Is pelvic ultrasound useful in the clinical assessment and management of women with right iliac fossa pain? A single-centre retrospective study.

INTRODUCTION: Acute right iliac fossa (RIF) pain is a common presenting symptom in surgical patients, with a wide range of differentials, particularly in premenopausal females. This study explores ultrasound usage in the management of women aged 16-55 years presenting with RIF pain. METHODS: A total of 1,082 patients who presented to a tertiary hospital over 12 months were included. Data were collected from patients' electronic records, including initial clinical impression, imaging, management, operative findings, histology and subsequent hospital attendances within 6 weeks and within 6 months. RESULTS: Following clinical assessment, 607 (56%) of patients underwent an ultrasound. Of these, 280 (25.9%) patients received no radiological imaging on initial presentation, and 252 (42%) had pathology identified on ultrasound. The most common finding was an ovarian cyst, closely followed by unexplained free pelvic fluid. Of the 607 patients scanned, 29 (4.8%) had an ultrasound diagnosis of appendicitis; 254 of 1,082 (23.5%) patients underwent operative management. Of the 254 patients who had surgery, 179 (70.5%) had preoperative imaging. Of the 29 (11.4%) cases where the intraoperative finding was gynaecological, 15 (51.7%) cases had not had any preoperative imaging. The negative appendicectomy rate was 21.3% (45/211). Of the 45 patients who had a histologically normal appendix, 22 (48.9%) had not had any previous imaging. Ultrasound had a specificity of 78% for diagnosing appendicitis. CONCLUSIONS: In patients who underwent operative management, a negative finding or finding not requiring surgical management was associated with no preoperative imaging. This supports the use of ultrasound scans as an adjunct in a multimodal approach to the assessment of women presenting with RIF pain.

A Chiral-LC-MS Method for the Simultaneous Quantification of Short-Chain Fatty Acids and D/L-Lactate in the Ruminal Fluid of Dairy Cows.

Short-chain fatty acids (SCFA) and lactate in ruminal fluid are products resulting from the microbial fermentation of substrates and can be used to reflect the composition and activity of the ruminal microbiome. Determination of SCFA and D-/L-lactate in ruminal fluid currently requires two separate protocols, which is time-consuming and costly. In this study, we have optimised and validated a simple and unified 3-nitrophenylhydrazine (3-NPH) derivatisation protocol and a 20 min chiral-LC-MS method for the simultaneous quantification of all SCFA and D- and L-lactate in ruminal fluid. This method, which requires no sample pretreatment or purification shows adequate sensitivity (limit of detection (LOD): 0.01 µg/mL), satisfactory accuracy (recovery: 88-103%), and excellent reproducibility (relative standard deviation (RSD) for repeated analyses < 3% for most analytes). The application of this method to a cohort of 24 animals allowed us to reveal a large inter-cow variation in ruminal SCFA and lactate level, the concentration range for each species, the widespread correlation between different SCFA, and the strong correlation between D- and L-lactate.

Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer.

BACKGROUND: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. PATIENTS AND METHODS: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. RESULTS: A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. CONCLUSIONS: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

Predation risk drives long-term shifts in migratory behaviour and demography in a large herbivore population.

