The effects of the atrial natriuretic peptide deficiency on renal cortical mitochondrial bioenergetics in the Dahl SS rat.

Atrial Natriuretic Peptide (ANP) plays an important role in blood pressure regulation. Low levels of ANP correlate with the development of salt-sensitive hypertension (SS-HTN). Our previous studies indicated that ANP deficiency exacerbated renal function decline in SS-HTN. In the heart and fat tissue, ANP was reported to affect lipid peroxidation and mitochondrial bioenergetics but the effects of ANP on mitochondrial function in the kidney are unexplored. We hypothesized that ANP deficiency in SS-HTN causes renal bioenergetic shift, leading to disruption of mitochondrial network and oxidative stress. To address the hypothesis, we placed Dahl SS wild-type (SSWT) and ANP knockout (SSNPPA-/-) rats on 4% NaCl high salt (HS) diet to induce HTN or maintained them on 0.4% NaCl normal salt (NS) diet and assessed mitochondrial bioenergetics and dynamics using spectrofluorimetry, Seahorse assay, electron paramagnetic resonance (EPR) spectroscopy, Western blotting, electron microscopy, PCR and cytokine assays. We report that under high salt conditions, associated with hypertension and renal damage, the SSNPPA-/- rats exhibit a decrease in mitochondrial membrane potential and elevation in mitochondrial ROS levels compared to SSWT. The redox shift is also evident by the presence of more pronounced medullar lipid peroxidation in the SSNPPA-/- strain. We also revealed fragmented, more damaged mitochondria in the SSNPPA-/- rats, accompanied by increased turnover and biogenesis. Overall, our data indicate that ANP deficiency causes disruptions in mitochondrial bioenergetics and dynamics which likely contributes to aggravation of the renal damage and hypertension in the Dahl SS rat; the major pathological effects are evident in the groups subjected to a combined salt and ANP deficiency-induced mitochondrial stress.

ACPSEM position paper: recommendations for a digital general X-ray quality assurance program.

This guideline has been prepared by the ACPSEM to provide a standardised quality assurance program to be used within General X-ray imaging environments. The guideline includes the responsibilities of various multidisciplinary team members within medical imaging facilities. It must be noted that the listed tests and testing frequencies are not intended to replace or become regulatory requirements. Implementing a quality assurance program as outlined in this position paper is there to ensure best practice for imaging facilities by providing a framework to establish and monitor correct equipment performance. The current document has been produced through an extensive review of current international practices and local experience within the Australasian healthcare environment. Due to the constant evolution of digital radiographic equipment, there is no current consensus in international quality assurance guidelines as they continue to be adapted and updated. This document describes the current state of the use of digital General X-ray equipment in the Australasian environment and provides recommendations of test procedures that may be best suited for the current medical imaging climate in Australasia. Due to the everchanging developments in the medical imaging environment and the ability of new technologies to perform more complex tasks it is believed that in the future this document will be further reviewed in the hopes of producing a more globally agreed upon standard quality assurance program. Any such adjustments that are deemed to be necessary to Version 1.0 of this document will be provided in electronic format on the ACPSEM website with a notification to all parties involved in the use of digital General X-ray equipment. This guideline does not provide detailed methodologies for all the quality control tests recommended as it is it is expected that the professionals implementing aspects of this quality assurance program have the working knowledge and access to appropriate resources to develop testing methodologies appropriate for their local imaging environment.

Climate-conscious sedation: how can we sustainably manage dental anxiety using inhalation sedation?

Climate change represents an urgent global threat. Without action, rising temperatures resulting from human activity will increasingly affect our health and wellbeing through changing patterns of disease, extreme weather events and availability of resources. Expedient decarbonisation of the UK economy is an ambitious goal to which we must all contribute.The NHS aims to be the world's first net-zero health service and reach carbon-neutral status by 2040. Dental services are particularly resource-intensive. Some dental anxiety management techniques have a disproportionately high impact on the environment relative to their usage. Inhalation sedation with nitrous oxide is one such example.Nitrous oxide is a greenhouse gas almost 300 times more potent than carbon dioxide, but its utility to facilitate dental treatment for anxious and vulnerable patients is well-documented. This paper balances the health utility with environmental and social harm of continuing to use nitrous oxide and suggests evidence-based methods we can apply to limit the environmental impact of sedation services.

