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No one can tell us—as individuals—how we should feel about environmental harm, be it upset at individual species loss, distress at systemic level change, or deeper existential angst. That universal truism applies as much to us, as scholars, as it does to us as world-citizens. Recognising that environmental harm is increasingly impacting lived experiences, this commentary both argues that we should not only reflect consciously on how this might affect our scholarship, but that we should proactively take steps to improve our mental health and self-care. Written collaboratively by an environmental lawyer and research clinical psychologists, the commentary concludes that acceptance of the challenges confronting us, and that it is all right to be anxious about them in our own lives, will not necessarily make our scholarship any better but it might allow us to avoid unhelpful, artificial, and potentially painful deep-seated, divisions within ourselves.

Background Ambulance off-load delays in transferring patient care to emergency departments (EDs) are increasingly common, but it is unclear whether clinical outcomes are impacted. Methods Population-based cohort study of ambulance attendances for non-traumatic chest pain transported to ED in Victoria, Australia (1/1/2015–30/6/2019) excluding patients transported to hospital with “lights and sirens” or triaged as ED category 1. Multivariable models were used to assess the relationship between ambulance off-load times and 30-day mortality and ambulance re-attendance for chest pain. Results The study included 213,544 ambulance attendances for chest pain (mean age 62 [SD 18] years; 51% female). Median ambulance off-load times increased across the study period from 21 minutes (interquartile range [IQR] 15–30) in 2015 to 24 minutes (IQR 17–37) in 2019. Patients were divided into tertiles according to off-load times with 69,247 patients included in tertile 1 (0–17 minutes), 73,109 patients in tertile 2 (18–28 minutes), and 71,188 patients in tertile 3 (>28 minutes). In multivariable models, ambulance off-load delays were associated with higher unadjusted and adjusted rates of 30-day mortality (1.57% tertile 3 vs. 1.29% tertile 1, adjusted risk difference 0.28% [95% CI 0.16% - 0.42%], p Conclusions Delays in ambulance off-load times appear to be associated with increased mortality and ambulance re-attendance risk among chest pain cohorts. This study has important policy implications given the increasing frequency of off-load delays in many healthcare settings. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Alfred health

Background Previous studies examining temporal variation in cardiovascular care have largely been limited to assessing weekend and after-hours effects whereby those presenting on the weekend or after-hours have a poorer outcome. However, emerging evidence suggests more complex patterns in patterns and outcomes may exist. Purpose We aimed to determine patterns of temporal variation in chest pain presentations and subsequent health-care quality and outcomes. Methods This was an observational, prospective-cohort study of adult patients aged 18 and over who were attended by emergency medical services for non-traumatic chest pain between 1 January 2015 and 30 June 2019 in Victoria, Australia. Major exclusion criteria included pre-hospital diagnosis of ST elevation myocardial infarction or an out of hospital cardiac arrest. The exposure variable was time of day and day of week stratified into 168 hourly time periods. The primary outcome measure was 30-day mortality. Results The study cohort comprised 196,365 ambulance attendances for acute non-traumatic chest pain; mean age 62.4 years (SD 18.3) and 99,497 (50.7%) females. Three temporal patterns were observed for chest pain presentations (Figure 1): (1) a diurnal pattern with a sharp increase in presentations from 8 am, peaking around midday, before decreasing into late evening with a nadir between 3–4 am, (2) a weekend effect where Saturday and Sunday had a relatively lower rate of presentations compared to during the week, and (3) a Monday – Sunday gradient where more presentations were likely earlier in the week, than later. Six patterns were identified across pre-hospital and hospital key performance indicators (KPI) (diurnal, in/after-hours, weekend effect, Monday – Sunday gradient, a peak period and morning vs afternoon/evening effect. Risk of 30-day mortality was associated with weekend presentation (OR 1.15, 95% CI 1.06–1.24, p=0.001) and morning presentation between midnight and midday (OR 1.17, 95% CI 1.09–1.25, p Conclusion Chest pain presentations, care quality and outcomes demonstrate complex temporal variation beyond the already established weekend and after-hours effect. Such relationships should be considered during resource allocation and quality improvement programs in order to improve treatment quality across all days and times of the week. Funding Acknowledgement Type of funding sources: None.