Migration is an adaptive life-history strategy across taxa that helps individuals maximise fitness by obtaining forage and avoiding predation risk. The mechanisms driving migratory changes are poorly understood, and links between migratory behaviour, space use, and demographic consequences are rare. Here, we use a nearly 20-year record of individual-based monitoring of a large herbivore, elk (Cervus canadensis) to test hypotheses for changing patterns of migration in and adjacent to a large protected area in Banff National Park (BNP), Canada. We test whether bottom-up (forage quality) or top-down (predation risk) factors explained trends in (i) the proportion of individuals using 5 different migratory tactics, (ii) differences in survival rates of migratory tactics during migration and whilst on summer ranges, (iii) cause-specific mortality by wolves and grizzly bears, and (iv) population abundance. We found dramatic shifts in migration consistent with behavioural plasticity in individual choice of annual migratory routes. Shifts were inconsistent with exposure to the bottom-up benefits of migration. Instead, exposure to landscape gradients in predation risk caused by exploitation outside the protected area drove migratory shifts. Carnivore exploitation outside the protected area led to higher survival rates for female elk remaining resident or migrating outside the protected area. Cause-specific mortality aligned with exposure to predation risk along migratory routes and summer ranges. Wolf predation risk was higher on migratory routes than summer ranges of montane-migrant tactics, but wolf predation risk traded-off with heightened risk from grizzly bears on summer ranges. A novel eastern migrant tactic emerged following a large forest fire that enhanced forage in an area with lower predation risk outside of the protected area. The changes in migratory behaviour translated to population abundance, where abundance of the montane-migratory tactics declined over time. The presence of diverse migratory life histories maintained a higher total population abundance than would have been the case with only one migratory tactic in the population. Our study demonstrates the complex ways in which migratory populations change over time through behavioural plasticity and associated demographic consequences because of individuals balancing predation risk and forage trade-offs.

Genetic variants associated with hantavirus infection in a reservoir host are related to regulation of inflammation and immune surveillance.

The immunogenetics of wildlife populations influence the epidemiology and evolutionary dynamic of the host-pathogen system. Profiling immune gene diversity present in wildlife may be especially important for those species that, while not at risk of disease or extinction themselves, are host to diseases that are a threat to humans, other wildlife, or livestock. Hantaviruses (genus: Orthohantavirus) are globally distributed zoonotic RNA viruses with pathogenic strains carried by a diverse group of rodent hosts. The marsh rice rat (Oryzomys palustris) is the reservoir host of Orthohantavirus bayoui, a hantavirus that causes fatal cases of hantavirus cardiopulmonary syndrome in humans. We performed a genome wide association study (GWAS) using the rice rat "immunome" (i.e., all exons related to the immune response) to identify genetic variants associated with infection status in wild-caught rice rats naturally infected with their endemic strain of hantavirus. First, we created an annotated reference genome using 10× Chromium Linked Reads sequencing technology. This reference genome was used to create custom baits which were then used to target enrich prepared rice rat libraries (n = 128) and isolate their immunomes prior to sequencing. Top SNPs in the association test were present in four genes (Socs5, Eprs, Mrc1, and Il1f8) which have not been previously implicated in hantavirus infections. However, these genes correspond with other loci or pathways with established importance in hantavirus susceptibility or infection tolerance in reservoir hosts: the JAK/STAT, MHC, and NFκB. These results serve as informative markers for future exploration and highlight the importance of immune pathways that repeatedly emerge across hantavirus systems. Our work aids in creating cross-species comparisons for better understanding mechanisms of genetic susceptibility and host-pathogen coevolution in hantavirus systems.

A Biomechanical Investigation of Cervical Spine Range of Motion for UH-60 Aviators in Real and Simulated Flight Environments.

INTRODUCTION: Military flight surgeons evaluating aviators for flight fitness based on the cervical spine range of motion (CROM) have no operationally relevant reference with which to make a reliable determination. The published physiological limits for the general population do not necessarily apply to military aviators. CROM requirements for rotary-wing aviators would ideally be defined by measurements taken directly within their operational environment. MATERIALS AND METHODS: Nine subjects performed the same predetermined 1-hour flight mission in a UH-60 aircraft and then, at least 2 days later, in the U.S. Army Aeromedical Research Laboratory (USAARL) NUH-60 flight simulator. Head position was recorded using an optical-based inertial tracker attached to the night vision goggle mount of the subjects' flight helmets. Matched-pair t-tests were implemented to compare the maximum CROM between aircraft and simulated flights and the published general population. RESULTS: The percent of flight time in severe flexion and lateral bending was not statistically different (P > 0.05) between real and simulated flights but was statistically lower in the simulator for severe twist rotation (P < 0.05). The maximum CROM for the advanced maneuvers was significantly lower than the norms for the general population (P < 0.05). CONCLUSIONS: The flight simulator could be a useful platform for flight surgeons determining CROM-related flight fitness if methods to increase the frequency of neck twist rotation movements during flight were implemented. The published maximum CROM values for the general population are not an appropriate reference for flight surgeons making flight fitness determinations related to CROM.