Experience with patient-specific quality assurance of dosimetrist-led online adaptive prostate SBRT.

INTRODUCTION: The aim of this study was to assess the results of the local pre-treatment verifications of online adaptive prostate SBRT plans performed by dosimetrists METHODS AND MATERIALS: Prostate SBRT treatments are planned in our department using an online adaptive method developed and validated by our group. The adaptive plans were computed on the daily CBCT scan using the Acuros XB v. 16.1 algorithm of the Varian Eclipse treatment planning system. Adaptive plans consisted of a single VMAT with 6 MV flattening-filter-free (FFF) energy performed on a Varian TrueBeam linac. Pre-treatment verification of the adaptive "plan-of-the-day" (POD) created in each treatment session was performed using the Mobius 3D v. 3.1 secondary dose calculation program (M3D). Commissioning of M3D included the tuning of the dosimetric leaf gap correction (DLGc) parameter. Generic and specific DLGc values were then derived using a set of plans for typical sites (prostate, head and neck, brain, lung and bone palliative) and another set were determined for specific online SBRT PODs (gDLGc and sDLGc, respectively). The first 50 prostate patients treated with the PACE-B schedule (5 × 7.25 Gy) were included, i.e., 250 adaptive SBRT PODs were collected in this study. For each online adaptive POD, a global 3D gamma comparison between the Eclipse 3D dose and the M3D dose in the patient CBCT was performed. Gamma passing rates (GPRs) for the whole external patient contour (Body) and the PTV were recorded, using the 5 % global /3 mm criteria. The target mean dose and target coverage differences between the Eclipse and M3D doses were also analyzed (ΔDmean and ΔD90 %, respectively). The accuracy of M3D was assessed against PRIMO Monte Carlo software. Twenty-five online prostate SBRT PODs were randomly selected from the set of 250 adaptive plans and simulated with PRIMO. RESULTS: Values of -1 mm and -0.14 mm were found as optimal gDLGc and sDLGc, respectively. Over the 250 online adaptive PODs, excellent GPR values ∼ 100 % were obtained for the Body and PTV structures, regardless the type of DLGc used. The use of the sDLGc instead of the gDLGc provided better results for ΔDmean (0.1 % ± 0.5% vs. -1.9 ± 0.7 %) and ΔD90 % (-1.0 % ± 0.5 %. vs. -3.5 % ± 0.8 %). This issue was also observed when M3D calculations were compared to PRIMO simulations. CONCLUSIONS: M3D can be effectively used for independent pre-treatment verifications of online adaptive prostate SBRT plans. The use of a specific DLGc value is advised for this SBRT online adaptive technique.

Interventions to Reduce Intra-Operative and Post-Operative Pain Associated with Routine Dental Procedures in Children: A Systematic Review and Meta-Analysis.

OBJECTIVE: implementing appropriate pharmacological and non-pharmacological interventions to alleviate pain related to routine dental procedures in paediatric patients could enhance children's ability to manage dental care. The aim of this review was to investigate the effectiveness of and provide recommendations for interventions that can be used to reduce intra-operative and post-operative pain associated with routine paediatric dental procedures. METHODS: A systematic review of randomised controlled clinical trials (RCT) was conducted. Multiple electronic databases were systematically searched. The Cochrane risk-of-bias tool for RCTs was used to evaluate the quality of the included studies. A meta-analysis was performed to determine the effectiveness of the interventions using the Cohen's d standardised mean differences (SMD) and 95% confidence intervals (CIs) for continuous outcomes. The GRADE tool was used to assess the certainty of evidence to make recommendations. RESULTS: The review included forty-five RCTs comprising 3093 children. Thirty-seven RCTs were included in the meta-analysis, which showed the effectiveness of behavioural interventions (SMD = -0.50, 95% CI -0.83 to -0.18), mechanoreceptor and thermal receptor stimulation (SMD = -1.38, 95% CI -2.02 to -0.73) for intra-operative pain, and pre-emptive oral analgesics (SMD = -0.77, 95% CI -1.21 to -0.33) for reducing post-operative pain in children receiving routine dental care. CONCLUSION: The GRADE results for these interventions were strong recommendation (IB) for their use, based on moderate evidence and their benefits far outweighing the harm, and they can be delivered readily with minimal training to reduce the pain experience of paediatric patients.

