The clinical, imaging, pathological and genetic landscape of bottom-of-sulcus dysplasia.

Bottom-of-sulcus dysplasia (BOSD) is increasingly recognized as a cause of drug-resistant, surgically-remediable, focal epilepsy, often in seemingly MRI-negative patients. We describe the clinical manifestations, morphological features, localization patterns and genetics of BOSD, with the aims of improving management and understanding pathogenesis. We studied 85 patients with BOSD diagnosed between 2005-2022. Presenting seizure and EEG characteristics, clinical course, genetic findings and treatment response were obtained from medical records. MRI (3 T) and 18F-FDG-PET scans were reviewed systematically for BOSD morphology and metabolism. Histopathological analysis and tissue genetic testing were performed in 64 operated patients. BOSD locations were transposed to common imaging space to study anatomical location, functional network localization and relationship to normal MTOR gene expression. All patients presented with stereotyped focal seizures with rapidly escalating frequency, prompting hospitalization in 48%. Despite 42% patients having seizure remissions, usually with sodium channel blocking medications, most eventually became drug-resistant and underwent surgery (86% seizure-free). Prior developmental delay was uncommon but intellectual, language and executive dysfunction were present in 24%, 48% and 29% when assessed preoperatively, low intellect being associated with greater epilepsy duration. BOSDs were missed on initial MRI in 68%, being ultimately recognized following repeat MRI, 18F-FDG-PET or image postprocessing. MRI features were grey-white junction blurring (100%), cortical thickening (91%), transmantle band (62%), increased cortical T1 signal (46%) and increased subcortical FLAIR signal (26%). BOSD hypometabolism was present on 18F-FDG-PET in 99%. Additional areas of cortical malformation or grey matter heterotopia were present in eight patients. BOSDs predominated in frontal and pericentral cortex and related functional networks, mostly sparing temporal and occipital cortex, and limbic and visual networks. Genetic testing yielded pathogenic mTOR pathway variants in 63% patients, including somatic MTOR variants in 47% operated patients and germline DEPDC5 or NPRL3 variants in 73% patients with familial focal epilepsy. BOSDs tended to occur in regions where the healthy brain normally shows lower MTOR expression, suggesting these regions may be more vulnerable to upregulation of MTOR activity. Consistent with the existing literature, these results highlight (i) clinical features raising suspicion of BOSD; (ii) the role of somatic and germline mTOR pathway variants in patients with sporadic and familial focal epilepsy associated with BOSD; and (iii) the role of 18F-FDG-PET alongside high-field MRI in detecting subtle BOSD. The anatomical and functional distribution of BOSDs likely explain their seizure, EEG and cognitive manifestations and may relate to relative MTOR expression.

Health-related quality of life in GALAHAD: A multicenter, open-label, phase 2 study of niraparib for patients with metastatic castration-resistant prostate cancer and DNA-repair gene defects.

