Search

BACKGROUND Metabolic and endocrine alterations in women with polycystic ovary syndrome (PCOS) affect adipose tissue mass and distribution. PCOS is characterised by hyperandrogenism, obesity and adipocyte dysfunction. Hyperandrogenism in PCOS drives dysfunctional adipocyte secretion of potentially harmful adipocytokines. Glucocorticoids and sex-steroids modulate adipocyte development and function. For their part, adipocyte products interact with adrenal and ovarian steroidogenic cells. Currently, the relationship between adipocyte and steroidogenic cells is not clear, and for these reasons, it is important to elucidate the interrelationship between these cells in women with and without PCOS. OBJECTIVE AND RATIONALE This comprehensive review aims to assess current knowledge regarding the interrelationship between adipocytes and adrenal and ovarian steroidogenic cells in animal models and humans with or without PCOS. SEARCH METHODS We searched for articles published in English and Portuguese in PubMed. Keywords were as follows: polycystic ovary syndrome, steroidogenesis, adrenal glands, theca cells, granulosa cells, adipocytes, adipocytokines, obesity, enzyme activation, and cytochrome P450 enzymes. We expanded the search into the references from the retrieved articles. OUTCOMES Glucocorticoids and sex-steroids modulate adipocyte differentiation and function. Dysfunctional adipocyte products play important roles in the metabolic and endocrine pathways in animals and women with PCOS. Most adipokines participate in the regulation of the hypothalamic–pituitary–adrenal and ovarian axes. In animal models of PCOS, hyperinsulinemia and poor fertility are common; various adipokines modulate ovarian steroidogenesis, depending on the species. Women with PCOS secrete unbalanced levels of adipocyte products, characterised by higher levels of leptin and lower levels of adiponectin. Leptin expression positively correlates with body mass index, waist/hip ratio and levels of total cholesterol, triglyceride, luteinising hormone, oestradiol and androgens. Leptin inhibits the production of oestradiol and, in granulosa cells, may modulate 17-hydroxylase and aromatase enzyme activities. Adiponectin levels negatively correlate with fat mass, body mass index, waist–hip ratio, glucose, insulin and triglycerides, and decrease androgen production by altering expression of luteinising hormone receptor, steroidogenic acute regulatory protein, cholesterol-side-chain cleavage enzyme and 17-hydroxylase. Resistin expression positively correlates with body mass index and testosterone, and promotes the expression of 17-hydroxylase enzyme in theca cells. The potential benefits of adipokines in the treatment of women with PCOS require more investigation. WIDER IMPLICATIONS The current data regarding the relationship between adipocyte products and steroidogenic cells are conflicting in animals and humans. Polycystic ovary syndrome is an excellent model to investigate the interrelationship among adipocyte and steroidogenic cells. Women with PCOS manifest some pathological conditions associated with hyperandrogenism and adipocyte products. In animals, cross-talk between cells may vary according to species, and the current review suggests opportunities to test new medications to prevent or even reverse several harmful sequelae of PCOS in humans. Further studies are required to investigate the possible therapeutic application of adipokines in women with obese and non-obese PCOS. Meanwhile, when appropriate, metformin use alone, or associated with flutamide, may be considered for therapeutic purposes.

Background: OnabotulinumtoxinA is a novel therapeutic intervention whose mechanism of action is believed to modify the negative facial feedback, thus abating symptoms of depression. This putative new antidepressant agent offers minimal systemic side effects and negligible risk of pharmacological interactions. We set out to examine the evidence for the use of onabotulinumtoxinA in major depression. Methods: A systematic search of the literature identified double-blind randomised controlled trials (RCTs) investigating the use of onabotulinumtoxinA in the treatment of major depression versus placebo. Data, reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), was combined in meta-analyses (PROSPERO registration ID: CRD42020183538). Results: The search identified five RCTs (four double-blind) comparing onabotulinumtoxinA to placebo. OnabotulinumtoxinA was more effective than placebo when administered within the 20–40 IU dose range in double-blind RCTs. The analysis was free of publication bias and significantly heterogeneous. Meta-regression analyses indicated that onabotulinumtoxinA was more efficacious in women and in higher doses in female patients and less effective with polypharmacy, especially when an increasing number of antidepressants were prescribed. The effectiveness of onabotulinumtoxinA was higher in more recently published double-blind RCTs. Conclusion: The meta-analysis supports the efficacy of the intervention with the results being highly heterogeneous across studies. In view of the heterogeneity of the findings and the significant moderators of benefit (sex, year of study completion and the interaction between sex and dose), more research is required to better understand the role of onabotulinumtoxinA in the treatment of depression.