S1.3 Malassezia: genetics, genomics, and biology, September 21, 2022, 11:00 AM - 12:30 PM Objectives Malassezia forms the dominant eukaryotic microbial community on the human skin. The Malassezia genus possesses a repertoire of secretory hydrolytic enzymes involved in protein and lipid metabolism which alter the external cutaneous environment. The exact role of most Malassezia secreted enzymes, including those in interaction with the epithelial surface, is not well characterized. Methods and Results In this study, we compared the expression level of secreted proteases, lipases, phospholipases, and sphingomyelinases of M. globosa in healthy subjects and seborrheic dermatitis or atopic dermatitis patients. We observed upregulated gene expression of the previously characterized secretory aspartyl protease MgSAP1 in both the lesional and non-lesional skin sites of affected compared to healthy subjects. To explore the functional roles of MgSAP1 in skin disease, we generated a knockout mutant of the homologous protease MfSAP1 in the genetically tractable M. furfur. We observed the loss of MfSAP1 resulted in dramatic changes in the cell adhesion and dispersal in both culture and a human 3D reconstituted epidermis model. In a murine model of Malassezia colonization, we further demonstrated MfSAP1 contributes to inflammation as observed by reduced edema and myeloid pustule formation with the knockout mutant versus wildtype. Conclusion Taken together, we show that this dominant secretory M. aspartyl protease has an important role in enabling a planktonic cellular state that can potentially aid in colonization and additionally as a virulence factor in barrier-compromised skin, further highlighting the importance of considering the contextual relevance when evaluating the functions of secreted microbial enzymes.

We report on the discovery and validation of TOI 813b (TIC 55525572 b), a transiting exoplanet identified by citizen scientists in data from NASA's Transiting Exoplanet Survey Satellite (TESS) and the first planet discovered by the Planet Hunters TESS project. The host star is a bright (V = 10.3 mag) subgiant ($R_\star=1.94\,R_\odot$, $M_\star=1.32\,M_\odot$). It was observed almost continuously by TESS during its first year of operations, during which time four individual transit events were detected. The candidate passed all the standard light curve-based vetting checks, and ground-based follow-up spectroscopy and speckle imaging enabled us to place an upper limit of $2 M_{Jup}$ (99 % confidence) on the mass of the companion, and to statistically validate its planetary nature. Detailed modelling of the transits yields a period of $83.8911_{ - 0.0031 } ^ { + 0.0027 }$ days, a planet radius of $6.71 \pm 0.38$ $R_{\oplus}$, and a semi major axis of $0.423_{ - 0.037 } ^ { + 0.031 }$ AU. The planet's orbital period combined with the evolved nature of the host star places this object in a relatively under-explored region of parameter space. We estimate that TOI-813b induces a reflex motion in its host star with a semi-amplitude of $\sim6$ ms$^{-1}$, making this system a promising target to measure the mass of a relatively long-period transiting planet., Accepted for publication in MNRAS (16 pages, 10 figures, 3 tables)

Background The role of skin microbiota in acne remains to be fully elucidated. Initial culture-based investigations were hampered by growth rate and selective media bias. Even with less biased genomic methods, sampling, lysis and methodology, the task of describing acne pathophysiology remains challenging. Acne occurs in sites dominated by Cutibacterium acnes (formerly Propionibacterium acnes) and Malassezia species, both of which can function either as commensal or pathogen. Objectives This article aims to review the current state of the art of the microbiome and acne. Methods The literature regarding the microbiome and acne was reviewed. Results It remains unclear whether there is a quantitative difference in microbial community distribution, making it challenging to understand any community shift from commensal to pathogenic nature. It is plausible that acne involves (i) change in the distribution of species/strains, (ii) stable distribution with pathogenic alteration in response to internal (intermicrobe) or external stimuli (host physiology or environmental) or (iii) a combination of these factors. Conclusions Understanding physiological changes in bacterial species and strains will be required to define their specific roles, and identify any potential intervention points, in acne pathogenesis and treatment. It will also be necessary to determine whether any fungal species are involved, and establish whether they play a significant role. Further investigation using robust, modern analytic tools in longitudinal studies with a large number of participants, may make it possible to determine whether the microbiota plays a causal role, is primarily involved in exacerbation, or is merely a bystander. It is likely that the final outcome will show that acne is the result of complex microbe-microbe and community-host interplay.

α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson’s disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson’s disease, there is evidence that parkin is inactivated in sporadic Parkinson’s disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson’s disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson’s disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s disease and related α-synucleinopathies.

CATH (https://www.cathdb.info) identifies domains in protein structures from wwPDB and classifies these into evolutionary superfamilies, thereby providing structural and functional annotations. There are two levels: CATH-B, a daily snapshot of the latest domain structures and superfamily assignments, and CATH+, with additional derived data, such as predicted sequence domains, and functionally coherent sequence subsets (Functional Families or FunFams). The latest CATH+ release, version 4.3, significantly increases coverage of structural and sequence data, with an addition of 65,351 fully-classified domains structures (+15%), providing 500 238 structural domains, and 151 million predicted sequence domains (+59%) assigned to 5481 superfamilies. The FunFam generation pipeline has been re-engineered to cope with the increased influx of data. Three times more sequences are captured in FunFams, with a concomitant increase in functional purity, information content and structural coverage. FunFam expansion increases the structural annotations provided for experimental GO terms (+59%). We also present CATH-FunVar web-pages displaying variations in protein sequences and their proximity to known or predicted functional sites. We present two case studies (1) putative cancer drivers and (2) SARS-CoV-2 proteins. Finally, we have improved links to and from CATH including SCOP, InterPro, Aquaria and 2DProt.

