Heat shock protein response during fixed intensity and self-paced exercise in the heat in young, healthy women on oral contraceptives compared with young healthy men.

Background: Heat shock proteins respond to a variety of physiological and environmental stresses, including heat stress, ischemia and endotoxic shock. Hormonal changes during the female menstrual cycle can have a thermogenic effect on body temperature. The monophasic oral contraceptive (OC) pill provides low doses of progesterone and oestrogen over the course of the normal menstrual phase. There is little evidence regarding the combined effects of OC on exercise performance and heat stress with respect to heat shock protein response. Objectives: This study aimed to determine the response of heat shock proteins (Hsp72) during fixed-intensity and self-paced exercise in the heat in young, healthy women on oral contraceptives compared with young healthy men. Methods: Sixteen physically active men and women performed 30 min fixed-intensity cycling at 50% of maximum workload, followed by 30 min of a self-paced time trial (TT) interspersed by 30 s maximal sprint at 9, 19 and 29 min respectively. Trials were undertaken in cool (20°C; 48±3% relative humidity (RH)) and warm (32°C; 66±2% RH) ambient conditions. Core (T c) and skin temperature, heart rate (HR) and subjective responses were measured before, during and post exercise. Results: The distance, mean and peak power output, mean and peak speed during the self-paced time trial showed no difference between the ambient temperatures for men and women. Hsp72 in females was higher than males at all sample points at both 20°C and 32°C, except for pre-exercise at 20°C (p< 0.04). Women also attained a higher T c than men at the end of the TT in the heat (38.5°C v 37.9°C for women and men, respectively; p<0.03), higher mean HR and perceived exertion. Conclusion: This study indicates that females who use oral contraceptives (OC) had higher levels of Hsp72 than males when tested under the same environmental conditions.

Assessment and outcomes of firefighter applicants with possible asthma.

BACKGROUND: Firefighter applicants (FFAs) with a history of asthma may be refused entry to the fire service because of potentially putting themselves and others at risk. AIMS: We undertook a service evaluation to identify respiratory and employment outcomes of FFAs with a history of asthma who had undergone additional respiratory assessment at our specialist occupational lung disease clinic during 2005-19. METHODS: We reviewed FFA medical records and categorized them as having either no current asthma or definite/probable asthma at the time of clinic assessment. 'No current asthma' was defined as negative non-specific bronchial hyper-responsiveness (BHR) to histamine/methacholine, and no symptoms or treatment within the 2 years before clinic. 'Definite/probable current asthma' was defined as either positive BHR, or negative BHR with symptoms and/or treatment within the previous 2 years. Around 1 year later, we contacted FFAs to enquire about their application outcome and current respiratory symptoms. RESULTS: Data were available on 116 applicants; of whom, 45% (n = 52) had definite/probable current asthma and were significantly more likely to be older, atopic to common aeroallergens, report atopic disease and have a lower forced expiratory volume in one second/forced vital capacity ratio compared with applicants with no current asthma. Only two individuals' applications were rejected due to asthma. At follow-up, just 2 (2%) of the 90 operational firefighters reported any recent trouble with asthma. CONCLUSIONS: A history of asthma alone is not sufficient to determine current asthma in FFAs. Even with a diagnosis of current asthma, FFAs are mostly successful in their application to join the fire service.

Development and Evaluation of a Prediction Model for Ascertaining Rheumatic Heart Disease Status in Administrative Data.