Introduction Pediatric patients with cardiomyopathies are at risk for sudden death and may need implantable cardioverter defibrillators (ICD’s), but given their small size and duration of use, children are at increased risk for complications associated with ICD use. The subcutaneous ICD presents a favorable option for children without pacing indications. Unfortunately, initial pediatric studies have demonstrated a high complication rate, likely due to the 3-incision technique employed. Material and methods Patients with ICD but no pacing indication were retrospectively reviewed after implantation of subcutaneous ICD via the two-incision technique. In half of the patients, 10-J impedance test was also performed to compare with impedance obtained after defibrillation threshold testing with 65-J. Results Twelve patients were included. The median age was 14 years (range 10–16 years) with eight males included (72.7%). The median weight was 55 kg (range 29 kg–75.1 kg). Follow-up had a median of 11.5 months (range 2–27 months). The median body mass index was 18.4 kg/m squared (range 15.5–27.9 kg/m squared). One patient suffered a minor complication after tearing off the incisional adhesive strips early and required a non-invasive repair in clinic. Shock impedance had a median of 55 J (range 48–68 J). There was one appropriate shock/charge and no inappropriate shocks during follow-up. Conclusion The two-incision, intermuscular technique appears to have a lower acute complication rate than prior reports, in our cohort of 12 pediatric patients.

Vascular rings (VRs) are rare aortic arch anomalies that may present with a wide variety of symptoms related to esophageal and/or airway compression. We reviewed our surgical experience in both symptomatic and asymptomatic children. All children (n = 58) who underwent surgical repair of VRs or slings (mean age 27.4 ± 45.60 months; 36 males [62%]) between March 2000 and April 2020 were included. The most common anatomic variant was a right aortic arch (RAA) with aberrant left subclavian artery (ALSCA) (n = 29; 50%). Kommerell's diverticulum was present in 23 of these patients (79%). The second most common variant was a double aortic arch (n = 22; 38%), followed by pulmonary artery sling (n = 4; 6%), RAA with mirror image branching and left ligamentum arteriosum (n = 3; 5.2%), and left aortic arch (LAA) with aberrant right subclavian artery (n = 1; 1.7%). One patient had a double ring with pulmonary artery sling and RAA with ALSCA. Symptoms were present in 42 patients (72%). Left lateral thoracotomy was the approach in 50 patients (86%), while sternotomy was used in 8 (14%). Symptomatic improvement occurred in the majority of symptomatic patients (93%). There was one perioperative mortality (1.7%) in the symptomatic group which was non-VR related. Morbidities included recurrent laryngeal nerve injury in three patients (5.2%) and transient chylothorax in two (3.4%). Persistence/recurrence of symptoms resulted in one early and one late reoperation. The mean follow-up was 3 ± 5 years. In the current era, VR repair in children including asymptomatic ones can be performed with excellent results. We recommend complete repair of RAA with aberrant LSCA by resection of Kommerell's diverticulum and translocation of the ALSCA to avoid recurrence.

PURPOSE: To assess the reasons why patients do not consent to patient-reported outcome (PRO) and electronic PRO data capture components of clinical trials and potential selection bias by having a separate consent. METHODS AND MATERIALS: Selected NRG Oncology trials were included based on disease site and inclusion of PROs and electronic PRO data capture via VisionTree Optimal Care as separate consent questions. Reasons for not participating were assessed. Pretreatment characteristics between patients who did and did not consent were tested using χ(2) and t tests for univariate comparisons and logistic regression for multivariable analyses. RESULTS: Ten trials were selected in head and neck, prostate, gynecologic, breast, lung, and gastrointestinal cancers, with 4 of these trials having electronic PRO data capture. Most patients consented to the PRO component (75.3%) but not electronic PRO data capture (37.8%). More white patients consented to PROs than nonwhite patients across all trials (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.45-0.63; P < .001), and more patients with education after high school consented compared with those with less education (OR, 1.71; 95% CI, 1.46-2.02; P < .001). Patients who are younger (OR, 0.63; 95% CI, 0.47-0.85; P = .002), white (OR, 0.60; 95% CI, 0.44-0.82; P = .001), and a never or former smoker (OR, 0.57; 95% CI, 0.41-0.78; P = .001) are more likely to participate in electronic PRO data capture. CONCLUSIONS: These results suggest that a patient’s race, age, and education can affect whether a patient chooses to consent or is offered to participate in PRO or electronic PRO data capture components. More investigation is needed, but this analysis provides support for making PROs integrated in the trial.

Objective Mechanisms of insulin resistance in polycystic ovary syndrome (PCOS) remain ill defined, contributing to sub-optimal therapies. Recognising skeletal muscle plays a key role in glucose homeostasis we investigated early insulin signalling, its association with aberrant transforming growth factor β (TGFβ)-regulated tissue fibrosis. We also explored the impact of aerobic exercise on these molecular pathways. Methods A secondary analysis from a cross-sectional study was undertaken in women with (n = 30) or without (n = 29) PCOS across lean and overweight BMIs. A subset of participants with (n = 8) or without (n = 8) PCOS who were overweight completed 12 weeks of aerobic exercise training. Muscle was sampled before and 30 min into a euglycaemic-hyperinsulinaemic clamp pre and post training. Results We found reduced signalling in PCOS of mechanistic target of rapamycin (mTOR). Exercise training augmented but did not completely rescue this signalling defect in women with PCOS. Genes in the TGFβ signalling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise training except for genes encoding LOX, collagen 1 and 3. Conclusions We provide new insights into defects in early insulin signalling, tissue fibrosis, and hyperandrogenism in PCOS-specific insulin resistance in lean and overweight women. PCOS-specific insulin signalling defects were isolated to mTOR, while gene expression implicated TGFβ ligand regulating a fibrosis in the PCOS-obesity synergy in insulin resistance and altered responses to exercise. Interestingly, there was little evidence for hyperandrogenism as a mechanism for insulin resistance.