BACKGROUND: Niraparib is a highly selective poly (adenosine diphosphateribose) polymerase-1 and poly (adenosine diphosphate-ribose) polymerase-2 inhibitor indicated for select patients with ovarian, fallopian tube, and primary peritoneal cancer. The phase 2 GALAHAD trial (NCT02854436) demonstrated that niraparib monotherapy is tolerable and efficacious in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations, particularly those with breast cancer gene (BRCA) alterations who had progressed on prior androgen signaling inhibitor therapy and taxane-based chemotherapy. OBJECTIVE: To report the prespecified patient-reported outcomes analysis from GALAHAD. METHODS: Eligible patients with alterations to BRCA1 and/or BRCA2 (BRCA cohort) and with pathogenic alterations in other HRR genes (other HRR cohort) were enrolled and received niraparib 300 mg once daily. Patient-reported outcome instruments included the Functional Assessment of Cancer Therapy-Prostate and the Brief Pain Inventory-Short Form. Changes from baseline were compared using a mixed-effect model for repeated measures. RESULTS: On average, health-related quality of life (HRQoL) improved in the BRCA cohort by cycle 3 (mean change = 6.03; 95% CI = 2.76-9.29) and was maintained above baseline until cycle 10 (mean change = 2.84; 95% CI = -1.95 to 7.63), whereas the other HRR cohort showed no early change in HRQoL from baseline (mean change = -0.07; 95% CI = -4.69 to 4.55) and declined by cycle 10 (mean change = -5.10; 95% CI = -15.3 to 5.06). Median time to deterioration in pain intensity and pain interference could not be estimated in either cohort. CONCLUSIONS: Patients with advanced mCRPC and BRCA alterations treated with niraparib experienced more meaningful improvement in overall HRQoL, pain intensity, and pain interference compared with those with other HRR alterations. In this population of castrate, heavily pretreated patients with mCRPC and HRR alterations, stabilization, and improvement in HRQoL may be relevant to consider when making treatment decisions. DISCLOSURES: This work was supported by Janssen Research & Development, LLC (no grant number). Dr Smith has received grants and personal fees from Bayer, Amgen, Janssen, and Lilly; and has received personal fees from Astellas Pharma, Novartis, and Pfizer. Dr Sandhu has received grants from Amgen, Endocyte, and Genentech; has received grants and personal fees from AstraZeneca and Merck; and has received personal fees from Bristol Myers Squibb and Merck Serono. Dr George has received personal fees from the American Association for Cancer Research, Axess Oncology, Capio Biosciences, Constellation Pharma, EMD Serono, Flatiron, Ipsen, Merck Sharp & Dohme, Michael J. Hennessey Association, Millennium Medical Publishing, Modra Pharma, Myovant Sciences, Inc., NCI Genitourinary, Nektar Therapeutics, Physician Education Resource, Propella TX, RevHealth, LLC, and UroGPO; has received grants and personal fees from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, and Pfizer; has received personal fees and nonfinancial support from Bayer and UroToday; has received grants from Calithera and Novartis; and has received grants, personal fees, and nonfinancial support from Exelixis, Inc., Sanofi, and Janssen Pharma. Dr Chi has received grants from Janssen during the conduct of the study; has received grants and personal fees from AstraZeneca, Bayer, Astellas Pharma, Novartis, Pfizer, POINT Biopharma, Roche, and Sanofi; and has received personal fees from Daiichi Sankyo, Merck, and Bristol Myers Squibb. Dr Saad has received grants, personal fees, and nonfinancial support from Janssen during the conduct of the study; and has received grants, personal fees, and nonfinancial support from AstraZeneca, Astellas Pharma, Pfizer, Bayer, Myovant, Sanofi, and Novartis. Dr Thiery-Vuillemin has received grants, personal fees, and nonfinancial support from Pfizer; has received personal fees and nonfinancial support from AstraZeneca, Janssen, Ipsen, Roche/Genentech, Merck Sharp & Dohme, and Astellas Pharma; and has received personal fees from Sanofi, Novartis, and Bristol Myers Squibb. Dr Olmos has received grants, personal fees, and nonfinancial support from AstraZeneca, Bayer, Janssen, and Pfizer; has received personal fees from Clovis, Daiichi Sankyo, and Merck Sharp & Dohme; and has received nonfinancial support from Astellas Pharma, F. Hoffman-LaRoche, Genentech, and Ipsen. Dr Danila has received research support from the US Department of Defense, the American Society of Clinical Oncology, the Prostate Cancer Foundation, Stand Up to Cancer, Janssen Research & Development, Astellas Pharma, Medivation, Agensys, Genentech, and CreaTV. Dr Gafanov has received grants from Janssen during the conduct of the study. Dr Castro has received grants from Janssen during the conduct of the study; has received grants and personal fees from Janssen, Bayer, AstraZeneca, and Pfizer; and has received personal fees from Astellas Pharma, Merck Sharp & Dohme, Roche, and Clovis. Dr Moon has received research funding from SeaGen, HuyaBio, Janssen, BMS, Aveo, Xencor, and has received personal fees from Axess Oncology, MJH, EMD Serono, and Pfizer. Dr Joshua has received nonfinancial support from Janssen; consulted or served in an advisory role for Neoleukin, Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Noxopharm, IQvia, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, and Eisai; and received research funding from Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, MacroGenics, Lilly, Pfizer, AstraZeneca, and Corvus Pharmaceuticals. Drs Mason, Liu, Bevans, Lopez-Gitlitz, and Francis and Mr Espina are employees of Janssen Research & Development. Dr Mason owns stocks with Janssen. Dr Fizazi has participated in advisory boards and talks for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, and Sanofi, with honoraria to his institution (Institut Gustave Roussy); has participated in advisory boards for, with personal honoraria from, Arvinas, CureVac, MacroGenics, and Orion. Study registration number: NCT02854436.