BACKGROUND: Previous research has raised substantial concerns regarding the validity of the International Statistical Classification of Diseases and Related Health Problems (ICD) codes (ICD-10 I05-I09) for rheumatic heart disease (RHD) due to likely misclassification of non-rheumatic valvular disease (non-rheumatic VHD) as RHD. There is currently no validated, quantitative approach for reliable case ascertainment of RHD in administrative hospital data. METHODS: A comprehensive dataset of validated Australian RHD cases was compiled and linked to inpatient hospital records with an RHD ICD code (2000-2018, n=7555). A prediction model was developed based on a generalized linear mixed model structure considering an extensive range of demographic and clinical variables. It was validated internally using randomly selected cross-validation samples and externally. Conditional optimal probability cutpoints were calculated, maximising discrimination separately for high-risk versus low-risk populations. RESULTS: The proposed model reduced the false-positive rate (FPR) from acute rheumatic fever (ARF) cases misclassified as RHD from 0.59 to 0.27; similarly for non-rheumatic VHD from 0.77 to 0.22. Overall, the model achieved strong discriminant capacity (AUC: 0.93) and maintained a similar robust performance during external validation (AUC: 0.88). It can also be used when only basic demographic and diagnosis data are available. CONCLUSION: This paper is the first to show that not only misclassification of non-rheumatic VHD but also of ARF as RHD yields substantial FPRs. Both sources of bias can be successfully addressed with the proposed model which provides an effective solution for reliable RHD case ascertainment from hospital data for epidemiological disease monitoring and policy evaluation.

Single and mixture per- and polyfluoroalkyl substances accumulate in developing Northern leopard frog brains and produce complex neurotransmission alterations.

Per- and polyfluoroalkyl substances (PFAS) are present in water and >99% of human serum. They are found in brains of wildlife; however, little is known about effects on the developing brain. To determine the effects of PFAS on brain and cardiac innervation, we conducted an outdoor mesocosm experiment with Northern leopard frog larvae (Rana pipiens) exposed to control, 10 ppb perfluorooctane sulfonate (PFOS), or a PFAS mixture totaling 10 ppb that mimicked aqueous film forming foam-impacted surface water (4 ppb PFOS, 3 ppb perfluorohexane sulfonate, 1.25 ppb perfluorooctanoate, 1.25 ppb perfluorohexanoate, and 0.5 ppb perfluoro-n-pentanoate). Water was spiked with PFAS and 25 larvae (Gosner stage (GS) 25) added to each mesocosm (n = 4 mesocosms per treatment). After 30 days, we harvested eight brains per mesocosm and remaining larvae developed to GS 46 (i.e. metamorphosis) before brains and hearts were collected. Weight, length, GS, and time to metamorphosis were recorded. Brain concentrations of all five PFAS were quantified using LC/MS/MS. Dopamine and metabolites, serotonin and its metabolite, norepinephrine, γ-aminobutyric acid, and glutamate were quantified using High Performance Liquid Chromatography with electrochemical detection while acetylcholine and acetylcholinesterase activity were quantified with the Invitrogen Amplex Red Acetylcholine Assay. PFOS accumulated in the brain time- and dose-dependently. After 30 days, the mixture decreased serotonin while both PFAS treatments decreased glutamate. Interestingly, acetylcholine increased in PFAS treatments at GS 46. This research shows that developmental environmentally relevant exposure to PFAS changes neurotransmitters, especially acetylcholine.

Follow-up survey of patients with occupational asthma.

BACKGROUND: Occupational asthma (OA) is often associated with a poor prognosis and the impact of a diagnosis on an individual's career and income can be significant. AIMS: We sought to understand the consequences of a diagnosis of OA to patients attending our clinic. METHODS: Using a postal questionnaire, we surveyed all patients attending our specialist occupational lung disease clinic 1 year after having received a diagnosis of OA due to a sensitizer (n = 125). We enquired about their current health and employment status and impact of their diagnosis on various aspects of their life. Additional information was collected by review of clinical records. RESULTS: We received responses from 71 (57%) patients; 77% were referred by an occupational health (OH) provider. The median duration of symptoms prior to referral was 18 months (interquartile range (IQR) 8-48). At 1 year, 79% respondents were no longer exposed to the causal agent. Whilst the unexposed patients reported an improvement in symptoms compared with those still exposed (82% versus 53%; P = 0.023), they had poorer outcomes in terms of career, income and how they felt treated by their employer; particularly those not currently employed. Almost all (>90%) of those still employed had been referred by an OH provider compared with 56% of those currently unemployed (P = 0.002)x. CONCLUSIONS: The negative impact of OA on people's careers, livelihood and quality of life should not be underestimated. However, with early detection and specialist care, the prognosis is often good and particularly so for those with access to occupational health.