Expert-level sleep staging using an electrocardiography-only feed-forward neural network.

Reliable classification of sleep stages is crucial in sleep medicine and neuroscience research for providing valuable insights, diagnoses, and understanding of brain states. The current gold standard method for sleep stage classification is polysomnography (PSG). Unfortunately, PSG is an expensive and cumbersome process involving numerous electrodes, often conducted in an unfamiliar clinic and annotated by a professional. Although commercial devices like smartwatches track sleep, their performance is well below PSG. To address these disadvantages, we present a feed-forward neural network that achieves gold-standard levels of agreement using only a single lead of electrocardiography (ECG) data. Specifically, the median five-stage Cohen's kappa is 0.725 on a large, diverse dataset of 5 to 90-year-old subjects. Comparisons with a comprehensive meta-analysis of between-human inter-rater agreement confirm the non-inferior performance of our model. Finally, we developed a novel loss function to align the training objective with Cohen's kappa. Our method offers an inexpensive, automated, and convenient alternative for sleep stage classification-further enhanced by a real-time scoring option. Cardiosomnography, or a sleep study conducted with ECG only, could take expert-level sleep studies outside the confines of clinics and laboratories and into realistic settings. This advancement democratizes access to high-quality sleep studies, considerably enhancing the field of sleep medicine and neuroscience. It makes less-expensive, higher-quality studies accessible to a broader community, enabling improved sleep research and more personalized, accessible sleep-related healthcare interventions.

Are There Sensitive Periods for Skill Development in Male Adolescent Basketball Players?

PURPOSE: Although spurts in physical capacities during adolescence are well known, little is known about the existence of such spurts in sport-specific skill development, especially during the period of rapid growth in stature. Our aims were to examine the timing, intensity, and sequence of basketball-specific skill spurts aligned with biological (years from peak height velocity (PHV)) rather than chronological age. We then defined putative sensitive periods (windows of optimal development) for each skill aligned to the adolescent growth spurt. METHODS: Altogether, 160 adolescent male basketballers aged 11-15 yr were tested biannually over 3 consecutive years. The years from attainment of PHV was estimated, and six skill tests were aligned to each year from PHV in 3-month intervals. Skill velocities were estimated using a nonsmooth polynomial model. RESULTS: Maximal gains in slalom dribble occurred 12 months before PHV attainment (intensity, 0.18 m·s -1 ·yr -1 ), whereas in speed shot shooting (intensity, 9.91 pts·yr -1 ), passing (intensity, 19.13 pts·yr -1 ), and slalom sprint (intensity, 0.19 m·s -1 ·yr -1 ), these skill spurts were attained 6 months before PHV attainment. The mean gains in control dribble (intensity, 0.10 m·s -1 ·yr -1 ) and defensive movement (intensity, 0.12 m·s -1 ·yr -1 ) peaks coincided with attainment of PHV. We identified different sized windows for optimal development for each skill. CONCLUSIONS: Peak spurts in skill development, for most basketball skills, were attained at the same time as PHV. The multiple peaks observed within the defined windows of optimal development suggest that there is room for skill improvement even if gains might be greater earlier rather than later in practice. Our findings highlight the need to make coaches aware of where their players are relative to the attainment of PHV because different skills appear to develop differently relative to PHV. Such knowledge may help in designing more relevant training regimes that incorporate the athlete's current growth status so that skill development can be maximized.

Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury in vivo.

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant Gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected/inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident in vitro that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells in vivo. We discovered that dextrin conjugation effectively reduced colistin's toxicity towards human kidney proximal tubular epithelial cells (HK-2) in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistin's renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs.

Regioselective Fluorohydrin Synthesis from Allylsilanes and Evidence for a Silicon-Fluorine Gauche Effect.

Allylsilanes can be regioselectively transformed into the corresponding 3-silylfluorohydrin in good yield using a sequence of epoxidation followed by treatment with HF·Et3N with or without isolation of the intermediate epoxide. Various silicon-substitutions are tolerated, resulting in a range of 2-fluoro-3-silylpropan-1-ol products from this method. Whereas other fluorohydrin syntheses by epoxide opening using HF·Et3N generally require more forcing conditions (e.g., higher reaction temperature), opening of allylsilane-derived epoxides with this reagent occurs at room temperature. We attribute this rate acceleration along with the observed regioselectivity to a ß-silyl effect that stabilizes a proposed cationic intermediate. The use of enantioenriched epoxides indicates that both SN1- and SN2-type mechanisms may be operable depending on substitution at silicon. Conformational analysis by NMR and theory along with a crystal structure obtained by X-ray diffraction points to a preference for silicon and fluorine to be proximal to one another in the products, perhaps favored due to electrostatic interactions.

Macroscopy of specimens from the head and neck.

Macroscopic examination of surgical resections from the head and neck may be difficult due to the complex anatomy of this area. Recognition of normal anatomical structures is essential for accurate assessment of the extent of a disease process. Communication with the surgical team, correct specimen orientation and sampling are critical for assessment and the importance of radiological and clinical correlation is emphasised. Tumour involvement at each subsite is highlighted with reference to where there are implications on pathological staging and the potential need for adjuvant therapy.