Despite the growing off-label use of ketamine for depression and other psychiatric indications, its long-term safety profile and abuse potential remain unclear. We present a case of a patient who presented with paranoia and personality changes attributed to ketamine misuse, which illustrates the need for more robust screening and systematic monitoring with this medication. Continued evaluation of the abuse potential of ketamine in long-term treatment as well as restricted access and in-office administration are important, to develop a better understanding of the risk-benefit profile of this drug.

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Objective We report the case of a 34-year-old female diagnosed concurrently with idiopathic intracranial hypertension (IIH) and aplastic anaemia. Case A 34-year-old female with recent weight gain presented with headache and fatigue. Clinical examination revealed conjunctival pallor and occasional bruising, with fundoscopy and optic coherence tomography demonstrating bilateral papilloedema (grade III). There were enlarged blind spots bilaterally. The cerebrospinal fluid (CSF) opening pressure was greater than 30 cmH2O. An MRI brain was normal and there was no venous sinus thrombosis. A diagnosis of IIH was made, and she was treated with therapeutic removal of CSF, acetazolamide and weight loss strategies. Concurrently, a bone marrow biopsy to investigate profound panyctopaenia was consistent with aplastic anaemia. The patient had worsening IIH features during fertility preservation treatment in preparation for stem cell transplant. At five months, there was complete resolution of subretinal fluid and clinical papilloedema. Anti-thymocyte globulin and cyclosporine treatment was subsequently commenced. Conclusion Previous case reports have emphasised the interplay between the pathophysiology of anaemia and IIH,1 with treatment of aplastic anaemia contributing to resolution of IIH.2,3 We believe this is the first reported case of concomitant IIH and aplastic anaemia with resolution of papilloedema prior to treatment of anaemia. We also highlight the challenges of managing IIH during fertility and cyclosporine treatment. References Biossue V, et al. Anaemia and papilledema. American Journal of Ophthalmology 2003;135(4):437. Nazir SA, et al. Pseudotumor cerebri in idiopathic aplastic anemia. Journal of AAPOS 2003;7(1):71. Lilley ER, Bruggers CS, Pollock SC. Papilledema in a patient with aplastic anemia. Arch Ophthalmol 1990;108:1674–5.

PurposeWe report efficacy of a prospective phase 2 trial (NCT00450411) of salvage low-dose-rate (LDR) prostate brachytherapy (BT) for local failure (LF) after prior external beam radiation therapy (EBRT) with minimum 5-years' follow-up.Methods and materialsEligible patients had low/intermediate risk prostate cancer (PCa) before EBRT and biopsy-proven LF >30 months after EBRT, with prostate-specific antigen

Author(s): Hsu, I-Chow; Rodgers, Joseph P; Shinohara, Katsuto; Purdy, James; Michalski, Jeff; Roach, Mack; Vigneault, Eric; Ivker, Robert A; Pryzant, Rodger M; Kuettel, Michael; Taussky, Daniel; Gustafson, Gary S; Raben, Adam; Sandler, Howard M | Abstract: PurposeTo report the long-term outcome of patients with prostate cancer treated with external beam radiation therapy and high dose rate (HDR) brachytherapy from a prospective multi-institutional trial conducted by NRG Oncology/RTOG.Methods and materialsPatients with clinically localized (T1c-T3b) prostate cancer without prior history of transurethral resection of prostate or hip prosthesis were eligible for this study. All patients were treated with a combination of 45 Gy in 25 fractions from external beam radiation therapy and one HDR implant delivering 19 Gy in 2 fractions. Adverse events (AE) were collected using Common Toxicity Criteria for Adverse Events, version 3. Cumulative incidence was used to estimate time to severe late gastrointestinal (GI)/genitourinary (GU) toxicity, biochemical failure, disease-specific mortality, local failure, and distant failure. Overall survival was estimated using the Kaplan-Meier method.ResultsOne hundred and twenty-nine patients were enrolled from July 2004 to May 2006. AE data was available for 115 patients. Patients were National Comprehensive Cancer Network (NCCN) intermediate to very high risk. The median age was 68, T1c-T2c 91%, T3a-T3b 9%, PSA ≤10 70%, PSA g10 to ≤20 30%, GS 6 10%, GS 7 72%, and GS 8 to 10 18%. Forty-three percent of patients received hormonal therapy. At a median follow-up time of 10 years, there were 6 (5%) patients with grade 3 GI and GU treatment-related AEs, and no late grade 4 to 5 GI and GU AEs. At 5 and 10 years, the rate of late grade 3ngastrointestinal and genitourinary AEs was 4% and 5%, respectively. Five- and 10-year overall survival rates were 95% and 76%. Biochemical failure rates per Phoenix definition at 5 and 10 years were 14% and 23%. The 10-year rate of disease-specific mortality was 6%. At 5 and 10 years, the rates of distant failure were 4% and 8%, respectively. The rates of local failure at 5 and 10 years were 2% at both time points.ConclusionsCombined modality treatment using HDR prostate brachytherapy leads to excellent long-term clinical outcomes in this prospective multi-institutional trial.

Background Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Aims This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. Materials and methods International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Results Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where first- or second-line ovulation induction therapies have failed. Conclusion This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.