Early removal of catheters in an Enhanced Recovery Pathway (ERP) with intrathecal opioid injection does not affect postoperative urinary outcomes.

BACKGROUND: Postoperative urinary retention (POUR) and catheter-associated urinary tract infections (CAUTI) are associated with significantly longer hospital length-of-stay and increased costs.1 This study investigates the effect of early removal of urinary catheters on POUR and CAUTI in patients undergoing an ERP with a preoperative intrathecal injection. METHODS: Retrospective cohort study of a prospectively maintained database of patients who underwent elective colorectal surgery in an Enhanced Recovery pathway was compared to historical National Surgical Quality Improvement Program cohort of patients. Primary outcomes measured are 30-day POUR and postoperative CAUTI rates. RESULTS: The overall POUR rate of ERP patients compared to non-ERP patients was significantly less (8% vs. 13%, p < 0.05). CAUTI rates were not significantly different between pre-ERP and ERP patients (1.2 vs 2.3%, p = 0.19). CONCLUSIONS: For patients undergoing ERP with a preoperative intrathecal opioid injection, early removal of urinary catheter significantly decreased POUR and did not significantly affect CAUTI rates. SUMMARY: The effect of early removal of urinary catheters on postoperative urinary retention and catheter-associated UTI rates in patients undergoing an ERP with a single preoperative intrathecal opioid injection was studied. Early urinary catheter removal after intrathecal injection was associated with decreased rates of POUR and equivalent CAUTI rates.

Environmental and social determinants of acute rheumatic fever: a longitudinal cohort study.

Acute rheumatic fever (ARF), an auto-immune response to a group A Streptococcus infection and precursor to rheumatic heart disease (RHD), remains endemic in many socio-economically disadvantaged settings. A Global Resolution on ARF and RHD was recently adopted at the 71st World Health Assembly where governments committed to improving efforts to prevent and control ARF and RHD. To inform these efforts, the objectives of this study were to examine associations between childhood ARF in the UK between 1958 and 1969 and a range of environmental and social factors. Of 17 416 children from the nationally representative birth cohort of the National Child Development Study, ARF was reported in 23 children during early childhood (between birth and the 7-year follow-up) and in 29 additional children during middle childhood (between the 7- and 11-year follow-ups). Risk factors associated with ARF in both early and middle childhood were: a large family size; attendance at a private nursery or class; a history of nephritis, kidney or urinary tract infections; and a history of throat or ear infections. Risk factors for ARF in early childhood alone were families with fathers in a professional or semi-professional occupation and families who moved out of their local neighbourhood. Risk factors in late childhood alone included overcrowding and free school meals. These data suggest that prevention strategies in ARF endemic settings may be enhanced by targeting, for example, new members entering a community and children in environments of close contact, such as a nursery or shared bedrooms.

Epidemiology and risk factors for recurrent severe lower limb cellulitis: a longitudinal cohort study.