Effect of forage type on swallowed bolus mass and a method for counting swallows in dairy cattle.

Dry matter intake (DMI) is a primary determinant of milk production in grazing dairy cows and an ability to measure the DMI of individual cows would allow herd managers to formulate supplementary rations that consider the amount of nutrients ingested from grass. The 2 related aims of this experiment were to define the mean number of swallowed boli and mass of the swallowed boli in Holstein-Friesian dairy cattle offered a variety of forages commonly fed in the dairy industry of southeastern Australia, and to evaluate 2 indirect methods for counting the number of swallows. Twelve ruminally-fistulated, lactating Holstein-Friesian cows were randomly assigned to 3 replicated 4 × 4 Latin square designs and offered 4 forages: fresh chicory (FC), fresh perennial ryegrass (RP), alfalfa hay (AH), and perennial ryegrass silage (RS). The experiment was conducted over 28 d with each of 4 periods consisting of 7 d with 3 d of measurement. Forage diets were offered to individual cows following the partial evacuation of the rumen. The first 20 min after forage was offered constituted the measurement period, during which all swallowed boli were manually captured by samplers who placed their hand through the ruminal fistula and over the cardia entrance of the rumen of each cow. Concurrently, microphones and video cameras were used for the indirect measurement of swallows. The average swallowed bolus mass overall was 17.4 g dry matter (DM) per bolus with the lowest mass observed in cows offered FC (8.9 g DM/bolus), followed by RP (14.9 g DM/bolus), compared with cows offered AH (23.6 g DM/bolus) and RS (22.3 g DM/bolus). The swallowing rate was greater in cows offered FC (78 swallows/20 min) than in cows offered RP, AH, and RS (62.3 swallows/20 min). The audio recording method showed greater concordance (Lin's concordance correlation coefficient = 0.90) with the physical capturing of the boli through the rumen, than the video recording method did (Lin's concordance correlation coefficient = 0.54). It is concluded that the mass of the swallowed boli is related to forage type and that using a microphone attached to the cow's forehead can provide an accurate measure of the number of swallows when verified against the actual number of swallows counted by manual interception of the boli at the rumen cardia.

Body composition, gastrointestinal, and reproductive differences between broiler breeders fed using everyday or skip-a-day rearing programs.

Broiler breeder feed restriction practices have intensified as broiler feed efficiency has been improved. Skip-a-day (SAD) rearing regimen has controlled breeder growth, although this practice has become questionable for the modern breeder. We compared everyday (ED) and SAD programs and evaluated their impact on pullet growth performance, body composition, gastrointestinal tract development, and reproduction. At d 0, Ross 708 (Aviagen) pullet chicks (n = 1,778) were randomly assigned to 7 floor pens. Three pens were fed using the ED and 4 pens with SAD program through wk 21 using a chain-feeder system. ED and SAD grower diets were formulated to be isonutritious, with the only difference that ED diets had more crude fiber. Pullets (n = 44 per pen) were moved to 16 hen pens by treatment at wk 21 with 3 YP males (Aviagen) in each pen. All birds were fed common laying diets. In addition to BW data, sampled pullets and hens were scanned using dual energy X-ray absorptiometry (DEXA) to obtain body bone density and composition. Hen performance and hatchery metrics were recorded through wk 60. ED birds were heavier with similar nutrient intake from wk 10 to 45 (P ≤ 0.013). Pullet uniformity was unaffected by feeding method (P ≥ 0.443). SAD pullets had less body fat at wk 19 (P = 0.034) compared to ED pullets, likely as a metabolic consequence of intermittent feeding. SAD birds had lower bone density at wk 7, 15, and 19 (P ≤ 0.026). At 4 wk of age, SAD pullets had less intestinal villi goblet cells compared to ED pullets (P ≤ 0.050), possibly explained by the effect that feed removal has on cell migration rates. Overall egg-specific gravity (P = 0.057) and hatch of fertile % (P = 0.088) tended to be higher in eggs from ED hens. Altogether, ED feeding increased young pullet intestinal goblet cells and increased both bone density and body fat at wk 19. ED program improved pullet feed conversion (2.6% less feed) and increased eggshell quality and hatch of fertile.