Interventions for managing oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic disease of the oral cavity that causes progressive constriction of the cheeks and mouth accompanied by severe pain and reduced mouth opening. OSF has a significant impact on eating and swallowing, affecting quality of life. There is an increased risk of oral malignancy in people with OSF. The main risk factor for OSF is areca nut chewing, and the mainstay of treatment has been behavioural interventions to support habit cessation. This review is an update of a version last published in 2008. OBJECTIVES: To evaluate the benefits and harms of interventions for the management of oral submucous fibrosis. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 5 September 2022. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) of adults with a biopsy-confirmed diagnosis of OSF treated with systemic, locally delivered or topical drugs at any dosage, duration or delivery method compared against placebo or each other. We considered surgical procedures compared against other treatments or no active intervention. We also considered other interventions such as physiotherapy, ultrasound or alternative therapies. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. participant-reported resumption of normal eating, chewing and speech; 2. change or improvement in maximal mouth opening (interincisal distance); 3. improvement in range of jaw movement; 4. change in severity of oral/mucosal burning pain/sensation; 5. ADVERSE EFFECTS: Our secondary outcomes were 6. quality of life; 7. postoperative discomfort or pain as a result of the intervention; 8. participant satisfaction; 9. hospital admission; 10. direct costs of medication, hospital bed days and any associated inpatient costs for the surgical interventions. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included 30 RCTs (2176 participants) in this updated review. We assessed one study at low risk of bias, five studies at unclear risk of bias and 24 studies at high risk of bias. We found diverse interventions, which we categorised according to putative mechanism of action. We present below our main findings for the comparison 'any intervention compared with placebo or no active treatment' (though most trials included habit cessation for all participants). Results for head-to-head comparisons of active interventions are presented in full in the main review. Any intervention versus placebo or no active treatment Participant-reported resumption of normal eating, chewing and speech No studies reported this outcome. Interincisal distance Antioxidants may increase mouth opening (indicated by interincisal distance (mm)) when measured at less than three months (mean difference (MD) 3.11 mm, 95% confidence interval (CI) 0.46 to 5.77; 2 studies, 520 participants; low-certainty evidence), and probably increase mouth opening slightly at three to six months (MD 8.83 mm, 95% CI 8.22 to 9.45; 3 studies, 620 participants; moderate-certainty evidence). Antioxidants may make no difference to interincisal distance at six-month follow-up or greater (MD -1.41 mm, 95% CI -5.74 to 2.92; 1 study, 90 participants; low-certainty evidence). Pentoxifylline may increase mouth opening slightly (MD 1.80 mm, 95% CI 1.02 to 2.58; 1 study, 106 participants; low-certainty evidence). However, it should be noted that these results are all less than 10 mm, which could be considered the minimal change that is meaningful to someone with oral submucous fibrosis. The evidence was very uncertain for all other interventions compared to placebo or no active treatment (intralesional dexamethasone injections, pentoxifylline, hydrocortisone plus hyaluronidase, physiotherapy). Burning sensation Antioxidants probably reduce burning sensation visual analogue scale (VAS) scores at less than three months (MD -30.92 mm, 95% CI -31.57 to -30.27; 1 study, 400 participants; moderate-certainty evidence), at three to six months (MD -70.82 mm, 95% CI -94.39 to -47.25; 2 studies, 500 participants; moderate-certainty evidence) and at more than six months (MD -27.60 mm, 95% CI -36.21 to -18.99; 1 study, 90 participants; moderate-certainty evidence). The evidence was very uncertain for the other interventions that were compared to placebo and measured burning sensation (intralesional dexamethasone, vasodilators). Adverse effects Fifteen studies reported adverse effects as an outcome. Six of these studies found no adverse effects. One study evaluating abdominal dermal fat graft reported serious adverse effects resulting in prolonged hospital stay for 3/30 participants. There were mild and transient general adverse effects to systemic drugs, such as dyspepsia, abdominal pain and bloating, gastritis and nausea, in studies evaluating vasodilators and antioxidants in particular. AUTHORS' CONCLUSIONS: We found moderate-certainty evidence that antioxidants administered systemically probably improve mouth opening slightly at three to six months and improve burning sensation VAS scores up to and beyond six months. We found only low/very low-certainty evidence for all other comparisons and outcomes. There was insufficient evidence to make an informed judgement about potential adverse effects associated with any of these treatments. There was insufficient evidence to support or refute the effectiveness of the other interventions tested. High-quality, adequately powered intervention trials with a low risk of bias that compare biologically plausible treatments for OSF are needed. It is important that relevant participant-reported outcomes are evaluated.

Community pharmacists' perceptions on managing people with oral health problems-A prioritisation survey.

BACKGROUND: Alternative sources of oral health information are likely to be of benefit to the public, particularly where access to dental services is limited. There is evidence that community pharmacists are willing to advocate for oral health, but it is unclear what is needed to develop this role. OBJECTIVES: The aims of this study were to obtain the views of community pharmacy staff on the frequency and type of oral health conditions they encounter challenges in management and training/research priorities. METHODS: An anonymous online survey targeted pharmacy staff and elicited quantitative data related to the types and frequencies of oral health conditions experienced. Participants were stratified by age, gender, ethnicity, experience and setting. Free text responses allowed participants to detail challenging aspects of patient management, their priorities for service development and future research. Reflexive thematic analysis of free text responses identified key themes. RESULTS: Oral/facial pain and swelling were seen weekly by most respondents, and daily by 28.8%. Other commonly presenting conditions were ulcers, dry-mouth, thrush and denture issues. Challenges in managing oral health conditions included: access to NHS dentistry, awareness of referral pathways, examination/diagnosis and understanding 'Red Flags'. CONCLUSION: Acute and chronic oral health conditions commonly present to community pharmacists who lack necessary knowledge/training, which may result in missing 'red flag' symptoms for oral cancer or acute facial swellings which can be life threatening. There is a need to support pharmacists, who are willing to act as oral health advocates, in recognition, prevention and onward referral for oral diseases.