OBJECTIVE: To describe the epidemiology and risk factors for recurrence of severe lower leg cellulitis (LLC). METHODS: A longitudinal cohort study using state-wide data of adults presenting with recurrent LLC following a primary episode occurring between January 2002 and December 2013. The incidence of recurrent LLC was estimated using the cumulative incidence function, accounting for mortality. Independent risk factors for recurrence were identified using Fine-Gray sub-distribution and Cox proportional hazards models. RESULTS: Of 36 276 patients presenting with their first episode of LLC, 4598 had at least one recurrence during the follow-up period. The cumulative incidence of first, second, and third recurrences at 12 months since previous infection was 6.3% (95% CI 6.0-6.5), 17.2% (95% CI 16.1-18.4), and 29.4% (95% CI 26.8-31.9), respectively, and at 5 years was 13.9% (95% CI 13.5-14.3), 35.9% (95% CI 34.2-37.5), and 52.9% (95% CI 49.5-56.2), respectively. The length of hospitalization increased from 3 days for the primary episode to 4 and 5 days for first and all subsequent recurrences, respectively. Independent risk factors for recurrent LLC included age, ethnicity (Indigenous Australian), local factors relating to lower leg pathology, conditions that commonly result in peripheral oedema, and systemic conditions that may be associated with increased leg size. CONCLUSIONS: LLC recurrences are frequent, and each episode increases the likelihood of subsequent recurrence and length of hospitalization. These data provide context and scope to develop workable and effective strategies to prevent secondary episodes for all cases of primary LLC.

Severe lower limb cellulitis: defining the epidemiology and risk factors for primary episodes in a population-based case-control study.

OBJECTIVE: To describe the epidemiology and risk factors for primary episodes of severe lower leg cellulitis (LLC). METHODS: This was a longitudinal cohort study using state-wide data linkage of adults presenting to Western Australian (WA) hospitals with a first ever LLC from January 2002 to December 2013. The study aimed at determining risk factors, medical records from the index patient, together with comparable data from controls matched by age, sex, postcode, and month of admission. RESULTS: During the period, 36 276 patients presented with their first episode of LLC. The incidence increased by 4.7% per annum, reaching 204.8 (95% CI 198.6-211.1) per 100 000 population by December 2013. Analysis of 29 062 case-control pairs showed several conditions with lower limb pathology were independently associated with LLC, including varicose veins (AOR 2.95, 95% CI 2.50-3.48, p < 0.001), lymphoedema (AOR 2.65, 95% CI 1.71-4.10, p < 0.001), tinea pedis (AOR 3.05, 95% CI 1.45-6.42, p 0.003), and saphenous vein harvest during coronary artery bypass grafting (AOR 1.74, 95% CI 1.32-2.30, p < 0.001). Also associated with LLC was obesity (AOR 2.05, 95% CI 1.82-2.31, p < 0.001), renal disease (AOR 1.28, 95% CI 1.14-1.44, p < 0.001), rheumatologic conditions (AOR 2.12, 95% CI 1.72-2.60, p < 0.001), hemiplegia/paraplegia (AOR 1.31, 95% CI 1.13-1.52, p < 0.001), and liver disease (AOR 1.77, 95% CI 1.51-2.06, p < 0.001). CONCLUSIONS: LLC presents a major burden to the health sector and is increasing with an ageing population. Given the high rates of recurrence, long-term morbidity, and economic impact, efforts to reduce primary episodes should be incorporated into the infectious diseases and healthy ageing research agenda.

Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma

BACKGROUND: The resuscitation of severely injured bleeding patients has evolved into a multi-modal strategy termed damage control resuscitation (DCR). This guideline evaluates several aspects of DCR including the role of massive transfusion (MT) protocols, the optimal target ratio of plasma (PLAS) and platelets (PLT) to red blood cells (RBC) during DCR, and the role of recombinant activated factor VII (rVIIa) and tranexamic acid (TXA). METHODS: Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines (PMG) Section of EAST conducted a systematic review using MEDLINE and EMBASE. Articles in English from1985 through 2015 were considered in evaluating four PICO questions relevant to DCR. RESULT: A total of 37 studies were identified for analysis, of which 31 met criteria for quantitative meta-analysis. In these studies, mortality decreased with use of an MT/DCR protocol vs. no protocol (OR 0.61, 95% CI 0.43-0.87, p = 0.006) and with a high ratio of PLAS:RBC and PLT:RBC (relatively more PLAS and PLT) vs. a low ratio (OR 0.60, 95% CI 0.46-0.77, p < 0.0001; OR 0.44, 95% CI 0.28-0.71, p = 0.0003). Mortality and blood product use were no different with either rVIIa vs. no rVIIa or with TXA vs. no TXA. CONCLUSION: DCR can significantly improve outcomes in severely injured bleeding patients. After a review of the best available evidence, we recommend the use of a MT/DCR protocol in hospitals that manage such patients and recommend that the protocol target a high ratio of PLAS and PLT to RBC. This is best achieved by transfusing equal amounts of RBC, PLAS, and PLT during the early, empiric phase of resuscitation. We cannot recommend for or against the use of rVIIa based on the available evidence. Finally, we conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients.