Proneural transcription factors (TFs) drive highly efficient differentiation of pluripotent stem cells to lineage-specific neurons. However, current strategies mainly rely on genome-integrating viruses. Here, we used synthetic mRNAs coding two proneural TFs (Atoh1 and Ngn2) to differentiate induced pluripotent stem cells (iPSCs) into midbrain dopaminergic (mDA) neurons. mRNAs coding Atoh1 and Ngn2 with defined phosphosite modifications led to higher and more stable protein expression, and induced more efficient neuron conversion, as compared to mRNAs coding wild-type proteins. Using these two modified mRNAs with morphogens, we established a 5-day protocol that can rapidly generate mDA neurons with >90% purity from normal and Parkinson’s disease iPSCs. After in vitro maturation, these mRNA-induced mDA (miDA) neurons recapitulate key biochemical and electrophysiological features of primary mDA neurons and can provide high-content neuron cultures for drug discovery. Proteomic analysis of Atoh1-binding proteins identified the nonmuscle myosin II (NM-II) complex as a new binding partner of nuclear Atoh1. The NM-II complex, commonly known as an ATP-dependent molecular motor, binds more strongly to phosphosite-modified Atoh1 than the wild type. Blebbistatin, an NM-II complex antagonist, and bradykinin, an NM-II complex agonist, inhibited and promoted, respectively, the transcriptional activity of Atoh1 and the efficiency of miDA neuron generation. These findings established the first mRNA-driven strategy for efficient iPSC differentiation to mDA neurons. We further identified the NM-II complex as a positive modulator of Atoh1-driven neuron differentiation. The methodology described here will facilitate the development of mRNA-driven differentiation strategies for generating iPSC-derived progenies widely applicable to disease modeling and cell replacement therapy. Stem Cells Translational Medicine 2019;8:112&12

Objectives To determine whether use of a patient portal during hospitalization is associated with improvement in hospital outcomes, 30-day readmissions, inpatient mortality, and 30-day mortality. Materials and Methods We performed a retrospective propensity score–matched study that included all adult patients admitted to Mayo Clinic Hospital in Jacksonville, Florida, from August 1, 2012, to July 31, 2014, who had signed up for a patient portal account prior to hospitalization (N = 7538). Results Out of the admitted patients with a portal account, 1566 (20.8%) accessed the portal while in the hospital. Compared to patients who did not access the portal, patients who accessed the portal were younger (58.8 years vs 62.3 years), had fewer elective admissions (54.2% vs 64.1%), were more frequently admitted to medical services (45.8% vs 35.2%), and were more likely to have liver disease (21.9% vs 12.9%) and higher disease severity scores (0.653 vs 0.456). After propensity score matching, there was no statistically significant difference between the 2 cohorts with respect to 30-day readmission (P = .13), inpatient mortality (P = .82), or 30-day mortality (P = .082). Conclusion Use of the patient portal in the inpatient setting may not improve hospital outcomes. Future research should examine the association of portal use with more immediate inpatient health outcomes such as patient experience, patient engagement, medication reconciliation, and prevention of adverse events.

Objective To understand the relationship between opioid use in patients with congestive heart failure and outcomes, we compared length of stay (LOS), 30-day readmission rates, and 30- and 90-day mortality in patients discharged with a primary diagnosis of congestive heart failure (CHF) who were taking opioids. Design Retrospective study design. Setting Patients were seen at a 320-bed academic hospital. Subjects All patients not awaiting transplant who were discharged with a primary diagnosis of heart failure from January 1, 2011, through December 31, 2014. Methods Records were reviewed for demographic data, comorbidities, and opioid status at admission or discharge. The association of opioid use (at admission and discharge) with LOS, 30-day readmission, and 30- and 90-day mortality was examined. Results Six hundred eighty-two patients with a principle diagnosis of heart failure were admitted during the study period, with 168 (24.6%) taking opioids at admission. Opioid use at admission was not significantly associated with 30-day readmission (odds ratio [OR] = 1.24, 95% confidence interval [CI] = 0.80-1.93), 30-day mortality (hazard ratio [HR] = 0.91, 95% CI = 0.47-1.78), 90-day mortality (HR = 0.95, 95% CI = 0.58-1.54), or LOS (parameter estimate = -0.21, 95% CI = -0.91 to 0.48). One hundred ninety-three patients (28.3%) were prescribed opioids at discharge. No significant differences were observed between those who were and were not taking opioids at discharge for 30-day readmission (OR = 1.10, 95% CI = 0.72-1.69) or for 30- or 90-day mortality (HR = 0.51, 95% CI = 0.24-1.06, and HR = 0.67, 95% CI = 0.41-1.10, respectively). LOS was slightly shorter for patients not using opioids at discharge than for those who were (mean = 3.8 vs 4.6 days, respectively). Conclusions Opioid use at admission or discharge in patients with CHF did not appear to affect outcomes.