Blood eosinophil-guided oral prednisolone for COPD exacerbations in primary care in the UK (STARR2): a non-inferiority, multicentre, double-blind, placebo-controlled, randomised controlled trial.

BACKGROUND: Systemic glucocorticoids are recommended for use in chronic obstructive pulmonary disease (COPD) exacerbations; however, there is increased harm associated with their use. We hypothesised that the use of eosinophil biomarker-directed oral prednisolone therapy at the time of an exacerbation of COPD was effective at reducing prednisolone use without affecting adverse outcomes. METHODS: The studying acute exacerbations and response (STARR2) study was a multicentre, randomised, double-blind, placebo-controlled trial conducted in 14 primary care practices in the UK. We included adults (aged ≥40 years), who were current or former smokers (with at least a 10 pack year smoking history) with a diagnosis of COPD, defined as a post-bronchodilator FEV1/forced vital capacity ratio of less than 0·7 previously recorded by the primary care physician, and a history of at least one exacerbation in the previous 12 months requiring systemic corticosteroids with or without antibiotics. All study staff and participants were masked to study group allocation and to treatment allocation. Participants were randomly assigned (1:1) to blood eosinophil-directed treatment (BET; to receive oral prednisolone 30 mg once daily if eosinophil count was high [≥2%] or placebo if eosinophil count was low [<2%]) or to standard care treatment (ST; to receive prednisolone 30 mg once daily irrespective of the point-of-care eosinophil result). Treatment was prescribed for 14 days and all patients also received antibiotics. The primary outcome was the rate of treatment failure, defined as any need for re-treatment with antibiotics or steroids, hospitalisation for any cause, or death, assessed at 30 days after exacerbation in the modified intention-to-treat population. Participants were eligible for re-randomisation at further exacerbations (with a maximum of four exacerbations per participant). A safety analysis was conducted on all randomly assigned participants. Although designed as a superiority trial, after identification of an error in the randomisation code before data lock the study converted to show non-inferiority. An upper margin of 1·105 for the 95% CI was defined as the non-inferiority margin. This study was registered with EudraCT, 2017-001586-24, and is complete. FINDINGS: Between Nov 6, 2017, and April 30, 2020, 308 participants were recruited from 14 general practices. 144 exacerbations (73 in the BET group and 71 in the ST group) from 93 participants (mean age 70 years [range 46-84] and mean percent predicted FEV1 60·9% [SD 19·4]; 52 [56%] male and 41 [44%] female; ethnicity data was not collected]) were included in the modified intention-to-treat analysis. There were 14 (19%) treatment failures at 30 days post-exacerbation in the BET group and 23 (32%) in the ST group; we found a large non-significant estimated effect between BET and ST (RR 0·60 [95% CI 0·33-1·04]; p=0·070) in reducing treatment failures after a COPD exacerbation. The non-inferiority analysis supported that BET was non-inferior to ST. Frequency of adverse events were similar between the study groups; glycosuria (2/102 [2%] in BET group and 1/101 [1%] in the ST group) and hospital admission for COPD exacerbation (2/102 [2%] in BET group and 1/101 [1%] in the ST group) were the two most common adverse events in both groups. No deaths occurred in the study. INTERPRETATION: Blood eosinophil-directed prednisolone therapy at the time of an acute exacerbation of COPD is non-inferior to standard care and can be used to safely reduce systemic glucocorticoid use in clinical practice. FUNDING: National Institute for Health and Care Research.

The relationship between sexual dimorphism and androgen response element proliferation in primate genomes.

In males of many vertebrate species, sexual selection has led to the evolution of sexually dimorphic traits, which are often developmentally controlled by androgen signaling involving androgen response elements (AREs). Evolutionary changes in the number and genomic locations of AREs can modify patterns of receptor regulation and potentially alter gene expression. Here, we use recently sequenced primate genomes to evaluate the hypothesis that the strength of sexual selection is related to the genome-wide number of AREs in a diversifying lineage. In humans, we find a higher incidence of AREs near male-biased genes and androgen-responsive genes when compared with randomly selected genes from the genome. In a set of primates, we find that gains or losses of AREs proximal to genes are correlated with changes in male expression levels and the degree of sex-biased expression of those genes. In a larger set of primates, we find that an increase in one indicator of sexual selection, canine size sexual dimorphism, is correlated with genome-wide ARE counts. Our results suggest that the responsiveness of the genome to androgens in humans and their close relatives has been shaped by sexual selection that arises from competition among males for mating access to females.