Obtaining medication histories via telepharmacy: an observational study.

BACKGROUND: Medication reconciliation is an effective strategy to reduce medication errors upon hospital admission. The process involves obtaining a best possible medication history (BPMH), which can be both time-consuming and resource-intensive. During the COVID-19 pandemic, telepharmacy was used to reduce the risk of viral transmission. Telepharmacy is the remote provision of pharmacy-led clinical services, such as obtaining BPMHs, using telecommunications. However, the accuracy of telephone-obtained BPMHs has not yet been evaluated. Therefore, the primary aim of this study was to evaluate the proportion of patients who have an accurate BPMH from the telephone-obtained BPMH compared to an in-person obtained BPMH. METHODS: This prospective, observational study took place in a large tertiary hospital. Recruited patients or carers had their BPMH obtained by a pharmacist over the telephone. The same patients or carers then had their BPMH conducted in-person to identify any deviations between the telephone-obtained and in-person obtained BPMH. All telephone-obtained BPMHs were timed with a stopwatch. Any deviations were categorised according to their potential consequence. An accurate BPMH was defined as having no deviations. Descriptive statistics were used to report all quantitative variables. A multivariable logistic regression was conducted to identify risk factors for patients and medications for having medication deviations. RESULTS: In total, 116 patients were recruited to receive both a telephone-obtained and in-person obtained BPMH. Of these, 91 patients (78%) had an accurate BPMH with no deviations. Of the 1104 medications documented across all the BPMHs, 1064 (96%) had no deviation. Of the 40 (4%) medication deviations, 38 were deemed low-risk (3%) and 2 high-risk (1%). A patient was more likely to have a deviation if they are taking more medications (aOR: 1.11; 95% CI: 1.01-1.22; p < 0.05). A medication was more likely to have a deviation if it was regular non-prescription medication (aOR: 4.82; 95% CI: 2.14-10.82; p < 0.001) or 'when required' non-prescription medication (aOR: 3.12; 95% CI: 1.20-8.11; p = 0.02) or a topical medication (aOR: 12.53; 95% CI: 4.34-42.17; p < 0.001). CONCLUSIONS: Telepharmacy represents a reliable and time-efficient alternative to in-person BPMHs.

Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition. METHODS: MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort. RESULTS: Median rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events. CONCLUSION: Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP.[Media: see text].

Optimized Whole-Body PET MRI Sequence Workflow in Pediatric Hodgkin Lymphoma Patients.

18F-FDG PET/MRI might be the diagnostic method of choice for Hodgkin lymphoma patients, as it combines significant metabolic information from PET with excellent soft-tissue contrast from MRI and avoids radiation exposure from CT. However, a major issue is longer examination times than for PET/CT, especially for younger children needing anesthesia. Thus, a targeted selection of suitable whole-body MRI sequences is important to optimize the PET/MRI workflow. Methods: The initial PET/MRI scans of 84 EuroNet-PHL-C2 study patients from 13 international PET centers were evaluated. In each available MRI sequence, 5 PET-positive lymph nodes were assessed. If extranodal involvement occurred, 2 splenic lesions, 2 skeletal lesions, and 2 lung lesions were also assessed. A detection rate was calculated dividing the number of visible, anatomically assignable, and measurable lesions in the respective MRI sequence by the total number of lesions. Results: Relaxation time-weighted (T2w) transverse sequences with fat saturation (fs) yielded the best result, with detection rates of 95% for nodal lesions, 62% for splenic lesions, 94% for skeletal lesions, and 83% for lung lesions, followed by T2w transverse sequences without fs (86%, 49%, 16%, and 59%, respectively) and longitudinal relaxation time-weighted contrast-enhanced transverse sequences with fs (74%, 35%, 57%, and 55%, respectively). Conclusion: T2w transverse sequences with fs yielded the highest detection rates and are well suited for accurate whole-body PET/MRI in lymphoma patients. There is no evidence to recommend the use of contrast agents.