Purpose of the study To reduce the number of unnecessary laboratory tests ordered through a measurement of effects of education and cost awareness on laboratory ordering behaviour by internal medicine residents for common tests, including complete blood cell count (CBC) and renal profile (RP), and to evaluate effects of cost awareness on hospitalisation, 30-day readmission rate and mortality rate. Study design 567 patients admitted during February, March and April 2014 were reviewed as the control group. Total CBC, CBC with differential and RP tests were counted, along with readmission and mortality rates. Interventions were education and visual cost reminders. The same tests were reassessed for 629 patients treated during 12 months after intervention in 2015. Results Data showed a significant increase in CBCs ordered after the intervention (mean number per hospitalisation changed from 1.7 to 2.3 (p Conclusions Education in the form of cost reminders did not significantly reduce the overall ordering of the most common daily laboratory testing in our academic teaching service. We believe further research is needed to fully evaluate the effectiveness of other education forms on the redundant ordering of tests in the hospital setting.

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.

Introduction Self-perceived pornography addiction (SPPA) has increasingly emerged as a concept in research and popular culture, and commentators warn of the reported negative impact that it has. Despite this, “pornography or porn addiction” is not a formally recognized disorder and there is disagreement among researchers regarding its definition or even its existence. Therefore, how SPPA is operationalized often varies, and this is likely to influence the conclusions made about the impact of SPPA. Aim This review aimed to examine what the supposed impact of SPPA is, and how the concept is operationalized. Methods A systematic review of quantitative and qualitative peer-reviewed journal articles was conducted. The following databases were searched up to November 2015: CINAHL (2001–2015), Embase (1974–2015), Medline (1946–2015), PsychARTICLES (1980), and PsychInfo (1806–2015). Terms used were porn*, sexually explicit material, SEM, erotic*, nonparaphilic, cyberpornography, addict*, problematic, excess*, compul*, impul*, impact, effec*, behav*, and cause. An asterisk after a term means that all terms that begin with that root were included in the search. Main Outcome Measures A review of the the current literature pertaining to SPPA and its reported impact. Results We found that SPPA is most frequently operationalized as excessive pornography use and negative consequences. As a result, researchers tended to focus on the frequency of pornography use and related impact as determinants of SPPA. SPPA is reported to affect users and their partners in similar ways, such as increased feelings of isolation and relationship breakdowns. However, we found some methodologic limitations of the primary studies, which limit the strength of the conclusions that can be drawn. Limitations include the lack of representative samples and inadequate measurements of SPPA and its impact. Conclusion There still exist a debate regarding the definition and etiology of SPPA as distinct from self-perceived sex addiction. As such, the research landscape is shaped by different theoretical perspectives. Without evidence to suggest one theoretical position as superior to another, clinicians might be at risk of recommending treatment that is in line with their theoretical perspective (or personal biases) but at odds with the motivations driving an individual to engage in particular sexual behaviors. In light of these findings, the review concludes with recommendations for future research.

Background The Accreditation Council for Graduate Medical Education requires residents to learn and demonstrate proficiency in practice improvement. Quality improvement (QI) projects are a way to improve patient care as well as facilitate education on this core competency. There are inherent barriers to completing these goals in the structure of residency training including rigorous resident schedules and a limited number of projects and resources. Objectives We developed a QI programme using an experiential class project and incorporated it into our Internal Medicine Resident Core Curriculum to improve the residents’ knowledge of QI methods. We assessed the residents’ experience, knowledge and interest in practice and QI subject matter with a survey preimplementation and postimplementation. Methods In 2009, 24 residents in the Internal Medicine resident programme completed a survey measuring their experience, knowledge and interest in QI initiatives. They then completed a QI 1-year programme, with monthly, 1-hour sessions combining didactics and a resident-designed project. At the conclusion of the year, the residents completed the same survey, and the results were compared and analysed. Results Postcurriculum questionnaires revealed residents were more knowledgeable about QI methods, showing improvement in knowledge about institutional-wide QI projects, better preparation for implementing a QI project, and more likely to participate in QI in the future. The project completed was one which improved patients’ knowledge of their anticipated date of discharge from the hospital. Conclusions A class quality project can teach QI to residents incorporating both didactic and practical methods to maximise the experience and minimise the barriers. We found that this method improved residents experience, knowledge and interest in quality initiatives.