A second-order and slice-specific linear shimming technique to improve spinal cord fMRI.

PURPOSE: To develop a second-order and slice-specific linear shimming technique and investigate its efficiency in the mitigation of signal loss and distortions, and the increase of temporal signal-to-noise ratio (tSNR) within the spinal cord during functional Magnetic Resonance Imaging (fMRI) of the human cervical spinal cord. METHODS: All scans were performed on a General Electric Discovery MR750 3 T scanner, using a head, neck and spine coil and a neurovascular array. To improve B0 homogeneity, a field map was acquired, and second-order shims (SOS) were optimized over manually defined regions of interest (ROIs). Signal loss from dephasing by susceptibility-induced gradients was reduced by optimizing slice-specific x-, y- and z-shims to maximize signal within the spinal cord. Spectral-spatial excitation pulses were used in both the slice-specific linear shimming calibration scan and fMRI acquisitions. The shimming technique's efficiency was initially tested on eight healthy volunteers by comparing tSNR between images acquired with the manufacturer's standard linear shimming and with our SOS and xyz-shimming technique. Subsequently, using an increased spatial resolution as needed for fMRI of the spinal cord, tSNR measurements were performed on resting-state fMRI images from 14 healthy participants. RESULTS: Spinal fMRI images acquired with only the standard linear shimming suffered from severe signal loss below the C5 vertebral level. The developed shimming technique compensated for this loss especially at levels C6 and C7, while tSNR was significantly higher at all vertebral levels with SOS and xyz-shimming than without it. CONCLUSION: A comprehensive shimming approach which includes the use of spectral-spatial excitation pulses along with both second-order and slice-specific linear shim optimization reduces regional signal loss and increases tSNR along the c-spine (C3-C7), improving the ability to record functional signals from the human spinal cord.

Issue 2 - "Update on adverse respiratory effects of indoor air pollution". Part 2): Indoor air pollution and respiratory diseases: Perspectives from Italy and some other GARD countries.

OBJECTIVE: to synthesize the Italian epidemiological contribution to knowledge on indoor pollution respiratory impact, and to analyze the perspective of some GARD countries on the health effects of indoor air pollution. RESULTS: Italian epidemiological analytical studies confirmed a strong relationship between indoor air pollution and health in general population. Environmental tobacco smoke, biomass (wood/coal) fuel for cooking/heating and indoor allergens (house dust mites, cat and dog dander, mold/damp) are the most relevant indoor pollution sources and are related to respiratory and allergic symptoms/diseases in Italy and in other GARD countries such as Mexico, Brazil, Vietnam, India, Nepal and Kyrgyzstan. Community-based global health collaborations are working to improve prevention, diagnosis and care of respiratory diseases around the world, specially in low- and middle-income countries, through research and education. CONCLUSIONS: in the last thirty years, the scientific evidence produced on respiratory health effects of indoor air pollution has been extensive, but the necessity to empower the synergies between scientific community and local administrations remains a challenge to address in order to implement effective interventions. Based on abundant evidence of indoor pollution health effect, WHO, scientific societies, patient organizations and other members of the health community should work together to pursue the GARD vision of "a world where all people breathe freely" and encourage policy makers to increase their engagement in advocacy for clean air.

Single-filament imaging mass spectrometry lipidomics in Arthrospira platensis.