Barefoot Running on Grass as a Potential Treatment for Plantar Fasciitis: A Prospective Case Series.

BACKGROUND: Foot characteristics and running biomechanics in shod populations are associated with the aetiology of plantar fasciitis, the most common musculoskeletal disease of the foot. Previous Case reports have demonstrated improvements in the symptoms of plantar fasciitis after a period of barefoot running on grass. METHODS: Recreational runners with symptomatic plantar fasciitis were prospectively enrolled into a 6-week grass based barefoot running programme. Duration of symptoms, previous management and current pain scores (NRS, VAS) were recorded at entry. Daily pain scores were recorded during the 6-week period and 12 weeks from entry to the programme. RESULTS: In total, 20 of 28 patients (71.4%) enrolled were included in the analysis. Relative to the entry point, pain at 6-weeks was lower (2.5 ± 1.4 vs. 3.9 ± 1.4, p < 0.001) and pain at the 12-week point was lower (1.5 (1.8), p = 0.002). 19 out of 20 patients had improved at week-6 (mean ± SD % change in pain score, -38.8 ± 21.5%) and at week-12 (median (IQR) % change in pain score, -58.3 (34.8) %). CONCLUSION: Barefoot running on grass improved pain associated with plantar fasciitis at the 6-week and 12-week follow up points. This type of barefoot running has the ability to improve symptoms whilst allowing patients to continue running, the intervention may also address some impairments of the foot associated with plantar fasciitis.

Lean Mass, Muscle Strength, and Muscle Quality in Retired Rugby Players: The UK Rugby Health Project.

Although athletes from sports such as rugby have greater lean mass and strength during their playing careers, little is known about these characteristics post-retirement. Therefore, this study investigated lean mass, strength, and muscle quality in retired elite and amateur rugby players and non-contact athletes. Retired elite male rugby players (n=42, 43.9±10.3 y; 101.1±13.4 kg; 1.82±0.09 m), amateur rugby players (n=46, 48.0±10.5 y; 98.9±16.6 kg; 1.79±0.07 m) and non-contact athletes (n=30, 51.3±12.5 y; 91.3±13.4 kg; 1.79±0.07 m) received one total body dual-energy X-ray absorptiometry assessment of appendicular lean mass (ALM) and ALM index (ALMI). Grip strength was measured, and muscle quality (grip strength/unit of arm lean mass) was calculated. Sarcopenia was identified as ALMI<7.23 kg/m2 and handgrip strength<37.2 kg. Total lean mass, ALM and grip strength were greater in the elite rugby compared to amateur rugby and non-contact groups (p<0.01). There were no significant differences in muscle quality or sarcopenia prevalence. Retired elite rugby players had greater lean mass and grip strength than amateur rugby and non-contact athletes, although muscle quality was similar. The greater lean mass and strength might reflect genetic influences or previous participation in a highly physical sport.

Age-related differences of vastus lateralis muscle morphology, contractile properties, upper body grip strength and lower extremity functional capability in healthy adults aged 18 to 70 years.

BACKGROUND: There is a lack of of cross-sectional research that has investigated muscle morphology, function, and functional capability in all age-bands of healthy adults. The primary aim of this study was to evaluate age-related differences in indices of vastus lateralis (VL) muscle morphology, function and functional capability in a sample of healthy males and females aged 18-70yrs. Secondary aims were to evaluate relationships between age and VL muscle morphology and function and functional capability. METHODS: B mode Ultrasonography and Tensiomyography were used to measure VL muscle thickness, pennation angle, fascicle length, and contractile properties in 274 healthy adults aged 18-70yrs. Measurements of grip strength and functional capability (1-min chair rise test) were also taken. Data analysis included descriptive statistics, correlations, one-way ANOVAs, and multiple regressions. RESULTS: Negative correlations were found between age and muscle thickness (rs = -.56), pennation angle (rs = -.50), fascicle length (rs = -.30), maximal displacement (rs = -.24), grip strength (rs = -.27) and the 1-min chair rise test (rs = -.32). Positive correlations were observed between age and the echo intensity of the muscle (rs = .40) and total contraction time (rs = .20). Differences in the indices of muscle health were noticeable between the 18-29 age band and the 50-59 and 60-70 age bands (p < 0.05). The interaction of age and level of physical activity predicted changes in the variables (r2 = .04-.32). CONCLUSION: Age-related differences in muscle health are noticeable at 50 years of age, and age-related differences are larger in females compared to males. It was suggested that the thickness of the VL changed the most with age across the adult lifespan and that physical activity likely acts to abate detrimental change.