Context Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting 8% to 13% of women across the lifespan. PCOS affects reproductive, metabolic, and mental health, generating a considerable health burden. Advances in treatment of women with PCOS has been hampered by evolving diagnostic criteria and poor recognition by clinicians. This has resulted in limited clinical and basic research. In this study, we provide insights into the current and future research on the metabolic features of PCOS, specifically as they relate to PCOS-specific insulin resistance (IR), that may affect the most metabolically active tissue, skeletal muscle. Current Knowledge PCOS is a highly heritable condition, yet it is phenotypically heterogeneous in both reproductive and metabolic features. Human studies thus far have not identified molecular mechanisms of PCOS-specific IR in skeletal muscle. However, recent research has provided new insights that implicate energy-sensing pathways regulated via epigenomic and resultant transcriptomic changes. Animal models, while in existence, have been underused in exploring molecular mechanisms of IR in PCOS and specifically in skeletal muscle. Future Directions Based on the latest evidence synthesis and technologies, researchers exploring molecular mechanisms of IR in PCOS, specifically in muscle, will likely need to generate new hypothesis to be tested in human and animal studies. Conclusion Investigations to elucidate the molecular mechanisms driving IR in PCOS are in their early stages, yet remarkable advances have been made in skeletal muscle. Overall, investigations have thus far created more questions than answers, which provide new opportunities to study complex endocrine conditions.

Purpose/Objective(s) To determine if hypofractionated post-operative prostate bed radiotherapy (HYPORT) does not increase patient-reported genitourinary (GU) or gastrointestinal (GI) toxicity over conventionally fractionated post-operative radiotherapy (COPORT). Materials/Methods Eligibility criteria were: 1) an undetectable PSA ( Results Between July 2017 and July 2018, 298 patients were screened and 296 were randomized: 144 to HYPORT and 152 to COPORT. Compliance with the EPIC was 100% at baseline, 83% at the end of RT, 77% at 6 months, 78% at 12 months, and 73% at 24 months. At the end of RT, the HYPORT and COPORT mean GU change scores were neither clinically significant nor significantly different and remained so at 6 and 12 months. The mean GI change scores for HYPORT and COPORT were both clinically significant and significantly different at the end of RT (HYPORT mean GI = -15.0 vs COPORT mean GI = -6.8 P ≤ 0.01). However, both the HYPORT and COPORT mean GI change scores clinically and statistically significant differences were resolved at 6 and 12 months. The 24-month mean GU and GI change scores for HYPORT and COPORT remained neither clinically nor statistically significant (HYPORT mean GU = -5.2 vs COPORT mean GU = -3.0, P = 0.81; HYPORT mean GI = -2.2 vs COPORT mean GI = -1.5, P = 0.12). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT versus COPORT for biochemical failure defined as a PSA ≥ 0.4 ng/mL followed by a value higher than the first by any amount (2-yr actuarial, 12% vs 8%, P = 0.29) or local failure (2-yr actuarial, 0.7% vs 0.8%, P = 0.35). Conclusion HYPORT is non-inferior to COPORT in terms of late patient-reported GU or GI toxicity. More follow-up is needed to appropriately assess disease control endpoints. In some clinic scenarios, HYPORT may be considered an acceptable practice standard.

A male infant was born at 22 5/7 weeks gestation with a birth weight of 520 g. He developed rapidly progressing pulmonary hypertension (PH) felt to be secondary to chronic lung disease of extreme prematurity. By 2 months of age, echocardiogram revealed moderate-severely depressed right ventricular

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance and impaired energy metabolism in skeletal muscle, the aetiology of which is currently unclear. Here, we mapped the gene expression profile of skeletal muscle from women with PCOS and determined if cultured primary myotubes retain the gene expression signature of PCOS in vivo. Transcriptomic analysis of vastus lateralis biopsies collected from PCOS women showed lower expression of genes associated with mitochondrial function, while the expression of genes associated with the extracellular matrix was higher compared to controls. Altered skeletal muscle mRNA expression of mitochondrial-associated genes in PCOS was associated with lower protein expression of mitochondrial complex II–V, but not complex I, with no difference in mitochondrial DNA content. Transcriptomic analysis of primary myotube cultures established from biopsies did not display any differentially expressed genes between controls and PCOS. Comparison of gene expression profiles in skeletal muscle biopsies and primary myotube cultures showed lower expression of mitochondrial and energy metabolism-related genes in vitro, irrespective of the group. Together, our results show that the altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the in vivo extracellular milieu, rather than genetic or epigenetic factors, may drive this alteration. Dysregulation of mitochondrial-associated genes in skeletal muscle by extracellular factors may contribute to the impaired energy metabolism associated with PCOS.

Background & Methods: We conducted an online COVID-19 survey as the vaccines became available, utilising the UK MS Register, to understand people with multiple sclerosis (pwMS) views on COVID-19 vaccination and the subsequent vaccine uptake rates. Results & Conclusion: 94.4% of 3191 pwMS surveyed indicated they would get a COVID-19 vaccine, while 5.6% would not. PwMS who have previously had an influenza vaccine, increasing age and the perception of having sufficient information about the vaccine were associated with increased likelihood of getting a vaccine. 51.7% of 3191 pwMS completed a follow-up survey indicating they received at least 1 dose of a COVID-19 vaccine. The proportion having had the vaccination based on their prior opinions was 53.2% in ‘Yes’ group and 27.0% in ‘No’ group, the latter reflecting a change based on their initial views. More information on COVID-19 vaccine safety in pwMS would be helpful for people to make informed decisions.