RATIONALE: Elucidating intra-organismal biochemical and lipid organization in photosynthetic biological cell factories of filamentous cyanobacteria, such as Arthrospira platensis (Spirulina), is important for tracking physiological response mechanisms during growth. Little is known about the filaments' biochemical organization and cellular structure and no label-free imaging techniques exist that provide molecular mapping. METHODS: We applied ultrahigh-resolution mass spectrometry (MS) with matrix-assisted laser desorption ionization (MALDI) imaging to immobilized Spirulina filaments to investigate the localization of lipids across distinct physiological regions. We optimized matrix selection and deposition methods with the goal of facilitating high spatial, and intra-filament, resolution using untargeted multivariate statistical spectral deconvolution across MS pixels. RESULTS: Our results demonstrate an improved two-step matrix application with an optimized procedure for intra-organismal lipid profiling to improve analyte sensitivity and achieve higher spatial resolution. We evaluate several conventional matrices, namely 2,5-dihydroxybenzoic acid (DHB), superDHB (sDHB), 1,5-diaminonaphthalene (DAN), and a 50:50 mix of DHB and sDHB, and compare delineation and pixel-based elucidation of intra-filament lipidomics. We identified a total of 1626 features that could be putatively assigned a lipid-like formula based on database query and 46 unique features, with associated lipid assignments that were significantly distinct in their intra-filament location. CONCLUSIONS: MALDI imaging MS with untargeted statistical spectral deconvolution was used to visualize intra-filament lipidomics organization in Spirulina filaments. Improvements in matrix deposition, including sequential sublimation and pneumatic spraying, increased signal abundance at high spatial resolution and allowed for identification of distinct lipid composition regions. This work outlines a methodology that may be used for micro-ecological untargeted molecular phenotyping.

The Effect of Direct-Fed Lactobacillus Species on Milk Production and Methane Emissions of Dairy Cows.

Using direct-fed microbials to mitigate enteric methane emissions could be sustainable and acceptable to both consumers and producers. Forty lactating, multiparous, Holstein-Friesian cows were randomly allocated one of two treatments: (1) a base of ad libitum vetch (Vicia sativa) hay and 7.0 kg DM/d of a grain mix, or (2) the basal diet plus 10 mL of MYLO® (Terragen Biotech Pty Ltd., Coolum Beach, Queensland, Australia) delivering 4.17 × 108 cfu of Lactobacillus per mL. Neither feed intake (25.4 kg/d vs. 24.8 kg/d) nor milk yield (29.9 vs. 30.3 kg/d) were affected by treatment. Feed conversion efficiency was not affected by treatment when expressed on an energy-corrected milk basis (1.15 vs. 1.18 kg/kg DMI). Neither methane yield (31.6 vs. 31.1 g/kg DMI) nor methane intensity (27.1 vs. 25.2 g/kg energy corrected milk) were affected by treatments. While these results are contrary to our expectations and not significant, all were numerically in a favorable direction. Given there are reports that diet and dose rate may impact the size of any effect, we recommend a dose-response study be undertaken using a basal diet that is commonly used in pasture-based dairy systems.

The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein.

Conformational diseases, such as Alzheimer, Parkinson and Huntington diseases, are part of a common class of neurological disorders characterized by the aggregation and progressive accumulation of proteins bearing aberrant conformations. Huntington disease (HD) has autosomal dominant inheritance and is caused by mutations leading to an abnormal expansion in the polyglutamine (polyQ) tract of the huntingtin (HTT) protein, leading to the formation of HTT inclusion bodies in neurons of affected patients. Interestingly, recent experimental evidence is challenging the conventional view by which the disease pathogenesis is solely a consequence of the intracellular accumulation of mutant protein aggregates. These studies reveal that transcellular transfer of mutated huntingtin protein is able to seed oligomers involving even the wild-type (WT) forms of the protein. To date, there is still no successful strategy to treat HD. Here, we describe a novel functional role for the HSPB1-p62/SQSTM1 complex, which acts as a cargo loading platform, allowing the unconventional secretion of mutant HTT by extracellular vesicles. HSPB1 interacts preferentially with polyQ-expanded HTT compared with the WT protein and affects its aggregation. Furthermore, HSPB1 levels correlate with the rate of mutant HTT secretion, which is controlled by the activity of the PI3K/AKT/mTOR signalling pathway. Finally, we show that these HTT-containing vesicular structures are biologically active and able to be internalized by recipient cells, therefore providing an additional mechanism to explain the prion-like spreading properties of mutant HTT. These findings might also have implications for the turn-over of other disease-associated, aggregation-prone proteins.