Measurement of the Developing Foot in Shod and Barefoot Paediatric Populations: A Narrative Review.

The theory that footwear may change foot shape dates back 100 years. Since this period, research has revealed the anatomical and functional consequences that footwear can cause to the foot. Children's feet remain malleable as they undergo developmental changes until adolescence, which is why childhood is arguably a crucial period to understand how footwear can affect natural foot development. This review explored the development of the foot in children and adolescents and the methods used to measure the different foot structures; it comments on the key issues with some of these methods and gives direction for future research. Various internal and external factors can affect foot development; the main factors are age, gender, ethnicity, body mass index (BMI) and footwear habits. Research on how footwear can affect foot development has increased over the years and the final section of this review aimed to unpick the findings. Studies investigating the influence of footwear habits on foot length and width have established inconsistent findings. Many of the studies in the review did not control for internal and external factors that can affect foot development. There was also a limited number of studies that investigated hallux valgus angle and muscle strength differences in those with different footwear habits. Moreover, multiple studies in the final section of this review did not successfully examine the footwear habits of the participants and instead used observations or self-assessments, which is a major limitation. Future research should examine footwear behaviors and other confounding factors when investigating the development of the foot in children and adolescents. Moreover, researchers should critically evaluate the methods used to quantify the different structures of the foot to ensure valid and reliable parameters are being used.

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial.

BACKGROUND: Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. METHODS: In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0-2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. FINDINGS: Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6-13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7-46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. INTERPRETATION: Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations. FUNDING: Janssen Research & Development.

Playing through the pain: The prevalence of perceived shoulder dysfunction in uninjured rugby players using the Rugby Shoulder Score.

OBJECTIVE: This study aimed to investigate the prevalence of self-reported shoulder dysfunction using the Rugby Shoulder Score (RSS) reported in arbitrary units (AU) of rugby players available for match selection (uninjured). DESIGN: Cross-sectional survey. METHODS: Paper survey at the mid-point of the season of uninjured players (n = 86 males (mean age (±SD): 26 ± 6.9y) from 8 squads (professional n = 34; amateur; n = 52)), using the RSS, subjective impact on rugby performance and previous shoulder injury, analysed using a Mann-Whitney U test. RESULTS: 55% of players reported a level of RSS dysfunction despite being uninjured. Players who also reported their shoulder was impacting on performance had significantly higher median RSS (61, IQR 28AU, p = 0.02) than those who reported no impact on performance (40, IQR 22AU). CONCLUSIONS: Findings from this study show that over half of players were playing with a level of self-reported shoulder dysfunction. This figure is higher in the professional game, for those with a history of previous injury and for forwards.

French Bulldogs differ to other dogs in the UK in propensity for many common disorders: a VetCompass study.