In the early phases of the UK COVID-19 outbreak, in the absence of clear evidence about the risks for people with multiple sclerosis (pwMS) and those taking immunomodulatory disease-modifying therapies (DMT), we launched a community-based study as part of the UK MS Register (UKMSR). We intended to capture the picture of COVID-19 among pwMS and their risk of contracting the disease. Here, we report our findings from 17 March to 24 April 2020. The COVID-19 study (clinicaltrials.gov:NCT04354519) is a prospective observational cohort launched on 17 March 2020 as part of the UKMSR (Ethics:16/SW/0194). PwMS completed a specific COVID-19 related survey which was combined with data held from before the pandemic where available. The primary outcome of the study is participant-reported self-diagnosis of COVID-19. Participants were asked if their diagnosis was confirmed by testing—the available test in the UK was reverse transcriptase-PCR. Participants reported if their sibling without MS, closest in age who was not living with them, had self-diagnosed COVID-19. The likelihood of having COVID-19 was assessed using multivariable regression analysis with the variables: age, gender, ethnicity, MS duration and type, self-isolation and DMTs. DMTs were considered after stratifying based on moderate-efficacy versus high-efficacy therapies (table 1). Disability was assessed using the last recorded web-based Expanded Disability Status Scale (webEDSS) or MS Impact Scale v2 (MSIS-29v2). View this table: Table 1 Distribution of individual disease-modifying therapies (DMTs) among participants of the COVID-19 study As of 24 April, out of 3910 participants, 237 (6.1% (95% CI 5.3% to 6.8%)) reported self-diagnosed COVID-19 among whom 54 (22.8% (17.5% to 28.2%)) also had a diagnosis by a healthcare professional based on symptoms and 37 (15.6% (11.2% to 20.6%)) a confirmed diagnosis by testing. Three participants reported hospitalisation due to COVID-19. No deaths were reported. Among 1283 siblings without MS, 79 (6.2%) had a reported diagnosis of COVID-19. …

PURPOSE: NRG Oncology, part of the National Cancer Institute’s National Clinical Trials Network, took efforts to increase patient reported outcome measures (PROMs) completion and institutional data submission rates within clinical trials. Lack of completion diminishes power to draw conclusions and can be a waste of resources. It is hypothesized that trials with automatic email reminders and past due notifications will have PROM forms submitted more timely with higher patient completion. METHODS: Automatic emails sent to the research associate were added to selected NRG Oncology trials. Comparisons between trials with and without automatic emails were analyzed using Chi-square tests with respect to patient completion and timeliness of form submission rates. Multivariable analyses were conducted using repeated measures generalized estimating equations. If PROMs were not completed, a form providing the reason why was submitted and counted towards form submission. RESULTS: For both disease sites, form submission was significantly higher within one month of the form’s due date for the studies with automatic emails vs. those without (prostate: 79.7% vs. 75.7%, p

Anomalous aortic origin of the pulmonary artery is rare. It can affect either of the main branches and can be an important cause of neonatal respiratory distress. Early diagnosis and surgical repair is associated with improved survival and long-term outcomes.

We present here a case of an infant who was prenatally diagnosed with an isolated left atrial appendage aneurysm. Although asymptomatic, we proceeded with surgical resection due to rapid progression of aneurysm size. Multimodality imaging – transthoracic echocardiography, transesophageal echocardiography, and cardiac computed tomography – was used for procedural planning, from which a detailed 3D computational model and 3D print of this patient’s heart were created. The aneurysmectomy was performed at 6 months of age, with an uneventful postoperative course.

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder affecting metabolic, reproductive and mental health of 8-13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 85% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole body insulin-stimulated glucose uptake, however, in PCOS this is reduced about 27% when assessed by hyperinsulinemic euglycemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). Previous work suggested that Transforming Growth Factor Beta (TGFβ) superfamily ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30ng/ml), a novel TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=10) and healthy controls (n=10). AMH negatively affected glucose uptake and insulin signalling increasing p-IRS1 (ser312) in a dose-dependent manner in myotubes from both women with and without PCOS. AMH did not appear to activate the canonical TGFβ/BMP signalling pathway. Conversely, TGFβ1 had an opposite effect in both PCOS and control myotubes cultures, decreasing phosphorylation of IRS1 (ser312) and enhancing glucose uptake via Smad2/3 signalling. In conclusion, these results suggest that AMH may play a role in skeletal muscle IR observed in PCOS, however, further research is required to elucidate its mechanisms of action and broader impact in this syndrome. References: (1) Stepto et al. Hum Reprod 2013 Mar;28(3):777-784. (2) Cassar et al. Hum Reprod 2016 Nov;31(11):2619-2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al. J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372-5381. (5) Raja-Khan et al. Reprod Sci 2014 Jan;21(1):20-31.

Objective: To assess the feasibility of collaboration and retrospective data harmonization among three multiple sclerosis (MS) registries by investigating employment status. Methods: We used the Maelstrom guidelines to facilitate retrospective harmonization of data from three MS registries, including the NARCOMS (North American Research Committee on MS) Registry, German MS Register (GMSR), and United Kingdom MS (UK-MS) Register. A protocol was developed based on the guidelines, and summary-level data were used to combine results. Employment status and a limited set of factors associated with employment (age, sex, education, and disability level) were harmonized. A meta-analytic approach was used to pool estimates using a weighted average of logistic regression estimates and their variances in a random effects model. Results: Employment status, age, sex, education, and disability were mapped. The overall employment rate was 57% (11,143 employed out of 19,562 persons with MS) with the GMSR having the highest proportion of participants employed (66.2%), followed by the UK-MS (55.2%) and NARCOMS (43.0%) registries. As disability level increased, the odds of not being employed increased. Conclusion: Harmonization across registries was feasible. The Maelstrom guidelines provide a valuable roadmap for conducting high-quality harmonization projects. The pooling of data sources has the potential to be an important mechanism for conducting research in MS.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting the reproductive, metabolic and psychological health of women. Clinic-based studies indicate that sleep disturbances and disorders including obstructive sleep apnea and excessive daytime sleepiness occur more frequently among women with PCOS compared to comparison groups without the syndrome. Evidence from the few available population-based studies is supportive. Women with PCOS tend to be overweight/obese, but this only partly accounts for their sleep problems as associations are generally upheld after adjustment for body mass index; sleep problems also occur in women with PCOS of normal weight. There are several, possibly bidirectional, pathways through which PCOS is associated with sleep disturbances. The pathophysiology of PCOS involves hyperandrogenemia, a form of insulin resistance unique to affected women, and possible changes in cortisol and melatonin secretion, arguably reflecting altered hypothalamic–pituitary–adrenal function. Psychological and behavioral pathways are also likely to play a role, as anxiety and depression, smoking, alcohol use and lack of physical activity are also common among women with PCOS, partly in response to the distressing symptoms they experience. The specific impact of sleep disturbances on the health of women with PCOS is not yet clear; however, both PCOS and sleep disturbances are associated with deterioration in cardiometabolic health in the longer term and increased risk of type 2 diabetes. Both immediate quality of life and longer-term health of women with PCOS are likely to benefit from diagnosis and management of sleep disorders as part of interdisciplinary health care. Refereed/Peer-reviewed

Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting metabolic and reproductive health of 8–13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 38–95% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole-body insulin-stimulated glucose uptake; however, in PCOS this is reduced by about 27% when assessed by a euglycaemic-hyperinsulinaemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that in vivo environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). A potential environmental mechanism contributing to the development of peripheral IR may be the extracellular matrix remodelling and aberrant transforming growth factor beta (TGFβ) signalling. Previous work demonstrated that TGFβ superfamily ligands are involved in the increased collagen deposition and fibrotic tissue in the ovaries, and suggested that these ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5 ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30 ng/ml), a TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=5) and healthy controls (n=5). TGFβ1 did not have a significant effect on insulin signalling but induced expression of some ECM related genes and proteins, and increased glucose uptake via Smad2/3 signalling in myotubes from both groups. Conversely, AMH did not appear to activate the TGFβ/Smad signalling pathway and had no significant impact on insulin signalling or glucose uptake in any of the groups. In conclusion, these findings suggest that TGFβ1, but not AMH, may play a role in skeletal muscle ECM remodelling/fibrosis and glucose metabolism in PCOS but does not have a direct effect on insulin signalling pathway. Further research is required to elucidate its contribution to the development of in vivo skeletal muscle IR and broader impact in this syndrome. References: (1) Stepto et al., Hum Reprod 2013 Mar;28(3):777–784. (2) Cassar et al., Hum Reprod 2016 Nov;31(11):2619–2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al., J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372–5381. (5) Raja-Khan et al., Reprod Sci 2014 Jan;21(1):20–31.

Background\ud In March 2020, the United Kingdom Multiple Sclerosis Register (UKMSR) established an electronic case return form, designed collaboratively by MS neurologists, to record data about COVID-19 infections in people with MS (pwMS).\ud \ud Objectives\ud Examine how hospital admission and mortality are affected by disability, age and disease modifying treatments (DMTs) in people with Multiple Sclerosis with COVID-19.\ud \ud Methods\ud Anonymised data were submitted by clinical teams. Regression models were tested for predictors of hospitalisation and mortality outcomes. Separate analyzes compared the first and second ‘waves’ of the pandemic.\ud \ud Results\ud Univariable analysis found hospitalisation and mortality were associated with increasing age, male gender, comorbidities, severe disability, and progressive MS; severe disability showed the highest magnitude of association. Being on a DMT was associated with a small, lower risk. Multivariable analysis found only age and male gender were significant. Post hoc analysis demonstrated that factors were significant for hospitalisation but not mortality. In the second wave, hospitalisation and mortality were lower. Separate models of the first and second wave using age and gender found they had a more important role in the second wave.\ud \ud Conclusions\ud Features associated with poor outcome in COVID-19 are similar to other populations and being on a DMT was not found to be associated with adverse outcomes, consistent with smaller studies. Once in hospital, no factors were predictive of mortality. Reassuringly, mortality appears lower in the second wave.

PURPOSE/OBJECTIVE(S) Decipher is a prognostic 22-gene genomic classifier (GC) prospectively validated post-prostatectomy. Herein, we validate the performance of the GC in pre-treatment biopsy samples within the context of three randomized phase III high-risk definitive radiotherapy trials. MATERIALS/METHODS Following a pre-specified and approved CTEP-CCSC analysis plan (NRG-GU-TS006), we obtained all available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on NRG/RTOG 9202, 9413, and 9902 phase III randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability of GC for distant metastases (DM), and secondary was prostate cancer-specific mortality (PCSM) and overall survival (OS), with Cox multivariable analyses (MVA). RESULTS GC scores were obtained on 385 samples (n = 90 on 9202, n = 172 on 9413, and n = 123 on 9902), of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9, 13). On MVA, the GC (per 0.1 unit) was independently associated with DM (HR 1.24, 95% CI 1.11-1.39), PCSM (HR 1.27, 95% CI 1.13-1.43), and OS (HR 1.12, 95% CI 1.05-1.20) after adjusting for age, PSA, Gleason score, cT-stage, trial, and randomized treatment arm. For categorical GC, on MVA, GC score ≥ 0.45 (representing the intermediate and high GC categories) had worse DM (HR 2.18, 95% CI 1.25-3.80), PCSM (HR 2.34, 95% CI 1.31-4.16), and OS (HR 1.45, 95% CI 1.03-2.04) outcomes as compared to those with low GC. Cumulative incidence of distant-metastasis at 10-years was 29% (95% CI 20-38%) for intermediate/high GC vs 13% (95% CI 7-18%) for low GC. For the subset with GC > 0.85, the threshold for inclusion in the intensification study of NRG GU009 (PREDICT-RT), at 5-years and 10-years DM was 29% (95% CI 7-52%) and 41% (95% CI 17-66%). GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy (ADT). CONCLUSION This is the first validation of any gene expression biomarker on pre-treatment biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT will further determine the optimal therapy based on GC score. NCT04513717.

PURPOSE/OBJECTIVE(S) To report the PROs of a phase III randomized trial evaluating TAS combined with dose-escalated RT for patients with intermediate risk prostate cancer. MATERIALS/METHODS Eligible patients had intermediate risk prostate cancer defined as harboring ≥ 1 of these risk factors: clinical stage T2b-T2c, Gleason score 7, or PSA > 10 to ≤ 20 ng/mL. Patients were randomized to dose-escalated RT alone (Arm 1) or RT plus TAS (Arm 2) consisting of LHRH agonist/antagonist with oral antiandrogen for 6 months. Validated PROs included the Expanded Prostate Cancer Index Composite (EPIC-50) and Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue short form. PRO change scores, calculated for each patient as the follow-up score minus baseline score (at end of RT, 6, 12, and 60 months from start of RT) were compared between treatment arms using a two-sample t test. An effect size (ES) of 0.50 SD (standard deviation) of the baseline measure was considered clinically meaningful. For the PRO sample size, 200 patients per arm would provide 90% statistical power to detect an ES < 0.50 if the completion rate was only 60%. Mixed effect regression models were also utilized. Clinical outcomes are reported in a separate abstract. RESULTS Of the 402 initial planned subset of trial patients who completed baseline PROs, PRO compliance was approximately 96%, 89%, 86% and 87% at end of RT, 6, 12 and 60 months, respectively. There were no significant differences between these 402 patients and the remaining patients on this trial with respect to age, race, performance status, # risk factors, or comorbidity score. While EPIC urinary and bowel scores decreased significantly by the end of RT in both arms, no clinically meaningful differences between arms were detected over time. For the EPIC hormonal and sexual domains, however, there were clinically meaningful differences between the two arms with greater (P < 0.0001) deficits in the RT + TAS arm. These differences improved over time, with ∼50% resolution by one year after treatment and no clinically meaningful differences by 5 years between arms. PROMIS-fatigue scores increased from baseline in both arms and were significantly higher in arm 2 at the end of RT (P = 0.016), though slightly lower at 12 and 60 months. CONCLUSION The addition of TAS to dose-escalated RT demonstrated significant clinically meaningful declines in the EPIC hormonal and sexual domains, and increases in the PROMIS-fatigue scores, compared to RT alone. These scores gradually improved over time, with no clinically meaningful differences between arms in fatigue by one year, or in hormonal and sexual domains by 5 years. Beyond the clinical outcomes, these PRO results directly from patients provide added value to help patients make informed decisions among treatment options.