Dairy Cows Offered Fresh Chicory Instead of Ensiled Pasture during an Acute Heat Challenge Produced More Milk and Had Lower Body Temperatures.

The frequency, duration, and intensity of heat waves in Australia are increasing. To reduce the impact of heat waves on milk production, novel management strategies are required. Altering the forage type and amount offered affect the heat load on dairy cows and offer potential strategies to ameliorate the effects of hot weather. Thirty-two multiparous, lactating Holstein-Friesian cows were assigned one of four dietary treatments: chicory high amount, chicory low amount, pasture silage high amount, or pasture silage low amount. These cows were exposed to a heat wave in controlled-environment chambers. Cows that were offered fresh chicory had similar feed intake to cows that were offered pasture silage (15.3 kg DM/d). However, cows that were offered chicory produced greater energy-corrected milk (21.9 vs. 17.2 kg/d) and had a lower maximum body temperature (39.4 vs. 39.6 °C) than cows that were offered pasture silage overall. Cows that were offered the high amount of forage had greater feed intake (16.5 vs. 14.1 kg DM/d) and energy corrected milk yield (20.0 vs. 17.9 kg/d) than cows that were offered the low amount, as intended, but with no difference in maximum body temperature (39.5 °C). We conclude that feeding chicory instead of pasture silage to dairy cows shows promise as a dietary strategy to ameliorate the effect of heat exposure, and there was no advantage in restricting feed amount.

The therapeutic and commercial landscape of stem cell vesicles in regenerative dermatology.

Extracellular vesicles (EVs) are lipid enveloped nanoparticles that are naturally produced by cells and function in the intercellular transfer of biological material such as proteins, RNAs and metabolites. They have been shown to act in an autocrine and paracrine manner to alter the functions of local and distant recipient cells, with a growing body of evidence highlighting their wide-ranging functions in regenerative processes such as stem cell maintenance, tissue repair and immune modulation. EVs offer several potential advantages over stem cell therapies such as improved safety profiles, scalability, and enhanced storage and quality control of the final product. In fact, many of the pro-regenerative outcomes of stem cell therapies have been attributed to the release of mesenchymal stem cell-derived EVs (MSC-EVs) and their potent effects on extracellular matrix turnover, local cell recruitment, proliferation and angiogenesis is now well described. These positive outcomes have led to clinical trials assessing the safety of MSC-EVs for applications in wound healing and the treatment of cutaneous ulcers, as well as the emergence of multiple commercial MSC-EV sources marketed for topical application in cosmetic medicine. However, regenerative EV therapeutics remain in their infancy and pertinent questions regarding product standardisation, potency and the regulatory landscape surrounding the development of these promising nano-therapeutics must be addressed to ensure safe and effective clinical adoption. In this article we provide an overview of the emerging landscape of MSC-EVs in regenerative dermatology and cosmetic science, highlighting the underlying biological mechanisms pertinent to their application and providing a perspective on current safety considerations, regulation and future directions in the field.

Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

Shark depredation: future directions in research and management.

Shark depredation is a complex social-ecological issue that affects a range of fisheries worldwide. Increasing concern about the impacts of shark depredation, and how it intersects with the broader context of fisheries management, has driven recent research in this area, especially in Australia and the United States. This review synthesises these recent advances and provides strategic guidance for researchers aiming to characterise the occurrence of depredation, identify the shark species responsible, and test deterrent and management approaches to reduce its impacts. Specifically, the review covers the application of social science approaches, as well as advances in video camera and genetic methods for identifying depredating species. The practicalities and considerations for testing magnetic, electrical, and acoustic deterrent devices are discussed in light of recent research. Key concepts for the management of shark depredation are reviewed, with recommendations made to guide future research and policy development. Specific management responses to address shark depredation are lacking, and this review emphasizes that a "silver bullet" approach for mitigating depredation does not yet exist. Rather, future efforts to manage shark depredation must rely on a diverse range of integrated approaches involving those in the fishery (fishers, scientists and fishery managers), social scientists, educators, and other stakeholders.