BACKGROUND: The French Bulldog is a highly popular dog breed but is linked with many serious health issues. A holistic view of breed health in French Bulldogs would assist efforts to appreciate the overall health strengths and weaknesses in the French Bulldog and to take appropriate steps to mitigate these. Based on random sampling of French Bulldogs and non-French Bulldogs under primary veterinary care during 2016 within the VetCompass Programme, a cohort study design was used to estimate the one-year (2016) period prevalence of the most commonly diagnosed disorders in each group. Risk factor analysis used multivariable logistic regression modelling methods. RESULTS: The analysis included 2,781 French Bulldogs and 21,850 non-French Bulldogs. French Bulldogs were younger (1.51 years, IQR 0.86 - 2.77 vs. 4.48 years, IQR 1.94 - 8.14) (p < 0.001) and lighter (12.45 kg, IQR 11.00 - 14.03 versus 13.80 kg, IQR 8.10 - 25.12) (p < 0.001) than non-French Bulldogs. Of 43 common specific-level disorders across both groups, French Bulldogs had significantly increased adjusted odds of 20/43 (46.5 %) disorders and significantly reduced adjusted odds of 11/43 (25.6 %) disorders compared to non-French Bulldogs. Highly predisposed disorders in French Bulldogs included stenotic nares (OR 42.14; 95 % CI 18.50 to 95.99; p < 0.001), Brachycephalic Obstructive Airway Syndrome (OR 30.89; 95 % CI 20.91 to 45.64; p < 0.001), aural discharge (OR 14.40; 95 % CI 9.08 to 22.86; p < 0.001), skin fold dermatitis (OR 11.18; 95 % CI 7.19 to 17.40; p < 0.001) and dystocia (OR 9.13; 95 % CI 5.17 to 16.13; p < 0.001). At a grouped-level of diagnostic precision, French Bulldogs had increased adjusted odds of 12/32 (37.5 %) disorders and reduced adjusted odds of 6/32 (18.8 %) disorders compared to non-French Bulldogs. CONCLUSIONS: These results identified ultra-predispositions with worryingly higher odds in French Bulldogs for several disorders, suggesting that the health of French Bulldogs has diverged substantially from, and may be lower than, the health of the wider non-French Bulldog population. Many of these predispositions are closely associated with the conformational extremes that define the French Bulldog breed. Shifting the typical conformation of the French Bulldog population towards a more moderate phenotype is proposed as a logical opportunity to reduce the serious health issues endemic in the French Bulldog breed.

The French Bulldog is currently a hugely popular dog breed in the UK. However, the breed is linked with a range of serious health issues. Using veterinary clinical data from the VetCompass Programme at the Royal Veterinary College, this study aimed to compare the frequency of common disorders in French Bulldogs against that of all remaining dogs to identify health strengths and weaknesses in French Bulldogs. This overall view of breed health can assist owners, breeders and veterinarians to take appropriate actions to improve the health of French Bulldogs.From an overall population of 905,544 dogs, random samples of 2,781 French Bulldogs and 21,850 non-French Bulldogs were included in the analysis. French Bulldogs were younger (1.51 years versus 4.48 years) and lighter (12.45 kg versus 13.80 kg) than non-French Bulldogs. French Bulldogs had increased risk of 20/43 (46.5 %) specific disorders and decreased risk of 11/43 (25.6 %) specific disorders compared to non-French Bulldogs. The disorders with greatest relative risk in French Bulldogs compared to non-French Bulldogs were narrowed nostrils (x 42.14), Brachycephalic Obstructive Airway Syndrome (x 30.89), ear discharge (x 14.40), skin fold dermatitis (x 11.18) and difficulty giving birth [dystocia] (x 9.13). When the disorders were grouped into broad disease categories, French Bulldogs had increased risk of 12/32 (37.5 %) disorder groups and reduced risk of 6/32 (18.8 %) disorder groups compared to non-French Bulldogs.This study suggests that the health of French Bulldogs is very different, and largely much poorer, that the health of the wider non-French Bulldog population. Many of these differences are closely associated with the extreme body shape that defines the French Bulldog breed. Shifting the body shape of French Bulldogs to become more moderate, and hence less extreme, is proposed as a logical opportunity to reduce the current serious and common health issues in the French Bulldog breed.

Incidence of injury in adult elite women's football: a systematic review and meta-analysis.

AIM: To estimate the incidence of injury in adult elite women's football and to characterise the nature and anatomical location of injuries. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Combinations of the key terms were entered into the following electronic databases (PubMed, SPORTDiscus, Science Direct and Discover) from inception to May 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: (1) Used a prospective cohort design; (2) captured data on elite adult women players; (3) reported injury incidence by anatomical site; (4) captured data of at least one season or national team tournament; (5) included a definition of injury; and (6) written in English. RESULTS: The search identified 1378 records. Twelve studies published between 1991 and 2018 were included in our review and sampled 129 teams. In domestic club football, injury incidence rate was estimated to be 5.7/1000 hours (total), 19.5/1000 hours (match) and 3.1/1000 hours (training). In tournament, football match incidence was estimated to be 55.7/1000 hours. The knee (22.8%; 368/1822) was the most common site of injury in domestic club football. The ankle (23.7%, 105/443) was the most common site of injury in tournament football. Ligament sprains were the most common type of injury (27.8%), followed by muscle strains (19.1%). Severn studies (58%) had a high risk of bias associated with exposure definition and measurement and considerable heterogeneity exists between the included studies (I2=49.7%-95%). SUMMARY/CONCLUSION: Ligament sprains occur more frequently in adult elite women football players. We advise caution in interpretating point estimates of the incidence of injury due to high statistical heterogeneity. Standardising injury reporting and the accurate recording of match and training exposure will overcome such limitations. PROSPERO REGISTRATION NUMBER: CRD42019130407.su.