Summary Background It has long been known that women lose satisfaction with their hair with ageing. Our data show that caucasian women perceive a decrease in hair amount in their mid 40s with a further decrease in the mid to late 50s, which leads to this dissatisfaction. Neither loss of density (hairs per cm2) nor shaft diameter alone can fully account for this perception. A new metric, ‘hair amount’, is proposed as a quantitative metric combining the impact of both density and diameter on the perception of hair loss. Objectives Creation of a single parameter combining the contribution of diameter and density to perception of female age-related hair loss. Methods In total, 1099 caucasian women (ages 18–66 years) with self-perceived hair loss and 315 caucasian women (ages 17–86 years) with no complaint of hair loss were evaluated. Scalp hair diameter was measured using optical fibre diameter and image analysis. Scalp hair density was measured by phototrichogram with manual or automated counting. Results Parietal scalp hair diameter increased from ages 20 to 40–45 years, then decreased. Hair density was highest in the youngest group, age 20–30 years, and decreased thereafter with increasing rate. In women self-perceiving hair loss, the rate of decrease in density was significantly faster than for women with no self-perception of hair loss. The combined metric ‘hair amount’ was relatively constant at younger ages, increasing very slightly to age 35 years, then decreasing significantly. Conclusions Increasing hair shaft diameter offsets decreasing hair density through the mid 30s. After that, a lower rate of diameter increase combined with the decrease in density begins to significantly impact the perception of hair amount so that thinning becomes increasingly more noticeable in the mid 40s to the mid to late 50s. Quantitative determination of hair amount is a useful tool to combine the contributions of hair density and diameter to women’s perception of age-related hair loss.

Summary Background Many of today’s treatments associated with ‘thinning hair’, such as female pattern hair loss and telogen effluvium, are focused on two of the key aspects of the condition. Over-the-counter or prescription medications are often focused on improving scalp hair density while high-quality cosmetic products work to prevent further hair damage and minimize mid-fibre breakage. Fibre diameter is another key contributor to thinning hair, but it is less often the focus of medical or cosmetic treatments. Objectives To examine the ability of a novel leave-on technology combination [caffeine, niacinamide, panthenol, dimethicone and an acrylate polymer (CNPDA)] to affect the diameter and behaviour of individual terminal scalp hair fibres as a new approach to counteract decreasing fibre diameters. Methods Testing methodology included fibre diameter measures via laser scan micrometer, assessment of fibre mechanical and behavioural properties via tensile break stress and torsion pendulum testing, and mechanistic studies including cryoscanning electron microscopy and autoradiographic analysis. Results CNPDA significantly increased the diameter of individual, existing terminal scalp hair fibres by 2–5 μm, which yields an increase in the cross-sectional area of approximately 10%. Beyond the diameter increase, the CNPDA-thickened fibres demonstrated the altered mechanical properties characteristic of thicker fibres: increased suppleness/pliability (decreased shear modulus) and better ability to withstand force without breaking (increased break stress). Conclusions Although cosmetic treatments will not reverse the condition, this new approach may help to mitigate the effects of thinning hair.

Androgenetic alopecia affects both men and women. In men it produces male pattern hair loss with bitemporal recession and vertex baldness. In women it produces female pattern hair loss (FPHL) with diffuse alopecia over the mid-frontal scalp. FPHL occurs as a result of nonuniform hair follicle miniaturization within follicular units. Diffuse alopecia is produced by a reduction in the number of terminal fibres per follicular unit. Baldness occurs only when all hairs within the follicular units are miniaturized and is a relatively late event in women. The concepts of follicular units and primary and secondary hair follicles within follicular units are well established in comparative mammalian studies, particularly in sheep. However, discovery of these structures in the human scalp hair and investigation of the changes in follicular unit anatomy during the development of androgenetic alopecia have provided a clearer understanding of the early stages of androgenetic alopecia and how the male and female patterns of hair loss are related. FPHL is the most common cause of alopecia in women and approximately one-third of adult caucasian women experience hair loss. The impact of FPHL is predominantly psychological. While men anticipate age-related hair loss, hair loss in women is usually unexpected and unwelcome at any age. Treatment options to arrest hair loss progression and stimulate partial hair regrowth for FPHL include the androgen receptor antagonists spironolactone and cyproterone acetate, the 5α-reductase inhibitor finasteride and the androgen-independent hair growth stimulator minoxidil. These treatments appear to work best when initiated early. Hair transplantation should be considered in advanced FPHL that is resistant to medical treatments. Hair transplantation requires well-preserved hair growth over the occipital donor area. The psychological impact of FPHL may also be reduced by cosmetic products that improve the appearance of the hair. These agents work to minimize hair fibre breakage, improve hair volume or conceal visible bald scalp.

Better Jobs Better Care was the nation's largest single initiative created to reduce the high vacancy and turnover rates of direct care workers and improve workforce quality through both policy and practice changes. In this article, we describe the important role and key characteristics of direct care workers, what motivated the unique partnership between a provider association and a direct care worker advocacy organization to create this initiative, and how the initiative was designed to respond to the key challenges through applied research and demonstration projects. We conclude by discussing how BJBC has influenced providers, policy makers, and direct care workers to think about these frontline caregivers, who are the crux of the long-term care workforce.

Introduction Phosphodiesterase type-5 (PDE-5) inhibitors have previously been evaluated for their efficacy and safety in various clinical trials in men with erectile dysfunction (ED) with or without associated comorbidities. Aim This is the first prospective, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a PDE-5 inhibitor (i.e., vardenafil) in an exclusive population of men with ED and dyslipidemia. Main Outcome Measures Three coprimary efficacy measurements (Sexual Encounter Performance [SEP]2, SEP3, International Index of Erectile Function-Erectile Function [IIEF-EF] domain scores) were used to assess the differential effect of vardenafil vs. placebo in this patient population. Adverse events (AEs) safety data were obtained to compare safety outcomes. Methods This 12-week of randomized, double-blind, placebo-controlled study was conducted in 59 U.S. centers. Patients received either on-demand, flexible-dose vardenafil 10 mg (titrated to 5 mg or 20 mg based upon efficacy and safety) or placebo. Results Of the 712 patients screened and entered into the study, 395 were randomized. Baseline demographics for the intent-to-treat population included: mean age, 54.4 years (±7.5 standard deviation [SD]); 76% Caucasian; mean body mass index (BMI), 31.7 kg/m 2 (±12.7 SD); 47% past/present smoker; and 42% severe ED. Aside from dyslipidemia, other comorbidities included hypertension, 61%; obesity (i.e., BMI ≥ 30), 51%; and type 1 or 2 diabetes, 40%. During the 12-week treatment period, the least squares (LS) adjusted mean success rates in patients on vardenafil vs. placebo were: SEP2, 79.09% vs. 51.92%; and SEP3, 66.69% vs. 33.83% ( P P Conclusions Vardenafil was demonstrated to be safe and effective for managing ED in men with ED and associated dyslipidemia. The results of this study support the role of expanded research on outcomes related to effective ED treatment and aggressive lipid control. Miner M, Gilderman L, Bailen J, Cook D, Dawson K, Stanislaus M, Beresford E, and Barnes A. Vardenafil in men with stable statin therapy and dyslipidemia.

Although ubiquitin-enriched protein inclusions represent an almost invariant feature of neurodegenerative diseases, the mechanism underlying their biogenesis remains unclear. In particular, whether the topology of ubiquitin linkages influences the dynamics of inclusions is not well explored. Here, we report that lysine 48 (K48)- and lysine 63 (K63)-linked polyubiquitination, as well as monoubiquitin modification contribute to the biogenesis of inclusions. K63-linked polyubiquitin is the most consistent enhancer of inclusions formation. Under basal conditions, ectopic expression of K63 mutant ubiquitin in cultured cells promotes the accumulation of proteins and the formation of intracellular inclusions in the apparent absence of proteasome impairment. When co-expressed with disease-associated tau and SOD1 mutants, K63 ubiquitin mutant facilitates the formation of tau- and SOD-1-positive inclusions. Moreover, K63-linked ubiquitination was found to selectively facilitate the clearance of inclusions via autophagy. These data indicate that K63-linked ubiquitin chains may represent a common denominator underlying inclusions biogenesis, as well as a general cellular strategy for defining cargo destined for the autophagic system. Collectively, our results provide a novel mechanistic route that underlies the life cycle of an inclusion body. Harnessing this pathway may offer innovative approaches in the treatment of neurodegenerative disorders.

The human and animal pathogenic yeast genus Malassezia has received considerable attention in recent years from dermatologists, other clinicians, veterinarians and mycologists. Some points highlighted in this review include recent advances in the technological developments related to detection, identification, and classification of Malassezia species. The clinical association of Malassezia species with a number of mammalian dermatological diseases including dandruff, seborrhoeic dermatitis, pityriasis versicolor, psoriasis, folliculitis and otitis is also discussed.