The incidence and burden of injury in male adolescent community rugby union in Australia.

OBJECTIVES: To describe the incidence, location, mechanism and burden of injury in community male adolescent rugby. METHODS: A prospective cohort injury surveillance study using sports trainers to record 'any physical complaint' over three seasons (2018/2019/2021) in 979 U13-U17 community male rugby union players. RESULTS: One hundred and fifty-two time-loss injuries (27.6/1000 hours) with an associated burden of 2313 days (419.7 days/1000 hours), 169 non-time loss medical attention (30.1/1000 hours) and 813 physical complaints (147.5/1000 hours) were recorded from 5511.7 exposure hours (matches 3932.5 hours, training 1579.2 hours). Time-loss injury incidence was highest in U16 (45/1000 hours) and lowest in U17 (16.6/1000 hours), with U17 significantly lower than U16 and U15 age-grades (p < 0.05). Injury burden was greatest in U13 (561.4 days/1000 hours), and significantly higher than U15 and U17 (p < 0.05). Collectively, injury incidence was greatest for the head/neck (11.8/1000 hours), bruise/contusions were most common (8.7/1000 hours) and concussion (4.5/1000 hours) accounted for the greatest injury burden (102 days/1000 hours). Being tackled was the most observed injury mechanism (10.0/1000 hours). Forwards had significantly higher incidence in mild injury (p < 0.01). The total burden (p < 0.001) associated with mild (p < 0.001) and moderate injuries (p < 0.001) was significantly higher in forwards, as was the burden of being tackled (p < 0.001), collisions (p < 0.001), trunk (p < 0.001) and lower limb (p < 0.01) injury locations. In contrast, ruck-related injury burden was greater in backs (p < 0.001). CONCLUSION: This study showed age-grade and positional differences in incidence and burden of injury in community adolescent rugby union. The rate of non-time loss relative to time-loss injury and muscle strain injury in U13-U14s suggests further research into injury risk and maturation in rugby is needed.

Accuracy and economic evaluation of screening tests for undiagnosed COPD among hypertensive individuals in Brazil.

In Brazil, prevalence of diagnosed COPD among adults aged 40 years and over is 16% although over 70% of cases remain undiagnosed. Hypertension is common and well-recorded in primary care, and frequently co-exists with COPD because of common causes such as tobacco smoking, therefore we conducted a cross-sectional screening test accuracy study in nine Basic Health Units in Brazil, among hypertensive patients aged ≥40 years to identify the optimum screening test/combinations to detect undiagnosed COPD. We compared six index tests (four screening questionnaires, microspirometer and peak flow) against the reference test defined as those below the lower limit of normal (LLN-GLI) on quality diagnostic spirometry, with confirmed COPD at clinical review. Of 1162 participants, 6.8% (n = 79) had clinically confirmed COPD. Peak flow had a higher specificity but lower sensitivity than microspirometry (sensitivity 44.3% [95% CI 33.1, 55.9], specificity 95.5% [95% CI 94.1, 96.6]). SBQ performed well compared to the other questionnaires (sensitivity 75.9% [95% CI 65.0, 84.9], specificity 59.2% [95% CI 56.2, 62.1]). A strategy requiring both SBQ and peak flow to be positive yielded sensitivity of 39.2% (95% CI 28.4, 50.9) and specificity of 97.0% (95% CI 95.7, 97.9). The use of simple screening tests was feasible within the Brazilian primary care setting. The combination of SBQ and peak flow appeared most efficient, when considering performance of the test, cost and ease of use (costing £1690 (5554 R$) with 26.7 cases detected per 1,000 patients). However, the choice of screening tests depends on the clinical setting and availability of resources.ISRCTN registration number: 11377960.