A Novel Instrument for Endoscopic Ear Surgery With a Steerable Flexible Tip: A Pediatric Anatomical Validation Study.

HYPOTHESIS: This study compares the reaching ability of two classes of transcanal endoscopic ear surgery (TEES) instruments when operating on difficult to access anatomical targets; two novel instruments with steerable flexible tips (SFT-A and SFT-B) and suction capability are compared with standard commercially available tools. BACKGROUND: TEES surgeons identified the need for a new surgical instrument that can enable accessibility of all areas visualized by the endoscope. This motivated the development of the two instrument prototypes. METHODS: Six temporal bone models were 3D printed based on CT data from five cholesteatoma patients. Four anatomical targets were marked on each model. Using these targets, the reaching ability while using four standard TEES instruments were compared with the SFT-A and SFT-B prototypes by five surgeon participants. Results were analysed to compare success rates of contacting each target using each tool by fitting four Firth's logistic regression models. This calculated the statistically significant differences (p < 0.05) in tool success rate. RESULTS: Using SFT-A to contact the sinus tympani (100%) was significantly more successful than the Panetti suction dissector for atticus (PAT) (77%) and to contact the sinodural angle (0%) was less successful than the PAT (10%) and SFT-B (93%). Using SFT-B to contact the lateral semicircular canal (90%) was significantly more successful than all current tools and to contact the sinodural angle (93%) was significantly more successful than all tools. CONCLUSION: Using SFT-B enables enhanced accessibility of anatomical structures during TEES which may lead to less extensive bone removal to facilitate minimally invasive TEES.

Management of Patients with Metastatic Castration-Sensitive Prostate Cancer in the Real-World Setting in the United States.

PURPOSE: This study provides a contemporary assessment of the treatment patterns, health care resource utilization (HRU) and costs among metastatic castration-sensitive prostate cancer (mCSPC) patients in the U.S. MATERIALS AND METHODS: Adults with mCSPC were selected from Optum's de-identified Clinformatics® Data Mart Database (Commercial insurance/Medicare Advantage [COM/MA]; January 1, 2014-July 31, 2019) or Medicare Fee-for-Service (FFS; January 1, 2014-December 31, 2017). The index date was the first metastatic disease diagnosis date on/after the first prostate cancer diagnosis (without prior evidence of castration resistance). Patients were observed for 12 months pre-index (baseline) through their mCSPC period (from index until castration resistance or followup end). First-line (1L) mCSPC therapy was assessed during the mCSPC period; all-cause HRU and health plan-paid costs per-patient-per-year (PPPY) were measured during baseline and mCSPC periods. RESULTS: Among 6,517 COM/MA and 13,324 Medicare-FFS mCSPC patients over ∼10 months (median mCSPC period), 38% and 48% remained untreated/deferred treatment, and 45% and 46% received 1L androgen deprivation therapy (ADT) monotherapy, respectively. 1L abiraterone acetate and docetaxel were used among 7% and 6% of COM/MA and 1% and 2% of Medicare-FFS patients, respectively. HRU increased from baseline to mCSPC period, resulting in increased health plan-paid costs from $21,201 to $108,767 in COM/MA and from $16,819 to $69,639 PPPY in Medicare-FFS. CONCLUSIONS: This study highlights the limited use of newer therapies that improve survival in men with mCSPC in the U.S. HRU and costs increased substantially after onset of metastasis. Given the emergence of newer effective mCSPC therapies, further evaluation of future real-world mCSPC treatment patterns and outcomes is warranted.

One-Stage, Limited-Resection Epilepsy Surgery for Bottom-of-Sulcus Dysplasia.

OBJECTIVE: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD). METHODS: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG. RESULTS: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication. CONCLUSION: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures.