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Insect pollinators provide crucial ecosystem services yet face increasing environmental pressures. The challenges posed by novel and reemerging pathogens on bee health means we need to improve our understanding of the immune system, an important barrier to infections and disease. Despite the importance of solitary bees, which are ecologically relevant, our understanding of the genomic basis and molecular mechanisms underlying their immune potential, and how intrinsic and extrinsic factors may influence it is limited. To improve our understanding of the genomic architecture underlying immunity of a key solitary bee pollinator, we characterized putative immune genes of the red mason bee, Osmia bicornis. In addition, we used publicly available RNA-seq datasets to determine how sexes differ in immune gene expression and splicing but also how pesticide exposure may affect immune gene expression in females. Through comparative genomics, we reveal an evolutionarily conserved set of more than 500 putative immune-related genes. We found genome-wide patterns of sex-biased gene expression, with greater enrichment of immune-related processes among genes with higher constitutive expression in males than females. Our results also suggest an up-regulation of immune-related genes in response to exposure to two common neonicotinoids, thiacloprid and imidacloprid. Collectively, our study provides important insights into the gene repertoire, regulation and expression differences in the sexes of O. bicornis, as well as providing additional support for how neonicotinoids can affect immune gene expression, which may affect the capacity of solitary bees to respond to pathogenic threats.

Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers have not substantially improved. Here, we analyzed genome-scale CRISPR-Cas9 loss-of-function screens across 851 human cancer cell lines and found that frequent overexpression of SLC34A2-encoding a phosphate importer-is correlated with sensitivity to loss of the phosphate exporter XPR1, both in vitro and in vivo. In patient-derived tumor samples, we observed frequent PAX8-dependent overexpression of SLC34A2, XPR1 copy number amplifications and XPR1 messenger RNA overexpression. Mechanistically, in SLC34A2-high cancer cell lines, genetic or pharmacologic inhibition of XPR1-dependent phosphate efflux leads to the toxic accumulation of intracellular phosphate. Finally, we show that XPR1 requires the novel partner protein KIDINS220 for proper cellular localization and activity, and that disruption of this protein complex results in acidic "vacuolar" structures preceding cell death. These data point to the XPR1-KIDINS220 complex and phosphate dysregulation as a therapeutic vulnerability in ovarian cancer.

Universal screening of endometrial cancer for underlying Lynch syndrome (LS) using DNA mismatch repair immunohistochemistry (MMR IHC) has been recommended. The objective of this study was to assess the feasibility and outcomes of using office endometrial samplings in a community LS screening program.A community laboratory adopted Cancer Care Ontario's LS screening recommendations. All new endometrial cancers in women aged70 years were screened for LS using MMR IHC and MLH1 promoter methylation testing cascade for MLH1/PMS2-deficient cases. This retrospective validation study analyzes the first year's results.Of 693 new endometrial cancers, 467 (67.4%) were eligible for LS screening. Both MMR IHC and MLH1 promoter methylation testing were conclusive in98% of cases. MMR deficiency (MMRd), which includes LS screen-positive cases, was identified in 25.9% of patients (121/467). LS screen-positive tumours comprised 5.9% (27/467) of all cases.Endometrial samplings from community practice are suitable for pre-operative LS screening. This testing can identify MMRd endometrial cancers with significant prognostic implications. Approximately 1 in 20 Ontario women70 years of age with endometrial cancer screen positive for LS. Pre-operative and/or operative assessment for co-existent colonic neoplasms needs to be considered in this high-risk group. In addition, these women should be referred to genetic counselling.

PURPOSE To provide expert guidance to clinicians and policymakers in three resource-constrained settings on diagnosis and staging of adult women with ovarian masses and treatment of patients with epithelial ovarian (including fallopian tube and primary peritoneal) cancer. METHODS A multidisciplinary, multinational ASCO Expert Panel reviewed existing guidelines, conducted a modified ADAPTE process, and conducted a formal consensus process with additional experts. RESULTS Existing sets of guidelines from eight guideline developers were found and reviewed for resource-constrained settings; adapted recommendations from nine guidelines form the evidence base, informing two rounds of formal consensus; and all recommendations received ≥ 75% agreement. RECOMMENDATIONS Evaluation of adult symptomatic women in all settings includes symptom assessment, family history, and ultrasound and cancer antigen 125 serum tumor marker levels where feasible. In limited and enhanced settings, additional imaging may be requested. Diagnosis, staging, and/or treatment involves surgery. Presurgical workup of every suspected ovarian cancer requires a metastatic workup. Only trained clinicians with logistical support should perform surgical staging; treatment requires histologic confirmation; surgical goal is staging disease and performing complete cytoreduction to no gross residual disease. In first-line therapy, platinum-based chemotherapy is recommended; in advanced stages, patients may receive neoadjuvant chemotherapy. After neoadjuvant chemotherapy, all patients should be evaluated for interval debulking surgery. Targeted therapy is not recommended in basic or limited settings. Specialized interventions are resource-dependent, for example, laparoscopy, fertility-sparing surgery, genetic testing, and targeted therapy. Multidisciplinary cancer care and palliative care should be offered. Additional information can be found at www.asco.org/resource-stratified-guidelines . It is ASCO's view that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines. [Media: see text]

Background: To estimate the prevalence and impact of chronic edema (CE) in two Irish health care settings as part of LIMPRINT, an international study developed and co-ordinated by the International...

Purpose To describe interventionalist and workflow characteristics of an acute stroke endovascular thrombectomy (EVT) center without a dedicated interventional neuroradiology service and report clinical and radiologic outcomes. Materials and Methods Retrospective review was performed of all patients receiving EVT at Christchurch Hospital, New Zealand, from June 2014 to the end of December 2019 from a prospective reperfusion registry. During the study period, 5 peripheral vascular interventional radiologists, 2 of whom had experience in other neuroendovascular procedures, performed 210 EVT procedures. Median age of patients was 76 years (interquartile range: 64–83 y), and 107 (51%) were men. Results The most commonly occluded vessel was the M1 middle cerebral artery (n = 114; 54%). Successful reperfusion (Modified Treatment In Cerebral Ischemia score 2b–3) was achieved in 180 (86%) procedures. Favorable 90-day outcome (modified Rankin Scale score 0–2) was achieved in 102 (54%) patients with no disability before stroke. Symptomatic intracranial hemorrhage occurred in 3 (1.4%) patients. Treatment rates in the local catchment area increased from 6 per 100,000 population in 2017 to 15 per 100,000 in 2019. Conclusions The results of this study suggest peripheral vascular interventional radiologists with specific training can successfully perform EVT resulting in a significant increase in EVT provision.

Background The Joint Trauma System database estimates that about 1,200 individuals have sustained a combat-related amputation during the Global War on Terror. Previous retrospective studies have demonstrated that combat-related amputees develop obesity and cardiovascular disease, but the incidence of obesity and associated comorbidities in this population is unknown. The objectives of this study are to determine the prevalence of obesity in the military amputee population and to compare this with the general population. Methods This is a retrospective review of 978 patients who sustained a combat-related amputation from 2003 to 2014. Prevalence of obesity and comorbid conditions were determined. A multivariate logistic regression model was performed to identify risk factors for postamputation obesity. Kaplan-Meier curves were constructed using obesity as the event of interest. Results A total of 1,233 charts were reviewed with 978 patients included for analysis. The median age of injury was 24 years. Median follow-up time was 8.7 years, ranging from 0.5 years to 16.9 years. The average Injury Severity Score was 23.3. The average body mass index preinjury was 25.6 kg/m2, and the average most recent corrected body mass index was found to be 31.4 kg/m2. Prevalence of comorbidities was higher in the amputee population. Fifty percent of patients who progressed to obesity did so within 1.3 years. Conclusion There is a notable prevalence of obesity that develops in the amputee population that is much higher than the general population. We determined that the amputee population is at risk, and these patients should be closely monitored for 1 to 2.5 years following injury. This study provides a targeted period for which monitoring and intervention can be implemented. Level of evidence Retrospective, basic science, outcomes analysis, level III/IV.

For patients with recurrent implantation failure in IVF, histologic or transcriptomic testing of the endometrium during the mid-secretory phase is often considered. Histological dating of endometrial biopsies (Noyes criteria) can determine if endometrial morphology is consistent with the period of receptivity. Alternatively, endometrial tissue can be sent for a commercial Endometrial Receptivity Array (ERA) test which characterizes the gene expression of the endometrium using a panel of 238 genes that have been implicated in endometrial receptivity. This study aimed to compare the two tests to assess their concordance and to examine the ability of the ERA to successfully predict implantation and pregnancy in a subsequent personalized embryo transfer. A retrospective review was done of 97 patients with a history of implantation failure who underwent an ERA, 35 of whom had histologic dating on the same sample. ERA and histology were classified as 'concordant' when samples were receptive by both tests or non-receptive by both tests. The ERA result was then used to personalize the embryo transfer day, and pregnancy rates from the first subsequent frozen transfer cycle were analyzed. The results indicated that there is poor concordance between ERA and histological dating with only 40.0% agreement and a kappa (95%CI) = -0.18 (-0.50, 0.14). According to the ERA, 48.5% of biopsies were receptive, 47.4% were non-receptive and 2.01% were insufficient tissue for analysis. The clinical pregnancy rate in patients shown to be receptive by ERA was 26.7% and non-receptive was 22.5% following the subsequent personalized ET (p = 0.66). This study concludes that there is a high degree of discordance between histological dating of the endometrium and molecular analysis by ERA. There was no evidence of clinical benefit when embryo transfer was personalized according to ERA in patients with a history of implantation failure.

Background The relationship between von Willebrand factor antigen (VWF:Ag), VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio, ADAMTS13 activity, and microembolic signal (MES) status in carotid stenosis is unknown. Methods This prospective, multicenter study simultaneously assessed plasma VWF:Ag levels, VWFpp levels and ADAMTS13 activity, and their relationship with MES in asymptomatic versus symptomatic moderate-to-severe (≥50–99%) carotid stenosis patients. One-hour transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES+ve or MES−ve. Results Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the “early phase” (≤4 weeks) and 37 patients in the “late phase” (≥3 months) after transient ischemic attack (TIA)/ischemic stroke. VWF:Ag levels were higher (p = 0.049) and VWFpp/VWF:Ag ratios lower (p = 0.006) in early symptomatic than in asymptomatic patients overall, and in early symptomatic versus asymptomatic MES−ve subgroups (p ≤0.02). There were no intergroup differences in VWFpp expression or ADAMTS13 activity (p ≥0.05). VWF:Ag levels and ADAMTS13 activity decreased (p ≤ 0.048) and VWFpp/VWF:Ag ratios increased (p = 0.03) in symptomatic patients followed up from the early to late phases after TIA/stroke. Although there were no differences in the proportions of symptomatic and asymptomatic patients with blood group O, a combined analysis of early symptomatic and asymptomatic patients revealed lower median VWF:Ag levels in patients with blood group O versus those without blood group O (9.59 vs. 12.32 µg/mL, p = 0.035). Discussion VWF:Ag expression, a marker of endothelial ± platelet activation, is enhanced in recently symptomatic versus asymptomatic carotid stenosis patients, including in MES−ve patients, and decreases with ADAMTS13 activity over time following atherosclerotic TIA/ischemic stroke.

Objective Sleep plays a critical role in children’s growth and development. This study examined the frequency and persistence of children’s sleep problems following a natural disaster, risk factors for children’s sleep problems, and the bidirectional relationship between children’s sleep problems and posttraumatic stress symptoms (PTSS) over time. Methods This study assessed 269 children (53% female, M = 8.70 years, SD = 0.95) exposed to Hurricane Ike at 8 months (Time 1) and 15 months (Time 2) post-disaster. Children completed measures of hurricane exposure and related stressors, stressful life events, sleep problems, and PTSS. Results Children’s sleep problems were significantly correlated from Time 1 to Time 2 (r = .28, p < .001). Risk factors for sleep problems at Time 2 were younger age, sleep problems at Time 1, and PTSS, not including sleep items, at Time 1. Examinations of the bidirectional relationship between sleep problems and PTSS indicated that PTSS significantly predicted later sleep problems, but sleep problems did not significantly predict later PTSS. Conclusions Findings demonstrate that PTSS may contribute to the development and course of children’s sleep problems post-disaster.

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

The pathophysiological link between adiposity and blood pressure is not completely understood, and evidence suggests an influence of sex and genetic determinants. We aimed to identify the relationship between adiposity and blood pressure, independent of a robust set of lifestyle and metabolic factors, and to examine the modulating role of sex and Angiotensin-Converting Enzyme (ACE) insertion/deletion (I/D) polymorphisms. In the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) study cohort, 1211 normotensive individuals, aged 30 to 60 years and followed-up after 3.3 years, were characterized for lifestyle and metabolic factors, body composition, and ACE genotype. Body mass index (BMI) and waist circumference (WC) were independently associated with mean arterial pressure, with a stronger relationship in women than men (BMI: r =0.40 versus 0.30; WC: r =0.40 versus 0.30, both P ID and II ACE genotypes in both sexes ( P ACE genotype only in women ( P =0.03). A 5 cm larger WC at baseline increased the risk of developing hypertension at follow-up only in women (odds ratio, 1.56 [95% CI, 1.15–2.10], P =0.004) and in II genotype carriers (odds ratio, 1.87 [95% CI, 1.09–3.20], P =0.023). The hypertensive effect of adiposity is more pronounced in women and in people carrying the II variant of the ACE genotype, a marker of salt sensitivity.

Summary In many countries, osteoporosis is predominantly managed by primary care physicians; however, management after a fragility fracture has not been widely investigated. We describe osteoporosis care gaps in a real-world patient cohort. Our findings help inform initiatives to identify and overcome obstacles to effective management of patients after fragility fracture. Purpose A fragility fracture is a major risk factor for subsequent fracture in adults aged ≥ 50 years. This retrospective observational study aimed to characterize post-fracture management in Canadian primary care. Methods A total of 778 patients with an index fragility fracture (low-trauma, excluding small bones) occurring between 2014 and 2016 were identified from medical records at 76 primary care centers in Canada, with follow-up until January 2018. Results Of 778 patients (80.5% female, median age [IQR] 73 [64–80]), 215 were on osteoporosis treatment and 269 had osteoporosis diagnosis recorded prior to their index fracture. The median follow-up was 363 (IQR 91–808) days. Of patients not on osteoporosis treatment at their index fracture, 60.2% (n = 339/563) remained untreated after their index fracture and 62.2% (n = 23/37) continued untreated after their subsequent fracture. After their index fracture, fracture risk assessment (FRAX or CAROC) was not performed in 83.2% (n = 647/778) of patients, and 59.9% (n = 466/778) of patients did not receive bone mineral density testing. Of patients without osteoporosis diagnosis recorded prior to their index date, 61.3% (n = 300/489) remained undiagnosed after their index fracture. At least one subsequent fracture occurred in 11.5% (n = 86/778) of patients. Conclusion In the primary care setting, fragility fracture infrequently resulted in osteoporosis treatment or fracture risk assessment, even after multiple fragility fractures. These results suggest a fragility fracture is not recognized as a major risk factor for subsequent fracture and its occurrence does not prompt primary care physicians to intervene. These data urge initiatives to identify and overcome obstacles to primary care physicians’ effective management of patients after fragility fractures.

NF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.

Aims The aim of this study was to examine trends in the management of fractures of the distal radius in Ireland over a ten-year period, and to determine if there were any changes in response to the English Distal Radius Acute Fracture Fixation Trial (DRAFFT). Patients and Methods Data was grouped into annual intervals from 2008 to 2017. All adult inpatient episodes that involved emergency surgery for fractures of the distal radius were included Results In 2008 Kirschner-wire (K-wire) fixation accounted for 59% of operations for fractures of the distal radius, and plate fixation for 21%. In 2017, the rate of K-wire fixation had fallen to 30%, and the proportion of patients who underwent plate fixation had risen to 62%. Conclusion There is an increasing trend towards open reduction and internal fixation for fractures of the distal radius in Ireland. This has been accompanied by a decrease in popularity for K-wire fixation. DRAFFT did not appear to influence trends in the management of fractures of the distal radius in Ireland. Cite this article: Bone Joint J 2019;101-B:1550–1556

Objective The aim of this guideline is to aid primary care physicians and gynaecologists in the initial evaluation of women with suspected endometrial hyperplasia, to recommend the use of the 2014 World Health Organization classification for endometrial hyperplasia by all health care providers, and to guide the optimal treatment of women diagnosed with endometrial hyperplasia. Intended Users Physicians, including gynaecologists, obstetricians, family physicians, general surgeons, emergency medicine specialists; nurses, including registered nurses and nurse practitioners; medical trainees, including medical students, residents, and fellows; and all other health care providers. Target Population Adult women (18 years and older) presenting with suspected or confirmed endometrial hyperplasia. Options The discussion relates to the medical therapy as well as surgical treatment options for women with and without atypical endometrial hyperplasia. Evidence For this guideline, relevant studies were searched in PubMed, Cochrane Wiley, and the Cochrane Systematic Reviews using the following terms, either alone or in combination, with the search limited to English language materials, human subjects, and published since 2000: (endometrial hyperplasia, endometrial intraepithelial neoplasia, endometrial sampling, endometrial curettage, diagnosis) AND (treatment, progestin therapy, surgery, LNG-IUS, aromatase inhibitors, metformin ), AND (obesity). The search was performed in April 2018. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional significant articles were identified through cross-referencing the identified reviews. The total number of studies identified was 2152, and 82 studies were included in this review. Validation Methods The content and recommendations were drafted and agreed upon by the authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology framework. The interpretation of strong and weak recommendations was also included. The Summary of Findings is available upon request. Benefits, Harms, and/or Costs It is expected that this guideline will benefit women with endometrial hyperplasia. This should guide patient informed consent before both medical and surgical management of this condition. Guideline Update Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. Summary Statements 1In addition to epidemiologic risk factors related to estrogen exposure, intermenstrual bleeding and postmenopausal bleeding are associated with increased risk of endometrial hyperplasia. Endometrial sampling should be carried out as per published algorithms with particular attention to women 40 years or older or with a body mass index of 30 kg/m2 or greater (moderate). 2Since the majority of cases of endometrial hyperplasia without atypia are successfully managed medically, hysterectomy is not considered first-line treatment and surgery is reserved for specific circumstances (moderate). 3A minimally invasive approach to hysterectomy is preferred for endometrial hyperplasia as it decreases perioperative morbidity and mortality (high). 4If hysterectomy is indicated for endometrial hyperplasia without atypia then postmenopausal women should also be offered bilateral salpingo-oophorectomy. This decision is individualized for premenopausal women due to increased mortality and morbidity associated with removal of the ovaries in young women with benign disease (moderate). 5Hysterectomy and bilateral salpingo-oophorectomy are the recommended treatment for atypical endometrial hyperplasia due to the underlying risk of malignancy or progression to endometrial cancer. Retention of the ovaries in premenopausal women may be considered (low). 6There is no evidence to support routine intraoperative frozen section analysis in cases of endometrial hyperplasia (low). 7There is no evidence to support routine lymphadenectomy for atypical endometrial hyperplasia (moderate). 8There is insufficient evidence to support endometrial ablation as first-line surgical treatment for endometrial hyperplasia without atypia (low). 9Endometrial hyperplasia found in endometrial polyps should be treated according to its histologic classification (low). Recommendations 1Health care providers should use the 2014 World Health Organization histopathologic classification of endometrial hyperplasia (strong, low). If endometrial cancer is suspected, endometrial tissue sampling using a Pipelle device in an outpatient setting is the most appropriate first step for diagnosis (strong, high). 2Those with recurrent symptoms of abnormal uterine bleeding after initial observation or medical treatment should be reassessed with an endometrial biopsy (strong, high). 3Patients with endometrial hyperplasia should be assessed for reversible risk factors and receive education and support from their clinicians in order to treat and reverse those conditions (strong, high). 4Patients with endometrial hyperplasia without atypia can be observed. They can be offered hormonal treatment if hyperplasia does not resolve with observation or experience abnormal uterine bleeding (weak, low). 5The levonorgestrel intrauterine system should be used as the first-line treatment for endometrial hyperplasia without atypia due to its effectiveness and favourable side effect profile (strong, high) and due to the fact that it can be kept in place for 5 years in patients showing treatment response (strong, moderate). 6Low-dose oral and injectable progestins remain an acceptable treatment option for women with endometrial hyperplasia with and without atypia desiring an alternative treatment modality (strong, high). For patients on oral progestins, we suggest starting on a low dose for a minimum of 6 months. We suggest that assessment of the endometrium be done mid-therapy as well as 3 weeks after completion of treatment to ensure proper interpretation (strong, very low). 7Surgical treatment of endometrial hyperplasia without atypia should be reserved for patients who do not want to preserve their fertility and experience progression to atypical hyperplasia or carcinoma during follow-up, whose hyperplasia fails to regress after 12 months of medical treatment or relapses after completing treatment with progestins, who continue to experience abnormal uterine bleeding despite treatment, or who decline endometrial surveillance or medical treatment (strong, high). 8If surgery is indicated for endometrial hyperplasia without atypia, the procedure should include total hysterectomy with opportunistic salpingectomy, with or without bilateral oophorectomy depending on menopausal status (strong, moderate). 9Total hysterectomy with bilateral salpingo-oophorectomy is recommended for treatment of atypical hyperplasia in premenopausal and postmenopausal women (strong, moderate). In premenopausal women, ovarian preservation should be discussed (strong, moderate). 10We recommend that subtotal (supracervical) hysterectomy and morcellation be avoided in all cases of endometrial hyperplasia (strong, low).

Objective: A large-scale capture method was developed to enable sterilisation of a macropod population in western Sydney from 2005 to 2018. Methods: Until March 2007, free ranging eastern grey kangaroos and red kangaroos were herded into purpose-built 15 m diameter capture yards (CYs) for darting with a projectile syringe. From March 2007 onwards, animals were free-range darted in large areas without herding. Kangaroos were darted with 1.33–5.10 mg/kg tiletamine/zolazepam and 0.01–0.02 mg/kg medetomidine, ± 0.03 mg/kg acepromazine. Deaths were monitored. Population counts were performed annually. Results: There were 5825 capture events involving 3963 kangaroos. Over 85% of all captures occurred from 2005 to 2008. Of all reported deaths (n = 523), 135 were attributed to ill health. Musculoskeletal injuries incurred during capture were the main project-related cause of death (n = 116). Post capture myopathy was uncommonly diagnosed following capture (n = 19). Conclusion: The herding and capture method enabled a large number of kangaroos to be mobilised and captured with low mortality rates, and the use of CYs resulted in fewer capture-related injuries and deaths than free-range capture. The drug doses and combinations used for darting were safe and effective, and the capture technique was successfully applied to a population management project.

Objective This study aims to assess whether acupuncture analgesia’s effects are local or systemic and whether there is a dose response for these effects. Methods Twenty-eight healthy volunteers aged 18–45 were randomized to two doses of acupuncture using points closely associated with peripheral nerves in the legs. The lower-dose group involved acupoints overlying the deep peroneal nerve (DP), and the higher-dose involved acupoints overlying the deep peroneal and posterior tibial nerves (DPTN). Baseline and acupuncture quantitative sensory testing (QST) assessments were obtained locally in the calf and great toe and systemically in the hand. Results were analyzed using factorial repeated-measures analysis of variance for each of the QST variables—cold detection threshold (CDT), vibration detection threshold (VDT), heat pain threshold (HP0.5), and heat pain perception of 5/10 (HP5.0). Location (leg/hand) and time (baseline/acupuncture) were within-subject factors. Intervention (DP/DPTN) was a between-subject factor. Results CDT was increased in the calf (P Conclusions Acupuncture caused comparable local and systemic analgesic effects in cold detection and heat pain perception and only local effects in vibration perception. There was no clear acupuncture dose response to these effects.

Background Ascariasis is a neglected tropical disease that affects 800 million people worldwide. Whereas most people only experience light worm burden, some people experience heavy worm burdens even after several rounds of chemotherapy, a phenomenon known as predisposition. Such heavy infections are associated with more severe symptoms and increased chronic morbidity. Methods In order to investigate potential mechanisms that may explain the observed predisposition, we infected mice with the porcine ascarid Ascaris suum using an established mouse model with two different mouse strains, where the C57BL/6J strain is more susceptible to infection and therefore a model for heavy infection and the CBA/Ca strain is more resistant and thus a model for light infection. At day 7 post-infection we investigated the liver proteome, using shotgun mass spectrometry, of both infected and control mice of each strain. Results We identified intrinsic differences, between the two mouse strains, in both oxidative phosphorylation proteins and proteins involved in retinol metabolism. Additionally, we found differences between the two mouse strains in activation of the complement system, where the CBA/Ca strain has higher protein abundances for lectin pathway proteins and the C57BL/6J strain has higher protein abundances for complement inhibiting proteins. The CBA/Ca strain had a higher abundance of proteins involved in the activation of the complement cascade via the lectin pathway. In contrast, the C57BL/6J strain demonstrated a higher abundance of proteins involved in arresting the complement pathway. Conclusions We observed clear differences between the two mouse strains both intrinsically and under infection. Electronic supplementary material The online version of this article (10.1186/s13071-019-3655-9) contains supplementary material, which is available to authorized users.

Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α–dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5(OXA) mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α’s critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.

© 2019 John Wiley & Sons Ltd Medication control in greyhound racing requires information from administration studies that measure drug levels in the urine as well as plasma, with time points that extend into the terminal phase of excretion. To characterize the plasma and the urinary pharmacokinetics of flunixin and enable regulatory advice for greyhound racing in respect of both medication and residue control limits, flunixin meglumine was administered intravenously on one occasion to six different greyhounds at the label dose of 1mg/kg and the levels of flunixin were measured in plasma for up to 96hr and in urine for up to 120hr. Using the standard methodology for medication control, the irrelevant plasma concentration was determined as 1ng/ml and the irrelevant urine concentration was determined as 30ng/ml. This information can be used by regulators to determine a screening limit, detection time and a residue limit. The greyhounds with the highest average urine pH had far greater flunixin exposure compared with the greyhounds that had the lowest. This is entirely consistent with the extent of ionization predicted by the Henderson–Hasselbalch equation. This variability in the urine pharmacokinetics reduces with time, and at 72hr postadministration, in the terminal phase, the variability in urine and plasma flunixin concentrations are similar and should not affect medication control.

Introduction Cerebral micro-embolic signals (MES) predict risk of stroke in carotid stenosis patients. However, MES-negative ‘recently symptomatic patients’ also have a higher stroke risk than ‘asymptomatic patients’. Differences in platelet activation status may contribute to this disparity in risk. Methods This prospective, observational study assessed platelet biomarkers and their relationship with MES in asymptomatic versus symptomatic moderate (≥50–69%) or severe (≥70–99%) carotid stenosis patients. Full blood count parameters were measured and whole-blood flow cytometry was used to quantify platelet surface CD62P and CD63 expression and leucocyte–platelet complex formation. Bilateral simultaneous transcranial Doppler ultrasound of the middle cerebral arteries classified patients as ‘MES positive’ or ‘MES negative’. Results Data from 34 asymptomatic patients were compared with those from 43 symptomatic patients in the ‘early phase’ (≤ 4 weeks) and 37 of these symptomatic patients in the ‘late phase’ (≥ 3 months) after transient ischaemic attack/ischaemic stroke. There were no differences in %CD62P or %CD63 expression between early or late symptomatic and asymptomatic patients overall (p > 0.05). The percentage of lymphocyte–platelet complexes was higher in early symptomatic than in asymptomatic patients (2.8 vs. 2.16%; p Conclusion These data add to the evidence that leucocyte–platelet complex formation/platelet activation is increased in recently symptomatic versus asymptomatic patients, and may contribute to the pathogenesis of first and subsequent strokes in carotid stenosis patients, including those who are MES negative.

Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is a rare and distinctive neoplasm of unclear histogenesis, and uncertain malignant potential. These neoplasms morphologically resemble sex-cord stromal tumors of the ovary, and possess a polyphenotypic immunophenotype. Their molecular pathogenesis has yet to be elucidated; notably, however, tumors lack alterations found in other uterine tumors bearing sex-cord-like differentiation, such as endometrial stromal sarcoma. Following identification of an index patient with an ESR1-NCOA3 fusion gene by RNA-sequencing, we undertook a retrospective review for additional cases of UTROSCT. We identified a total of 4 patients, with an average age of 53 years (range, 38 to 68 y). RNA-sequencing was performed in all cases, revealing an ESR1-NCOA3 fusion in 2 cases and one case each with related ESR1-NCOA2 and GREB1-NCOA2 fusions. Each of the tumors showed histologic and an immunophenotype features within the previously reported spectrum of UTROSCT; interestingly, one case contained prominent spindle cell fascicles and another was largely comprised of sheets of small round cells. Our results demonstrate UTROSCT are defined by recurrent fusions involving NCOA2 or NCOA3, a finding that is directly amenable to diagnostic evaluation. This study confirms UTROSCT is molecularly distinct from endometrial stromal sarcoma, and raises intriguing new questions into the pathogenesis of these neoplasms and possible relationship with other NCOA fusion-positive uterine tumors.

The gut microbiota is essential for human health. Microbial supply of short-chain fatty acids (SCFAs), particularly butyrate, is a well-established contributor to gut homeostasis and disease resistance. Reaching millimolar luminal concentrations, butyrate is sequestered and utilized in the colon as the favored energy source for intestinal epithelia. Given the steep oxygen gradient across the anoxic lumen and the highly oxygenated lamina propria, the colon provides a particularly interesting environment to study oxygen sensing. Previous studies have shown that the transcription factor hypoxia-inducible factor (HIF) is stabilized in healthy colonic epithelia. Here we show that butyrate directly inhibits HIF prolyl hydroxylases (PHDs) to stabilize HIF. We find that butyrate stabilizes HIF in vitro despite eliminating β-oxidation and resultant oxygen consumption. Using recombinant PHD protein in combination with nuclear magnetic resonance and enzymatic biochemical assays, we identify butyrate to bind and function as a unique, noncompetitive inhibitor of PHDs relative to other SCFAs. Butyrate inhibited PHD with a noncompetitive Ki of 5.3 ± 0.5 mM, a physiologically relevant concentration. We also confirm that microbiota-derived butyrate is necessary to stabilize HIF in mice colonic tissue through antibiotic-induced butyrate depletion and reconstitution experiments. Our results suggest that the co-evolution of mammals and mutualistic microbiota has selected for butyrate to impact a critical gene regulation pathway that can be extended beyond the mammalian gut. As PHDs are a major target for drug development in the stabilization of HIF, butyrate holds great potential as a well-tolerated endogenous inhibitor with far-reaching therapeutic impact.

To date, no research has explored the effects of low energy availability on cognitive performance using dietary and exercise regimens relevant to athletes. Twenty female participants (10 eumenorrheic, 10 oral contraceptive [OC] users) completed three 3-day conditions: 1) controlled-balanced energy availability without exercise (BAL; 45 kcal·kg lean body mass [LBM] 1·day 1); 2) diet-induced low energy availability without exercise (DIET; 15 kcal·kg LBM 1·day 1); and 3) exercise-induced low energy availability (EX; 15 kcal·kg LBM 1·day 1, including 30 kcal·kg LBM 1·day 1 treadmill running at 70% maximal oxygen uptake). A cognitive test battery was completed before and after each 3-day condition. Mental rotation test accuracy improved in the BAL condition, but there was a decline in accuracy in the EX condition (BAL, +2.5%; EX, 1.4%; P = 0.042, d = 0.85). DIET (+1.3%) was not different to BAL or EX (P > 0.05). All other measures of cognitive performance were not affected by condition (P > 0.05) and OC use did not affect cognitive responses (P > 0.05). Accuracy in the mental rotation test was impaired when low energy availability was induced through increased exercise energy expenditure. All other aspects of cognition were unaffected by 3 days of low energy availability through diet or exercise. OC use did not mediate the effect of low energy availability on cognition. Novelty: Cognitive function was not affected by 3 days of diet-induced low energy availability. Only spatial awareness was impaired during 3 days of exercise-induced low energy availability. Reproductive hormones affected spatial awareness independent of energy availability.

Purpose To assess current perceptions, practices and education needs pertaining to artificial intelligence (AI) in the medical physics field. Methods A web-based survey was distributed to the European Federation of Organizations for Medical Physics (EFOMP) through social media and email membership list. The survey included questions about education, personal knowledge, needs, research and professionalism around AI in medical physics. Demographics information were also collected. Responses were stratified and analysed by gender, type of institution and years of experience in medical physics. Statistical significance ( p 0.05 ) was assessed using paired t-test. Results 219 people from 31 countries took part in the survey. 81% (n = 177) of participants agreed that AI will improve the daily work of Medical Physics Experts (MPEs) and 88% (n = 193) of respondents expressed the need for MPEs of specific training on AI. The average level of AI knowledge among participants was 2.3 ± 1.0 (mean ± standard deviation) in a 1-to-5 scale and 96% (n = 210) of participants showed interest in improving their AI skills. A significantly lower AI knowledge was observed for female participants (2.0 ± 1.0), compared to male responders (2.4 ± 1.0). 64% of participants indicated that they are not involved in AI projects. The percentage of female leading AI projects was significantly lower than the male counterparts (3% vs 19%). Conclusions AI was perceived as a positive resource to support MPEs in their daily tasks. Participants demonstrated a strong interest in improving their current AI-related skills, enhancing the need for dedicated training for MPEs.

Recent preclinical data suggest that alterations in the gut microbiota may be an important factor linking obesity to vascular dysfunction, an early sign of cardiovascular disease. The purpose of this study was to begin translation of these preclinical data by examining whether vascular phenotypes in humans are transmissible through the gut microbiota. We hypothesized that germ-free mice colonized with gut microbiota from obese individuals would display diminished vascular function compared to germ-free mice receiving microbiota from lean individuals. We transplanted fecal material from obese and lean age-and sex-matched participants with disparate vascular function to germ-free mice. Using Principle Component Analysis, the microbiota of colonized mice separated by donor group along the first principle component, accounting for between 70–93% of the total variability in the dataset. The microbiota of mice receiving transplants from lean individuals was also characterized by increased alpha diversity, as well as increased relative abundance of potentially beneficial bacteria, including Bifidobacterium, Lactobacillus, and Bacteroides ovatis. Endothelium-dependent dilation, aortic pulse wave velocity and glucose tolerance were significantly altered in mice receiving microbiota from the obese donor relative to those receiving microbiota from the lean donor or those remaining germ-free. These data indicate that the obesity-associated human gut microbiota is sufficient to alter the vascular phenotype in germ-free mice in the absence of differences in body weight or dietary manipulation, and provide justification for future clinical trials to test the efficacy of microbiota-targeted therapies in the prevention or treatment of cardiovascular disease.

Objectives To evaluate the reproducibility of liver R2* measurements between a 2D cardiac ECG-gated and a 3D breath-hold liver CSE-MRI acquisition for liver iron quantification. Methods A total of 54 1.5 T MRI exams from 51 subjects (18 women, 36 men, age 35.2 ± 21.8) were included. These included two sub-studies with 23 clinical MRI exams from 19 patients identified retrospectively, 24 participants with known or suspected iron overload, and 7 healthy volunteers acquired prospectively. The 2D cardiac and the 3D liver R2* maps were acquired in the same exam. Either acquisitions were reconstructed using a complex R2* algorithm that accounts for the presence of fat and residual phase errors due to eddy currents. Data were analyzed using colocalized ROIs in the liver. Results Linear regression analysis demonstrated high Pearson’s correlation and Lin’s concordance coefficient for the overall study and both sub-studies. Bland–Altman analysis also showed good agreement, except for a slight increase of the mean R2* value above ~ 400 s−1. The Kolmogorow–Smirnow test revealed a non-normal distribution for (R2* 3D–R2* 2D) values from 0 to 600 s−1 in contrast to the 0–200 s−1 and 0–400 s−1 subpopulations. Linear regression analysis showed no relevant differences other than the intercept, likely due to only 7 measurements above 400 s−1. Conclusions The results demonstrate that R2*-measurements in the liver are feasible using 2D cardiac R2* maps compared to 3D liver R2* maps as the reference. Liver R2* may be underestimated for R2* > 400 s−1 using the 2D cardiac R2* mapping method.

Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p

Purpose Over the past three decades, the term Mini-Medical School (MMS) has been used to describe programs offered by schools of medicine, which provide health education to the lay public and health career exposure to youth. The University of Maryland School of Medicine has operated an MMS program since 2001. The purpose of this study was to assess the sociodemographic characteristics of MMS participants and the impacts of this program on their health. Methods We analyzed anonymous post-completion program evaluation survey responses and we conducted focus groups with some of the participants who had attended the program for ≥10 years. Results Most of the MMS participants were women (84%, n = 72), ≥55 years of age (88%), and well-educated (58% with college degree and higher); and 59% had attended the program for ≥5 years. The focus group discussions revealed acquisition of medical knowledge and community outreach as recurring themes; the former leading to empowerment of the participants for better self-care and care for others, while the latter driving them to health education and advocacy. Most of the participants showed interest in becoming “ambassadors” in their respective communities. Conclusion The health information provided by the MMS program is well-received and even anticipated by its participants. It has empowered them to care for themselves and for others by making them educated consumers and health advocates in their community. The MMS program should work with the School's community partners to make this resource more widely accessible, particularly to populations experiencing the most health disparities.

Hydatidiform moles (HM) are gestational trophoblastic diseases which arise due to an imbalance in genetic material and which are morphologically characterized by enlarged and irregular chorionic villi and trophoblastic hyperplasia, among other features. The morphologic differential diagnosis for HM encompasses a number of entities including androgenetic/biparental mosaic/chimeric (ABMC) conceptions, an interesting duo of lesions with a nonmolar form (placental mesenchymal dysplasia) and a molar form (typically with a complete HM component). ABMC conceptions contain a mixture of 2 cell populations (1 androgenetic and 1 biparental) and arise as a result of mosaicism (mitotic error in a zygote) or chimerism (fusion of 2 zygotes). Because of their unique molecular underpinnings, these rare lesions show a number of findings including the presence of multiple villous populations, discordant p57 immunostaining, and mixed genotypes. ABMC conceptions are important to accurately diagnose as the molar form in particular carries a risk for persistent gestational trophoblastic diseases and thus requires appropriate treatment and follow-up. In this report, we provide detailed characterizations of 2 such cases of ABMC conceptions with a molar component. Both patients (ages 34 and 31) were in the first trimester of pregnancy and had ultrasound findings concerning for HM. Increased comprehension of the pathogenesis and morphology of ABMC conceptions, combined with ancillary techniques including p57 immunohistochemistry, fluorescence in situ hybridization, and molar genotyping, has allowed us to accurately and efficiently identify these lesions. However, a number of pitfalls exist which may lead to misdiagnosis.

Synovial sarcoma most commonly occurs in the extremities but has rarely been described in the female genital tract. In this series, we describe the clinical, morphologic, immunohistochemical, and molecular features of 7 cases of vulvovaginal synovial sarcoma (vulva, n=6; vagina, n=1). We emphasize their wide morphologic spectrum, which can overlap significantly with other more common tumors at these sites, as highlighted by 2 cases initially diagnosed as other entities (endometrioid carcinoma and malignant peripheral nerve sheath tumor). The average patient age was 41 (range: 23 to 62) years and tumor size ranged from 0.8 to 7 cm. Histologically, the tumors were biphasic (n=6) and monophasic (n=1). All cases were confirmed with fluorescence in situ hybridization or sequencing, and 5/5 cases were positive for the novel immunohistochemical markers SSX and SS18-SSX. In 3 cases with follow-up, 2 patients died of disease and 1 was alive with no evidence of disease. Previously described cases arising in the female genital tract are also reviewed. Vulvovaginal monophasic synovial sarcoma raises a broad differential diagnosis, including smooth muscle tumors, spindled carcinomas, and melanoma. Biphasic synovial sarcoma may mimic Mullerian carcinosarcoma, endometrioid carcinoma with spindled, corded, and hyalinized elements, and mesonephric-like adenocarcinoma. Awareness that synovial sarcoma can occur in the female genital tract with a wide variety of histologic appearances is critical for correctly diagnosing this rare entity. In particular, synovial sarcoma should be considered for any deeply situated "adenocarcinoma" in the vulva, with attention to subtle spindle cell differentiation.

Asymptomatic bacteriuria, defined as the presence of bacteria in the urine in the absence of urinary symptoms, is a common clinical finding that often warrants a decision about whether to initiate antimicrobial therapy. There are few indications to treat asymptomatic bacteriuria, and inappropriate treatment contributes to the development of antimicrobial resistance. In 2019, the Infectious Diseases Society of America revised its 2005 guidelines on asymptomatic bacteriuria, incorporating new evidence. The updated guidelines recommend screening and appropriate treatment for asymptomatic bacteriuria in pregnant women and in individuals undergoing endourological procedures associated with mucosal trauma. The guidelines recommend against screening and treatment in infants and children; healthy adults, including nonpregnant pre- and postmenopausal women; and patients with diabetes mellitus, long-term indwelling catheters, or spinal cord injuries. The guidelines also recommend against screening and treatment in patients undergoing nonurological surgery, patients who have had a kidney transplant more than one month prior, recipients of other solid organ transplants, or those with impaired voiding following spinal cord injury. Although delirium in older adults can be caused by a urinary tract infection, the guidelines recommend that patients with delirium and no urinary or systemic symptoms be assessed for other causes of delirium, rather than initiating treatment for asymptomatic bacteriuria, because treatment has not been shown to have any beneficial effect on clinical outcomes.

The relationship between non-Hispanic White (NHW) women's decreased neighborhood income between early-life and adulthood, individual risk-status at delivery, and small for gestational age (weight for gestation 10th percentile, SGA) rates is unknown.To determine the extent to which NHW women's exposure to decreased neighborhood income is a risk factor for SGA births, and whether their own birth weight modifies this relationship.Stratified and multilevel logistic regression analyses were executed on the Illinois transgenerational dataset of mothers (born 1956-1976) and their infants (born 1989-1991) with appended U.S. census income information. Only NHW women with an early-life residence in top income quartile Chicago neighborhoods were studied.NHW women (n = 4889) unexposed to decreased neighborhood income between early-life and adulthood had an SGA rate of 7.1%. In contrast, NHW women exposed to slightly (n = 5112), modestly (n = 2158), or severely (n = 339) decreased neighborhood income by the time of delivery had SGA rates of 8.2%, 10.8%, and 10.8%, respectively; RR (95% CI) equaled 1.2 (1.0-1.3), 1.5 (1.3-1.8) and 1.5 (1.1-2.1), respectively. The relationship between maternal exposure to modestly decreased neighborhood income and SGA rates was present only among former non-low birth weight ( 2500 g, non-LBW) mothers. In multilevel logistic regression models, the adjusted (controlling for age, parity, prenatal care usage, and cigarette smoking) OR of SGA birth for former low birth weight ( 2500 g, LBW) and non-LBW NHW women exposed to modestly (compared to no) decreased neighborhood income equaled 0.7 (0.4, 1.4) and 1.3 (1.1-1.6), respectively.NHW women's exposure to modestly decreased neighborhood income is associated with an increased risk of SGA birth; this phenomenon is absent among former low birth weight women.

Importance Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. Objective To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. Design, Setting, and Participants This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)–positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. Interventions Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. Main Outcomes and Measures The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. Results The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change, –2.8;P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change, –2.3;P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. Conclusions and Relevance Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab–positive gMG. Near-complete complement inhibition appeared superior to submaximal inhibition. The observed safety and tolerability profile of zilucoplan was favorable. Trial Registration ClinicalTrials.gov Identifier:NCT03315130.

The affiliation details for Geltrude Mingrone are corrected below.

Despite the interest in mindfulness over the past 20 years, studies have only recently begun to examine mindfulness in older adults. The primary aim of this study was to evaluate pretreatment to post-treatment change in negative affect variability (NAV) following a mindfulness training among 134 mildly stressed, middle-aged to older adults. The secondary aim was to assess if the effects of mindfulness training on NAV would be partially explained by pretreatment to post-treatment reductions in perceived stress, a trend that would be congruent with several stress models. In this randomized control trial, participants were assigned to either a 6-week mindfulness meditation training programme or to a wait list control. Ecological momentary assessment, a data capturing technique that queries about present moment experiences in real time, captured NAV. Mixed-model ANOVAs and a path analysis were conducted. Participants in the mindfulness meditation training significantly reduced NAV when compared with wait list control participants. Further, there was a significant indirect group effect on reductions in NAV through change in perceived stress. Few studies have tested mechanisms of action, which connect changes that occur during mindfulness training with psychological outcomes in older adults. Understanding the mechanisms by which mindfulness enhances well-being may optimize interventions.

Endometrial stromal sarcoma encompasses a heterogeneous group of uterine mesenchymal neoplasms, which are currently divided into low-grade and high-grade subtypes. Low-grade endometrial stromal sarcoma is morphologically bland; molecularly, these tumors frequently contain JAZF1-SUZ12, JAZF1-PHF1, and EPC1-PHF1 fusions. In contrast, high-grade endometrial stromal sarcoma is characterized by morphologically undifferentiated neoplasms with high-grade nuclear features; these tumors likewise appear to be genetically diverse with YWHAE-NUTM2 and ZC3H7B-BCOR representing the most frequent gene fusions. Herein, we describe two novel EPC1 fusion genes in endometrial stromal sarcoma: EPC1-SUZ12 and EPC1-BCOR. Both tumors were characterized be an aggressive clinical course.

The oral tablet formulation of butylscopolamine, which is available without prescription, is commonly used by trainers of racing greyhounds to treat functional urethral obstruction. As medication control of butylscopolamine is therefore required for such use to ensure the integrity of greyhound racing an administration study was performed in six greyhounds to determine the pharmacokinetics of orally administered butylscopolamine. A single dose of one 10 mg butylscopolamine tablet was administered orally to simulate this use in greyhound racing. Blood, urine and faeces were collected at regular intervals from the greyhounds for up to 9 days and butylscopolamine concentrations determined. There was some, but very limited, absorption of butylscopolamine, with rapid elimination from plasma with a mean half-life of 2 hours. Urine concentrations initially declined in a similar manner to the plasma pharmacokinetics but then entered a much longer half-life of approximately 50 hours. Faecal concentrations declined to very low levels between 48 and 120 hours. The use of orally administered butylscopolamine for functional urethral obstruction in greyhounds is unjustified due this very limited drug absorption. Medication control of butylscopolamine’s anti-spasmodic effect on the digestive tract is possible by setting screening limits based on the urinary and faecal drug levels as determined in this study.

Nationally, 5% of the population have been prescribed topical lidocaine patches (TLPs). These patches cost €77–230 per month. The only licensed indication for TLP is post-herpetic neuralgia (PHN). It has not proven to be effective for any other indication including musculoskeletal and post-surgical pain. It is estimated that only 5–10% of patients on TLP have PHN. The aim of this study was to audit the number of inpatients currently prescribed TLP—appropriately and inappropriately—and to examine the prescribing patterns. The acute inpatient population was audited in August 2017 to determine TLP prevalence. Demographics, indication, prescriber grade, and whether TLP was commenced during the current admission were recorded. Education was given surrounding indications and licensed usage of TLP. The acute inpatient population was subsequently re-audited in February 2018. There were 304 patients included in the initial study and 300 in the repeat study. The most common indication was musculoskeletal pain in each study, 75 and 77.78%, respectively. The number of inpatients on TLP fell from 17.1% (n = 52) to 6% (n = 18) after the intervention. The potential savings between the study periods are therefore €31,418–93,840 in total and €23,100–69,000 in musculoskeletal patients. A large proportion of inpatients are inappropriately prescribed TLP predominantly for musculoskeletal pain, resulting in substantial avoidable cost to the hospital. Education of prescribers and implementation of policies is required to limit inappropriate prescribing.

Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed epithelial ovarian cancer histotype. Other identified risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation, during which the FTE cells become transiently exposed to follicular fluid (FF). To test whether mtBRCA1 or mtBRCA2 nonmalignant FTE cells respond differently to periovulatory FF exposure than control patient FTE cells, gene expression profiles from primary FTE cultures derived from BRCA1 or BRCA2 mutation carriers or control patients were compared at baseline, 24 hours after FF exposure, and 24 hours after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Gene set enrichment analysis revealed increased NFκB and EGFR signaling at baseline in mtBRCA1 samples, with increased interferon target gene expression, including members of the ISGylation pathway, observed after recovery from FF exposure. Gene set enrichment analysis did not identify altered pathway signaling in mtBRCA2 samples. An inverse relationship between EGFR signaling and ISGylation with BRCA1 protein levels was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1 cDNA. Suppression of ISG15 and ISGylated protein levels by increased BRCA1 expression was found to be mediated by decreased NFκB signaling. These studies indicate that increased NFκB signaling associated with decreased BRCA1 expression results in increased ISG15 and protein ISGylation following FF exposure, which may be involved in predisposition to HGSOC.

OBJECTIVE To develop a technique for permanent sterilisation of female eastern grey kangaroos (Macropus giganteus) and red kangaroos (M. rufus) as part of a large-scale macropod management program on an enclosed 1545-ha site in western Sydney. METHODS Free-ranging female kangaroos (n = 1409: 1285 eastern grey kangaroos, 124 red kangaroos) were anaesthetised via remote anaesthetic drug delivery of tiletamine/zolazepam, medetomidine and acepromazine prior to inhalational anaesthesia using isoflurane-oxygen. A laparoscopic ovariectomy technique was developed using standard laparoscopic equipment to effect permanent sterilisation of the kangaroos. The technique described was also adapted for use on immature animals weighing as little as 1 kg. No direct post-surgical care was provided once the animals had recovered from the anaesthetic. RESULTS The procedure was simple to perform and had a very high success rate, with an overall project mortality rate of 2.13% (n = 30). Seven kangaroos (0.05% of all operated kangaroos) were euthanased as a direct result of the surgical procedure. Surgical complications were rare but included inadvertent gastrointestinal tract puncture with the trocar, intraoperative haemorrhage and subcutaneous emphysema leading to pouch eversion following surgery. CONCLUSION The procedure described is a rapid and effective method of permanent fertility control in macropods and carries a low mortality rate.

Gonadoblastomas are rare mixed gonadal tumors that are almost always found in individuals with 46, XY karyotype or some other form of Y chromosome mosaicism. It is extremely rare to diagnose gonadoblastoma in phenotypically normal 46, XX females. Herein, we present a 20-year-old 46, XX female diagnosed with gonadoblastoma and dysgerminoma. Use of cytogenetic and molecular analyses to identify the presence of Y chromosome material in peripheral blood, gonadal, and tumor tissue can exclude mosaicism to provide reassurance to undertake conservative surgical management and preserve fertility.

Relapsed indolent lymphoma often becomes refractory to standard chemoimmunotherapy and requires new therapeutic strategies. Targeting the PI3K/mTOR pathway in several types of lymphoma has shown preclinical and clinical efficacy providing the rationale to test this strategy in the treatment of relapsed/refractory indolent lymphomas. We investigated in a phase II open label clinical trial the efficacy and safety of single agent everolimus, an inhibitor of mTORC1, in patients with relapsed/refractory indolent lymphomas. Eligible patients received oral everolimus 10 mg daily on a 28 day-cycle schedule. The primary endpoint was to evaluate the overall response rate (ORR) and safety of single-agent everolimus in this patient population. Fifty-five patients with indolent lymphoma were accrued. The median age was 67 years (range: 33-85) with a median of five prior therapies (range: 1-10). The ORR was 35% (19/55; 95% CI: 24-48%), with complete response unconfirmed in 4% (2/55), and partial response in 31% (17/55). The ORR was 61% (14/23) in the patients with FL. The median time to response was 2.3 months (range: 1.4-14.1), median duration of response of 11.5 months (95%-CI: 5.7-30.4), and a median progression-free survival of 7.2 months (95%-CI: 5.5-12.5). The most common toxicity was hematologic with grades 3-4 anemia, neutropenia, and thrombocytopenia documented in 15% (8/55), 22% (12/55), and 33% (18/55), respectively. There were no cases of febrile neutropenia, and eight patients discontinued therapy because of adverse events. Everolimus monotherapy is a valid therapeutic option in the relapsed and/or refractory indolent non-Hodgkin lymphoma patients and is well tolerated.

Aims To evaluate the feasibility and heart-sparing ability of the voluntary breath-hold (VBH) technique in a multicentre setting. Materials and methods Patients were recruited from 10 UK centres. Following surgery for early left breast cancer, patients with any heart inside the 50% isodose from a standard free-breathing tangential field treatment plan underwent a second planning computed tomography (CT) scan using the VBH technique. A separate treatment plan was prepared on the VBH CT scan and used for treatment. The mean heart, left anterior descending coronary artery (LAD) and lung doses were calculated. Daily electronic portal imaging (EPI) was carried out and scanning/treatment times were recorded. The primary end point was the percentage of patients achieving a reduction in mean heart dose with VBH. Population systematic (Σ) and random errors (σ) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests. Results In total, 101 patients were recruited during 2014. Primary end point data were available for 93 patients, 88 (95%) of whom achieved a reduction in mean heart dose with VBH. Mean cardiac doses (Gy) for free-breathing and VBH techniques, respectively, were: heart 1.8 and 1.1, LAD 12.1 and 5.4, maximum LAD 35.4 and 24.1 (all P

Background Communication among team members within hospitals is typically fragmented. Bedside interdisciplinary rounds (IDR) have the potential to improve communication and outcomes through enhanced structure and patient engagement. Objective To decrease length of stay (LOS) and complications through the transformation of daily IDR to a bedside model. Design Controlled trial. Setting 2 geographic areas of a medical unit using a clinical microsystem structure. Patients 2005 hospitalizations over a 12-month period. Interventions A bedside model (mobile interdisciplinary care rounds [MICRO]) was developed. MICRO featured a defined structure, scripting, patient engagement, and a patient safety checklist. Measurements The primary outcomes were clinical deterioration (composite of death, transfer to a higher level of care, or development of a hospital-acquired complication) and length of stay (LOS). Patient safety culture and perceptions of bedside interdisciplinary rounding were assessed pre- and postimplementation.. Results There was no difference in LOS (6.6 vs 7.0 days, P = 0.17, for the MICRO and control groups, respectively) or clinical deterioration (7.7% vs 9.3%, P = 0.46). LOS was reduced for patients transferred to the study unit (10.4 vs 14.0 days, P = 0.02, for the MICRO and control groups, respectively). Nurses and hospitalists gave significantly higher scores for patient safety climate and the efficiency of rounds after implementation of the MICRO model. Limitations The trial was performed at a single hospital. Conclusions Bedside IDR did not reduce overall LOS or clinical deterioration. Future studies should examine whether comprehensive transformation of medical units, including co-leadership, geographic cohorting of teams, and bedside interdisciplinary rounding, improves clinical outcomes compared to units without these features. Journal of Hospital Medicine 2017;12:137-142.

Ipilimumab was the first FDA-approved agent for advanced melanoma to improve survival and represents a paradigm shift in melanoma and cancer treatment. Its unique toxicity profile and kinetics of treatment response raise novel patient education challenges. We assessed patient perceptions of ipilimumab therapy across the treatment trajectory. Four patient cohorts were assessed at different time points relative to treatment initiation: (1) prior to initiation of ipilimumab (n = 10), (2) at weeks 10–12 before restaging studies (n = 11), (3) at week 12 following restaging studies indicating progression of disease (n = 10), and (4) at week 12 following restaging studies indicating either a radiographic response or disease stability (n = 10). Patients participated in a semistructured qualitative interview to assess their experiences with ipilimumab. Quality of life was assessed via the Functional Assessment of Cancer Therapy-General and its Melanoma-specific module. Perceived quality of life was comparable across cohorts, and a majority of the sample understood side effects from ipilimumab and the potential for a delayed treatment response. Patients without progression of disease following restaging studies at week 12 held more positive views regarding ipilimumab compared to patients who had progressed. Patients generally regarded ipilimumab positively despite the risk of unique toxicities and potential for delayed therapeutic responses; however, those with progression expressed uncertainty regarding whether taking ipilimumab was worthwhile. Physician communication practices and patient education regarding realistic expectations for therapeutic benefit as well as unique toxicities associated with ipilimumab should be developed so that patients can better understand the possible outcomes from treatment.

Background Alcohol withdrawal syndrome (AWS) is routinely treated with B-vitamins. However, the relationship between thiamine status and outcome is rarely examined. The aim of the present study was to examine the relationship between thiamine and magnesium status in patients with AWS. Methods Patients (n = 127) presenting to the Emergency Department with AWS were recruited to a prospective observational study. Blood samples were drawn to measure whole blood thiamine diphosphate (TDP) and serum magnesium concentrations. Routine biochemistry and haematology assays were also conducted. The Glasgow Modified Alcohol Withdrawal Score (GMAWS) measured severity of AWS. Seizure history and current medications were also recorded. Results The majority of patients (99%) had whole blood TDP concentration within/above the reference interval (275–675 ng/gHb) and had been prescribed thiamine (70%). In contrast, the majority of patients (60%) had low serum magnesium concentrations (2 (p Conclusion The prevalence of low circulating thiamine concentrations were rare and it was regularly prescribed in patients with AWS. In contrast, low serum magnesium concentrations were common and not prescribed. Low serum magnesium was associated more severe AWS and increased 1-year mortality.