's appraisal methods in August 2006 were compared. NICE's stated reasons for its restrictions were analysed., Results: Fifty-six cancer drugs in 38 appraisals were analysed. The proportion of 'negative' appraisals increased from 4% in period 1 to 27% in period 2. Findings were similar when analysed by drug assessment (11% versus 26%)., Conclusions: The higher rejection rate for cancer drugs is partly explained by the new appraisal process, but the principal reason for the observed change is the shift from an absence of evidence on cost-effectiveness to evidence of an absence of value-for-money.

Background: Chronic plaque psoriasis is the most common type of psoriasis and is characterised by redness, thickness and scaling. First line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar-based preparations, dithranol, salicylic acid and topical retinoids., Objectives: To compare the effectiveness, tolerability and safety of topical treatments for chronic plaque psoriasis with placebo; to compare vitamin D analogues with other topical treatments., Search Strategy: The Cochrane Skin Group's Trials Register was searched (2004/12). To update an unpublished 2002 review we also searched CENTRAL in The Cochrane Library (Issue 1,2005); MEDLINE (to 2005/02); EMBASE (to 2005/08); Science Citation Index (to 2005); Biosis (to 2005); Dissertation Abstracts (all publication years); Inside Conferences (all publication years); SIGLE (to 2005); National Research Register (all projects with a start date of 2001 to 2005); metaRegister of Current Controlled Trials., Selection Criteria: Randomised trials comparing treatments against placebo or against vitamin D analogues in people with chronic plaque psoriasis., Data Collection and Analysis: One author extracted study data and assessed study quality. A second author checked these data. We routinely contacted triallists and companies for missing data. We extracted data on withdrawals and adverse events., Main Results: The review included 131 RCTs with 21,448 participants. Vitamin D was significantly more effective than placebo, although there was a wide variation in effect size with the standardised mean difference (SMD) ranging from -0.82 (95% CI -1.34 to -0.29) to -1.90 (95% CI -2.09 to -1.71). With one exception, all corticosteroids performed better than placebo, with potent corticosteroids (SMD: -0.95 (95% CI: -1.11 to -0.80; I(2): 61.1%; 17 studies; 2386 participants)) having smaller benefits than very potent corticosteroids (SMD: -1.29 (95% CI: -1.45 to -1.13; I(2): 53.2%; 11 studies; 1571 participants)). Dithranol and tazarotene performed better than placebo. Head-to-head comparisons of vitamin D against potent or very potent corticosteroids found no significant differences. However, combined treatment with vitamin D /corticosteroid performed significantly better than either vitamin D alone or corticosteroid alone. Vitamin D performed better than coal tar, but findings relative to dithranol were mixed. Potent corticosteroids were less likely than vitamin D to cause local adverse events. No comparison of topical agents found a significant difference in systemic adverse effects., Authors' Conclusions: Corticosteroids perform as well as vitamin D analogues and are associated with a lower incidence of local adverse events. Further research is required to inform long-term maintenance treatment.

Primary cutaneous inoculation blastomycosis occurs less commonly than secondary blastomycosis, in which cutaneous lesions most often originate from a primary pulmonary infection which disseminates through the blood or lymphatics to involve the skin. In secondary cutaneous blastomycosis, the primary pulmonary infection is frequently subclinical at the time cutaneous lesions manifest. Here we report two cases that illustrate the difficulty in distinguishing between primary and secondary cutaneous involvement. We also review the expanding literature on blastomycosis since its identification over a century ago.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor commonly used in human immunodeficiency virus-1 multidrug regimens and associated with life-threatening cutaneous reactions. Here, we report the successful use of intravenous immunoglobulin in a pediatric patient with Stevens-Johnson syndrome and highlight the risk of nevirapine usage in human immunodeficiency virus postexposure prophylaxis.

Amyloidosis is a broad and complex class of diseases that comprises several etiologies, many manifestations, and a diversity of outcomes. We discuss a patient with primary systemic amyloidosis associated with multiple myeloma that illustrates many of the typical and atypical features of the disease process. Despite more in-depth assessment and accurate classification, survival for patients with primary systemic disease remains poor.

In Europe, the vast majority of the costs of cancer therapy fall on third-party payers, normally the government, or sickness funds. Therefore, the main focus of cost-effectiveness studies is to assist payers in deciding whether new therapies are worthwhile, despite their high cost. Drug budgets are regulated in most European countries. The main form of central control is price setting, with some form of reference pricing being the most common approach. This sets the price of drugs, either to an international standard, or to a common price for drugs in the same group or cluster. At the hospital level, the main control over cancer drugs is the hospital formulary. Studies have shown a wide variation among European countries in access to cancer drugs. Explanations for these variations include differences in research funding, the drug approval process, the role of health economics in decision making, and budgetary issues. Several countries in Europe now require economic data in making decisions about the reimbursement of new drugs. An examination of decisions made by the National Institute for Health and Clinical Excellence in the United Kingdom suggests that cancer drugs have fared quite well, with most recommendations being positive. This could be because of the seriousness of the health condition and the lack of alternative therapies for some cancer patients. If the policy of requesting cost-effectiveness evidence for pricing and reimbursement decisions becomes more popular, a major implication for the pharmaceutical industry is that studies should be conducted during phase III of clinical development to generate the required data.

Understanding the process by which hybrid incompatibility alleles become established in natural populations remains a major challenge to evolutionary biology. Previously, we discovered a two-locus Dobzhansky-Muller incompatibility that causes severe hybrid male sterility between two inbred lines of the incompletely isolated wildflower species, Mimulus guttatus and M. nasutus. An interspecific cross between these two inbred lines revealed that the M. guttatus (IM62) allele at hybrid male sterility 1 (hms1) acts dominantly in combination with recessive M. nasutus (SF5) alleles at hybrid male sterility 2 (hms2) to cause nearly complete hybrid male sterility. In this report, we extend these genetic analyses to investigate intraspecific variation for the hms1-hms2 incompatibility in natural populations of M. nasutus and M. guttatus, performing a series of interspecific crosses between individuals collected from a variety of geographic locales. Our results suggest that hms2 incompatibility alleles are common and geographically widespread within M. nasutus, but absent or rare in M. guttatus. In contrast, the hms1 locus is polymorphic within M. guttatus and the incompatibility allele appears to be extremely geographically restricted. We found evidence for the presence of the hms1 incompatibility allele in only two M. guttatus populations that exist within a few kilometers of each other. The restricted distribution of the hms1 incompatibility allele might currently limit the potential for the hms1-hms2 incompatibility to act as a species barrier between sympatric populations of M. guttatus and M. nasutus. Extensive sampling within a single M. guttatus population revealed that the hms1 locus is polymorphic and that the incompatibility allele appears to segregate at intermediate frequency, a pattern that is consistent with either genetic drift or natural selection.

Developing from a previous review, this article revisits the generalisability theme to summarise recent advances in methodology and provide an update of challenges faced by producers and users of pharmacoeconomic data. Our original evaluative criteria encompassed technical issues, applicability and transferability. The technical elements of best practice are comparatively uncontroversial: choosing relevant alternatives; transparent reporting of methods and findings; accessing and applying the best-quality evidence; using best methods to synthesise data; and using deterministic sensitivity analysis to explore potential systematic bias whilst employing probabilistic sensitivity analysis to explore the influence of random error at the whole model level. The applicability of economic findings within their original policy context (e.g. national analyses based on generalisable within-country data) can be determined, provided that best practice guidelines for economic modelling are adhered to. The transferability of economic findings (from one policy setting to another, e.g. country, region, clinical setting or patient population) requires careful exploration of changes in resource implications, unit prices and outcomes, a process facilitated again by transparent reporting of methods, adjustment for baseline risk and potentially by recent statistical developments intended to deal with hierarchically structured data. Although there is considerable consensus in the published literature about these key issues, limitations remain for economic analysis as implemented because of its opaqueness of method, failure to reflect the opportunity cost of decisions and lack of societal mandate. If the primary purpose of health economic evaluation is to help society to obtain the best value from limited resources, then, at a time when most technologically advanced societies need to engage with the realities of limited healthcare funding, technocratic solutions alone appear insufficient. Making health economic findings accessible to patients, clinicians and society, in the form of relevant narratives, will help this essential debate and expose assumptions underpinning economic analysis to broader critical inspection.