Mutations in parkin are currently recognized as the most common cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for the development of the more common, sporadic form of Parkinson's disease (PD). Supporting this, we have recently demonstrated that parkin solubility in the human brain becomes altered with age. As parkin apparently functions as a broad-spectrum neuroprotectant, the resulting decrease in the availability of soluble parkin with age may underlie the progressive susceptibility of the brain to stress. Interestingly, we also observed that many familial-PD mutations of parkin alter its solubility in a manner that is highly reminiscent of our observations with the aged brain. The converging effects on parkin brought about by aging and PD-causing mutations are probably not trivial and suggest that environmental modulators affecting parkin solubility would increase an individual's risk of developing PD. Using both cell culture and in vivo models, we demonstrate here that several PD-linked stressors, including neurotoxins (MPP+, rotenone, 6-hydroxydopamine), paraquat, NO, dopamine and iron, induce alterations in parkin solubility and result in its intracellular aggregation. Furthermore, the depletion of soluble, functional forms of parkin is associated with reduced proteasomal activities and increased cell death. Our results suggest that exogenously introduced stress as well as endogenous dopamine could affect the native structure of parkin, promote its misfolding, and concomitantly compromise its protective functions. Mechanistically, our results provide a link between the influence of environmental and intrinsic factors and genetic susceptibilities in PD pathogenesis.

Both homozygous (L166P, M26I, deletion) and heterozygous mutations (D149A, A104T) in the DJ-1 gene have been identified in Parkinson's disease (PD) patients. The biochemical function and subcellular localization of DJ-1 protein have not been clarified. To date the localization of DJ-1 protein has largely been described in studies over-expressing tagged DJ-1 protein in vitro. It is not known whether the subcellular localization of over-expressed DJ-1 protein is identical to that of endogenously expressed DJ-1 protein both in vitro and in vivo. To clarify the subcellular localization and function of DJ-1, we generated three highly specific antibodies to DJ-1 protein and investigated the subcellular localization of endogenous DJ-1 protein in both mouse brain tissues and human neuroblastoma cells. We have found that DJ-1 is widely distributed and is highly expressed in the brain. By cell fractionation and immunogold electron microscopy, we have identified an endogenous pool of DJ-1 in mitochondrial matrix and inter-membrane space. To further investigate whether pathogenic mutations might prevent the distribution of DJ-1 to mitochondria, we generated human neuroblastoma cells stably transfected with wild-type (WT) or mutant (M26I, L166P, A104T, D149A) DJ-1 and performed mitochondrial fractionation and confocal co-localization imaging studies. When compared with WT and other mutants, L166P mutant exhibits largely reduced protein level. However, the pathogenic mutations do not alter the distribution of DJ-1 to mitochondria. Thus, DJ-1 is an integral mitochondrial protein that may have important functions in regulating mitochondrial physiology. Our findings of DJ-1's mitochondrial localization may have important implications for understanding the pathogenesis of PD.

Objective: To determine the effect of fibrinogen concentration of dry fibrin bandages on blood loss after grade V liver injury. Methods: Twenty-four pigs were used. Grade V liver injuries were induced and treated with dry fibrin bandages containing 0, 4, 8, or 15 mg fibrinogen/cm 2 . Animals were monitored for 60 minutes. Blood loss, fluid use, hematological data, and hemostasis were assessed. Results: Post-treatment blood losses (mean and 95% confidence interval [CI]) were 1,560 mL (356-6,844), 372 mL (65-2,134), 225 mL (51-992), and 127 mL (22-732) in the 0-, 4-, 8-, and 15-mg groups, respectively. Only the 15-mg group had results significantly lower than the 0-mg group (p < 0.05). Blood loss was negatively related to fibrinogen concentration (p < 0.05). Conclusion: Fibrinogen concentration was inversely related to blood loss after grade V liver injury. The 15-mg formulation was the only one that significantly reduced blood loss.

In skeletal muscle, neuronal nitric oxide synthase (nNOS) is anchored to the sarcolemma via the dystrophin-glycoprotein complex. When dystrophin is absent, as in Duchenne muscular dystrophy patients and in mdx mice, nNOS is mislocalized to the interior of the muscle fiber where it continues to produce nitric oxide. This has led to the hypothesis that free radical toxicity from mislocalized nNOS may contribute to mdx muscle pathology. To test this hypothesis directly, we generated mice devoid of both nNOS and dystrophin. Overall, the nNOS-dystrophin null mice maintained the dystrophic characteristics of mdx mice. We evaluated the mice for several features of the dystrophic phenotype, including membrane damage and muscle morphology. Removal of nNOS did not alter the extent of sarcolemma damage, which is a hallmark of the dystrophic phenotype. Furthermore, muscle from nNOS-dystrophin null mice maintain the histological features of mdx pathology. Our results demonstrate that relocalization of nNOS to the cytosol does not contribute significantly to mdx pathogenesis.

The immunomodulatory effects of low-level, chronic polychlorinated biphenyl PCB; (Aroclor 1254) exposure were investigated in female rhesus (Macaca mulatta) monkeys. Five groups of monkeys (initially 16 monkeys/group) were orally administered PCB at levels of 0, 5, 20, 40 or 80 micrograms/kg body wt/day. Tests for immunomodulation were initiated after 55 months of exposure to PCBs. Statistically significant observed immune changes included a dose-related decrease in the anamnestic (IgM and IgG) response to sheep red blood cells. Conversely, the antibody response to pneumococcus antigen did not differ significantly across the test groups. A statistically significant dose-related decrease in lymphoproliferation was noted with increasing doses of PCBs when phytohemagglutinin and Concanavalin A, but not when pokeweed mitogen, were used as mitogens. A trend toward reduced peak chemiluminescence (mV/min) was observed in zymosan-activated peripheral blood monocytes. The time to peak chemiluminescence of phorbol myristate acetate activation was statistically increased in a dose-response fashion. Flow cytometric analysis results of peripheral blood lymphocytes using the markers CD4, CD8, and CD20 were similar across the test groups. The mean percentage levels for the CD2 marker in the treated groups were statistically lower than the mean in the control, while absolute numbers for CD2 were similar across the test groups. Serum hydrocortisone levels did not differ among the test groups. Taken together these results indicate that low-level, chronic PCB exposure alters a number of rhesus monkey immune system components and that these effects may be due to altered T-cell and/or macrophage function. These data may be of use in extrapolating potential human health effects following chronic PCB exposure.

Answers on p 547. An 84 year old woman was admitted to our acute stroke unit with sudden onset of slurred speech and right sided weakness of six hours’ duration. She gave a history of a previous myocardial infarct, chronic obstructive lung disease, and …

This paper advances previous arguments I have made about assessing the cultural significance of new religious movements (Dawson 1998a, 1998b) using the example of Soka Gakkai. An examination of this Japanese-based, but now world-wide, new religion highlights two things: (I) it denumstrates that there is an intimate relationship between the investigation of the "success" and the "significance" of a new religious movement, though the two concerns are not necessarily linked; adul (2), and it points to the most methodologically sound foci for future research on both topics through the comparative analysis of new religious movements. The success and significance of Soka Gakkai in the West is explained in terms of certain organizational adaptations and the elective affinity of its ethos with the emergent religious sensibilities of advanced industrial societies. Implicit to the study of new religious movements is the assumption that they are somehow of cultural significance, either as individual phenomena or as part of a larger pattern of social development. It is widely recognized, however, that even the most successful new religious movements (hereafter NRMs) are unlikely to achieve a size sufficient to directly influence the development of any Western society in the foreseeable future. Rather, as socially segregated and permitted realms of lifestyle experimentation, the significance of NRMs rests with their potential status as windows into broader patterns of social change. But what kind of change, and how are the different NRMs connected with the patterns of change? Sociologists have been trying to answer these basic questions for some time, acquiring in the process a much better grasp of the forms, functioning, and possible futures of the new religions in our midst (e.g., Bellah 1976; Wilson 1976; Campbell 1978; Stone 1978; Westley 1978; Hunter 1981; Johnson 1981; Robertson, 1985; Robertson and Chirico 1985; Bromley and Busching 1988; Robbins and Bromley 1992; Dawson 1998a and 1998b). But the efforts made to date are still fragmentary and handicapped by an explicit or implicit reliance on the conceptual parameters set by the debate over secularization in Western societies.

Is the emergence of new forms of religious life in North America indicative of significant changes in the nature and role of religion in our society or changes in the character of our culture as a whole ? Calling on a divergent array of theoretical frameworks sociologists have recurrently sought to explain the broader implications of the study of NRMs (New Religious Movements) by aligning them, in whole or in part, with various perceived anti-modernist, modernist, and post-modernist tendencies in our society. In a critical overview of some of this disparate literature, this paper argues that certain unnoticed convergences in the positions taken, point to a reading of the cultural significance of NRMs that transcends the inaccurate tendency to identify NRMs too exclusively with one side of various essentially invidious dichotomies (e.g., pre-modem and modern, anti-modern and modern, conservative and liberal, modern and post-modern)

L'A. demontre les contradictions inherentes aux arguments developpes par R. Otto en faveur de la nature " numineuse " de l'experience religieuse pour mieux faire ressortir ce qui constitue la veritable originalite de sa pensee : l'enracinement de la crainte dans l'experience du " tremendum ". Cette notion a une reelle valeur psychanalytique surtout si l'on reconceptualise l'essai de Freud " Das Unheimliche " (1919) a la lumiere de la psychologie du developpement