Macroscopic examination of pathology specimens: a critical reappraisal.

Meticulous macroscopic examination of specimens and tissue sampling are crucial for accurate histopathology reporting. However, macroscopy has generally received less attention than microscopy and may be delegated to relatively inexperienced practitioners with limited guidance and supervision. This introductory paper in the minisymposium, Macroscopy Under the Microscope, focuses on issues regarding macroscopic examination and tissue sampling that have been insufficiently addressed in the published literature. It highlights the importance of specimen examination and sampling, discusses some general principles, outlines challenges and suggests potential solutions. It is critical to get macroscopy right the first time as it may not be possible to rectify errors even with expert histological assessment or to retrospectively collect missing data after the specimen retention period. Dissectors must, therefore, receive adequate guidance and supervision until they are proficient in macroscopic specimen examination. We emphasise the importance of the clinical context, optimal specimen fixation, succinct and clinically relevant macroscopic descriptions, macrophotography and judicious tissue sampling. We note that current recommendations based on the number of blocks to be submitted per maximum tumour dimension are ambiguous as the amount of tissue submitted in a cassette is not standardised and it is unclear whether 'block' refers to a tissue block or a paraffin block. Concerns around potential oversampling of 'therapeutic' specimens that could result in overdiagnosis due to detection of incidentalomas are also discussed. We hope that the issues discussed in this paper will engender debate on this clinically critical aspect of pathology practice.

Involving young people and parents in decision-making for hypodontia.

Involving young people and their parents in decisions about their health care is ethically and professionally the right thing to do. Good decision-making relies on informed, value-based deliberation. Providing the right treatment for people with hypodontia is complex, both technically, in terms of the range of options available, and from a communication perspective. Treatment decisions faced by young people with hypodontia can have lifelong implications and the weight of this is felt both by the patient, who may have limited experience of dental treatment and decision-making, and their parents, who act as advocates. It is important that clinicians understand how they can best share the available evidence and their expertise in a way that can be understood and applied. Clinicians also have an important role in facilitating young people to recognise and communicate their own values, expectations, and ultimately, preferences for treatment. This paper outlines the challenges of navigating information sharing and engaging in shared decision-making specific to hypodontia. A scoping review of the literature by the authors was conducted to identify evidence-based advice for discussing uncertainties, risks and increasing engagement in decision-making. This may be useful to both primary and secondary care practitioners involved in decision-making with people with hypodontia.

The comparable tumour microenvironment in sporadic and NF2-related schwannomatosis vestibular schwannoma.

Bilateral vestibular schwannoma is the hallmark of NF2-related schwannomatosis, a rare tumour predisposition syndrome associated with a lifetime of surgical interventions, radiotherapy and off-label use of the anti-angiogenic drug bevacizumab. Unilateral vestibular schwannoma develops sporadically in non-NF2-related schwannomatosis patients for which there are no drug treatment options available. Tumour-infiltrating immune cells such as macrophages and T-cells correlate with increased vestibular schwannoma growth, which is suggested to be similar in sporadic and NF2-related schwannomatosis tumours. However, differences between NF2-related schwannomatosis and the more common sporadic disease include NF2-related schwannomatosis patients presenting an increased number of tumours, multiple tumour types and younger age at diagnosis. A comparison of the tumour microenvironment in sporadic and NF2-related schwannomatosis tumours is therefore required to underpin the development of immunotherapeutic targets, identify the possibility of extrapolating ex vivo data from sporadic vestibular schwannoma to NF2-related schwannomatosis and help inform clinical trial design with the feasibility of co-recruiting sporadic and NF2-related schwannomatosis patients. This study drew together bulk transcriptomic data from three published Affymetrix microarray datasets to compare the gene expression profiles of sporadic and NF2-related schwannomatosis vestibular schwannoma and subsequently deconvolved to predict the abundances of distinct tumour immune microenvironment populations. Data were validated using quantitative PCR and Hyperion imaging mass cytometry. Comparative bioinformatic analyses revealed close similarities in NF2-related schwannomatosis and sporadic vestibular schwannoma tumours across the three datasets. Significant inflammatory markers and signalling pathways were closely matched in NF2-related schwannomatosis and sporadic vestibular schwannoma, relating to the proliferation of macrophages, angiogenesis and inflammation. Bulk transcriptomic and imaging mass cytometry data identified macrophages as the most abundant immune population in vestibular schwannoma, comprising one-third of the cell mass in both NF2-related schwannomatosis and sporadic tumours. Importantly, there were no robust significant differences in signalling pathways, gene expression, cell type abundance or imaging mass cytometry staining between NF2-related schwannomatosis and sporadic vestibular schwannoma. These data indicate strong similarities in the tumour immune microenvironment of NF2-related schwannomatosis and sporadic vestibular schwannoma.

Parents, Teachers, and Community: A Team Approach to Developing Physical Competence in Children.

Increasing children's physical activity engagement has short- and long-term health benefits. Developing physical competence is a key component of children's engagement in physical activity. The purpose of our study was to assess if a 12-week home, school, and community-based physical literacy intervention improved the physical competence of children in kindergarten and grade one. Four schools were either assigned to receive the intervention (n = 2 schools) or continue with their usual practice (control sites) (n = 2 schools). Physical competence was evaluated pre- and post-intervention in 103 intervention (41 female) and 83 usual practice (36 female) children using PLAY Fun. PLAY Parent and PLAY Coach tools measured parent and teacher perspectives of children's physical competence, respectively. The intervention effect was assessed with repeated measures MANOVA to evaluate change in physical competence, with alpha set at p < 0.05. Children in both groups improved their locomotor, object control, and overall physical competence (p < 0.05) over the 12-week intervention. There was a significant intervention effect for locomotor and overall physical competence (p < 0.05). Interestingly, parents did not perceive these changes in physical competence (p > 0.05). However, teachers perceived improved physical competence for children in the intervention. Our physical literacy intervention improved the physical competence of children in kindergarten and grade one.

Single Dilation in Primary Inflatable Penile Prosthesis Placement Is Associated With Fewer Corporal Complications Than Sequential Dilation.

OBJECTIVE: To assess the difference in outcomes between single dilation (SingD) and sequential dilation (SeqD) in primary penile implantation, hypothesizing that patients who undergo SeqD had higher rates of noninfectious complications. METHODS: We performed a multicenter, retrospective study of men undergoing primary inflatable penile prosthesis placement. Intraoperative complications and postoperative noninfectious outcomes were assessed between the two groups. Multivariable analysis was performed to identify predictors of complications. RESULTS: A total of 3293 patients met inclusion criteria. After matching, there were 379 patients who underwent SingD and 379 patients who underwent SeqD. There was no significant difference in intraoperative complications between patients who underwent SingD vs SeqD, nor was there any difference in cylinder length (20 cm with interquartile range [IQR] 18-21 cm vs 20 cm with IQR 18-20 cm respectively, P = .4). On multivariable analysis, SeqD (OR 5.23 with IQR 2.74-10, P < .001) and older age (OR 1.04 with IQR 1.01-1.06, P = .007) were predictive of postoperative noninfectious complications. There was no significant difference in intraoperative complications between patients who underwent SingD vs SeqD, nor was there any difference in cylinder length. SeqD and older age were predictive of postoperative noninfectious complications. CONCLUSION: During inflatable penile prosthesis placement in the uncomplicated patient without fibrosis, SingD is a safe technique to utilize during implantation that will minimize postoperative adverse events, and promote device longevity without loss of cylinder length.