Morphine addiction in ants: a new model for self-administration and neurochemical analysis.

Conventional definitions of drug addiction are focused on characterizing the neurophysiological and behavioral responses of mammals. Although mammalian models have been invaluable in studying specific and complex aspects of addiction, invertebrate systems have proven advantageous in investigating how drugs of abuse corrupt the most basic motivational and neurochemical systems. It has recently been shown that invertebrates and mammals have remarkable similarities in their behavioral and neurochemical responses to drugs of abuse. However, until now only mammals have demonstrated drug seeking and self-administration without the concurrent presence of a natural reward, e.g. sucrose. Using a sucrose-fading paradigm, followed by a two-dish choice test, we establish ants as an invertebrate model of opioid addiction. The ant species Camponotus floridanus actively seeks and self-administers morphine even in the absence of caloric value or additional natural reward. Using HPLC equipped with electrochemical detection, the neurochemicals serotonin, octopamine and dopamine were identified and subsequently quantified, establishing the concurrent neurochemical response to the opioid morphine within the invertebrate brain. With this study, we demonstrate dopamine to be governing opioid addiction in the brains of ants. Thus, this study establishes ants as the first non-mammalian model of self-administration that is truly analogous to mammals.

Prevalence of sensitization to 'improver' enzymes in UK supermarket bakers.

BACKGROUND: Supermarket bakers are exposed not only to flour and alpha-amylase but also to other 'improver' enzymes, the nature of which is usually shrouded by commercial sensitivity. We aimed to determine the prevalence of sensitization to 'improver' enzymes in UK supermarket bakers. METHODS: We examined the prevalence of sensitization to enzymes in 300 bakers, employed by one of two large supermarket bakeries, who had declared work-related respiratory symptoms during routine health surveillance. Sensitization was determined using radioallergosorbent assay to eight individual enzymes contained in the specific 'improver' mix used by each supermarket. RESULTS: The prevalence of sensitization to 'improver' enzymes ranged from 5% to 15%. Sensitization was far more likely if the baker was sensitized also to either flour or alpha-amylase. The prevalence of sensitization to an 'improver' enzyme did not appear to be related to the concentration of that enzyme in the mix. CONCLUSIONS: We report substantial rates of sensitization to enzymes other than alpha-amylase in UK supermarket bakers; in only a small proportion of bakers was there evidence of sensitization to 'improver mix' enzymes without sensitization to either alpha-amylase or flour. The clinical significance of these findings needs further investigation, but our findings indicate that specific sensitization in symptomatic bakers may not be identified without consideration of a wide range of workplace antigens.

Opsin evolution in the Ambulacraria.

Opsins--G-protein coupled receptors involved in photoreception--have been extensively studied in the animal kingdom. The present work provides new insights into opsin-based photoreception and photoreceptor cell evolution with a first analysis of opsin sequence data for a major deuterostome clade, the Ambulacraria. Systematic data analysis, including for the first time hemichordate opsin sequences and an expanded echinoderm dataset, led to a robust opsin phylogeny for this cornerstone superphylum. Multiple genomic and transcriptomic resources were surveyed to cover each class of Hemichordata and Echinodermata. In total, 119 ambulacrarian opsin sequences were found, 22 new sequences in hemichordates and 97 in echinoderms (including 67 new sequences). We framed the ambulacrarian opsin repertoire within eumetazoan diversity by including selected reference opsins from non-ambulacrarians. Our findings corroborate the presence of all major ancestral bilaterian opsin groups in Ambulacraria. Furthermore, we identified two opsin groups specific to echinoderms. In conclusion, a molecular phylogenetic framework for investigating light-perception and photobiological behaviors in marine deuterostomes has been obtained.

Occupational asthma from tafenoquine in the pharmaceutical industry: implications for QSAR.

We report occupational asthma and rhinitis in a formulation pharmacist, employed in the development of tafenoquine. Tafenoquine is a new anti-malarial drug in development; the pure drug substance has an asthma hazard index of zero and previously was not known to be a respiratory sensitizing agent. The implications of this finding for the refinement of quantitative structural analysis of asthmagenic chemicals are discussed.

Perceptual and cerebro-spinal responses to graded innocuous and noxious stimuli following aerobic exercise.

AIM: The aim of this study was to evaluate the effect of aerobic exercise on perceptual and cerebro-spinal responses to graded electrocutaneous stimuli. METHODS: The design comprised 2 x 30 min of cycling exercise at 30% and 70% of peak oxygen consumption (VO2 peak) on separate occasions in a counter-balanced order in 10 healthy participants. Assessment of nociceptive withdrawal reflex threshold (NWR-T), pain threshold (PT), and somatosensory evoked potentials (SEPs) to graded electrocutaneous stimuli were performed before and after exercise. Perceptual magnitude ratings and SEPs were compared at 30%PT, 60%PT, 100%PT before (Pre), 5 min after (Post1), and 15 min after (Post2) aerobic exercise. RESULTS: There was no difference in the NWR-T and the PT following exercise at 30% and 70% of VO2 peak. ANOVA for the perceptual response within pooled electrocutaneous stimuli show a significant main effect for time (F2,18=5.41, P=0.01) but no difference for exercise intensity (F1,9=0.02, P=0.88). Within-subject contrasts reveal trend differences between 30%PT and 100%PT for Pre-Post1 (P=0.09) and Pre-Post2 (P=0.02). ANOVA for the SEPs peak-to-peak signal amplitude (N1-P1) show significant main effect for time (F2,18=4.04, P=0.04) but no difference for exercise intensity (F1,9=1.83, P=0.21). Pairwise comparisons for time reveal differences between Pre-Post1 (P=0.06) and Pre-Post2 (P=0.01). There was a significant interaction for SEPs N1-P1 between exercise intensity and stimulus intensity (F2,18=3.56, P=0.05). CONCLUSION: These results indicate that aerobic exercise did not increase the electrocutaneous threshold for pain and the NWR-T. Aerobic exercise attenuated perceptual responses to innocuous stimuli and SEPs N1-P1 response to noxious stimuli.

The H1047R point mutation in p110 alpha changes the morphology of human colon HCT116 cancer cells.

The class IA phosphatidylinositol 3-kinases (PI3K) is involved in controlling changes in cell morphology, which is a highly coordinated cellular event. This event is powered by actin filament polymerization and remodeling. The gain-of-function mutations in the catalytic subunit of p110α of class IA PI3K, which occur in up to one-third of human colorectal cancers (CRCs), are capable of causing dysregulation of cell signaling and thus may result in the alteration in cell morphology and motility and in turn cause cancer metastasis. In vivo studies have demonstrated that cell lines bearing the H1047R point mutation, the most frequent cancer-specific mutation in the kinase domain of p110α, are more metastatic than cells carrying wild-type p110α. In the current study, we show that the H1047R in p110α of PI3K decreases F-actin polymerization, increases the formation of filopodia and significantly changes the cell morphology in HCT116 cancer cells. The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), which is also involved in actin polymerization and cell migration, is downregulated by the H1047R mutation in p110α. Our data suggest that the H1047R mutation in PI3K is responsible for the rearrangement of the cytoskeleton, alteration in cell morphology and enhancing cell motility, and that Bcl-2 may be involved in the H1047R mutation-mediated morphological changes and increased migratory capability.