Mucopolysaccharidosis IH (MPS IH, Hurler syndrome) naturally leads to death within the first decade of life, primarily from cardiac and pulmonary causes. To determine how hematopoietic stem cell transplantation (HSCT) has altered mortality, we analyzed our institution’s 30-year experience of patients with MPS IH undergoing HSCT. Using chart review and the National Death Index, we determined survival status of 134 patients (males = 69) with MPS IH transplanted between 9/16/1983 and 7/25/2013 on 12/31/2013. Analysis included descriptive statistics, Kaplan-Meier curves, and regression analysis by Cox proportional hazards model. Overall survival (95% CI) at one- and 25-years was 70% (62–78%) and 37% (19–55%), respectively. From 2004 onward, overall survival at one- and 8-years was 84% (73–96%) and 81% (69–94%), respectively, compared to 65% (55–74%) and 57% (47–67%) prior to 2004 (Log-rank p = 0.032). Regardless of era, male survival was significantly better than female (HR 0.40, [95% CI: 0.21–0.74], p = 0.004). The cumulative incidence of death (95% CI) at 25 years was 63% (45–81%); incidence of pulmonary-related death was the highest at 27% (10–41%) compared to 8% (0.3–16%) for cardiac, 12% (6–17%) for infectious disease, and 16% (3–27%) from other complications. HSCT has increased survival in MPS IH beyond the third decade of life and decreased the incidence of cardiac mortality, but deaths after the third year post-HSCT occur in excess of expected US mortality. It is important to determine if improved transplant strategies since 2004 result in better long-term survival in the current patient population.

Background Intraoperative vascular imaging is a useful tool to evaluate coronary ostia in congenital heart patients with suboptimal preoperative imaging findings. Additionally, vascular imaging has potential value for visualization of the ascending aortic intima media thickness (IMT) in certain clinical scenarios. This study sought to evaluate the feasibility of intraoperative vascular imaging of coronary ostia and IMT during congenital heart surgery. Methods We describe the technique for performance of intraoperative vascular imaging by a pediatric cardiologist using a high-resolution linear sequential array transducer. Results Intraoperative vascular imaging was obtained on seven patients. Coronary ostia were normal in all except one. This patient had congenital stenosis of the left coronary ostium discovered during intraoperative imaging and confirmed by the surgeon. In another patient with Williams syndrome, the IMT was noted to be prominent. Conclusions It is feasible to perform intraoperative vascular imaging in less than 5 minutes of operator's time and provides superior visualization of the coronary ostia and IMT.

Objective Many complex diseases exhibit co-morbidities often requiring management by more than one health specialist. We examined cross-speciality issues that ultimately affect the health and wellbeing of patients with polycystic ovary syndrome (PCOS). PCOS was originally described as a reproductive condition but is now recognised to also be a metabolic and psychological condition affecting 8–13% of women of reproductive age. With a four-fold increased risk of type 2 diabetes (DM2), the Population Attributable Risk of DM2 that could be avoided if PCOS were eliminated is a substantial 19–28% of women of reproductive age. To determine the extent to which PCOS is an important consideration in diabetes development, we examined publications, funding, guidelines and predictors of risk of developing DM2. Results We found that the topic of PCOS appeared in specialist diabetes journals at only 10% the rate seen in endocrinology journals – about 1 in 500 articles. We found research funding to be substantially less than for diabetes and found that diabetes guidelines and predictive tools for DM2 risk mostly ignore PCOS. This is surprising since insulin resistance in women with PCOS has a different aetiology and additionally women with PCOS are at increased risk of becoming overweight or obese – high risk factors for DM2. Conclusions We consider the causes of these concerning anomalies and discuss current activities to address the co-morbidities of PCOS, including the recent development of international guidelines, an international PCOS awareness program and potentially changing the name of PCOS to better reflect its metabolic consequences.

This review aims to describe the assessment of pulmonary hypertension and ventricular function in neonates with congenital diaphragmatic hernia and the long-term follow-up of their pulmonary vascular disease. In 2015, the pediatric pulmonary hypertension guidelines from the American Heart Association and American Thoracic Society suggested class I level of evidence B guidelines for routine evaluation of patients with congenital diaphragmatic hernia, including longitudinal care in an interdisciplinary pulmonary hypertension program and following the recommendations offered for all children with pulmonary hypertension. Congenital diaphragmatic hernia causes compression of the lungs during critical stages of fetal development and results in lung hypoplasia. As a result, there is abnormal development of pulmonary vasculature that leads to post-natal pulmonary hypertension and increased afterload to the right ventricle. Left ventricular filling is affected by decreased pre-load and mechanical compression by abdominal content leading to decreased systemic perfusion. Persistent pulmonary hypertension after surgical repair of congenital diaphragmatic hernia is associated with increased mortality. Assessment and monitoring of pulmonary hypertension and ventricular function in this population of neonates is crucial to determine response to medical treatment, the need for extracorporeal membrane oxygenation, and the timing of surgical repair.

This report documents a case of sinus bradycardia in a hospitalised 27-month-old girl with a history of moderate persistent asthma, recent suspected viral respiratory infection and suspicion for multisystem inflammatory syndrome in children (MIS-C). This patient developed profound sinus bradycardia during her hospitalisation despite an overall well clinical appearance and good outcome. Reports of bradycardia related to COVID-19 infection are few but growing in number. In this article, we discuss what has been observed in the literature about bradycardia in relation to COVID-19 and MIS-C. We also propose sinus bradycardia as a potential sign of MIS-C with recent respiratory symptoms, which would warrant close follow-up of such patients.

Breeding bulls are commonly fed high-energy diets, which may induce subacute ruminal acidosis (SARA). In this experiment, 8 Santa Gertrudis bulls (age 20 ± 6 mo) were used to evaluate the extent and duration of effects of SARA on semen quality and the associated changes in circulating hormones and metabolites. The bulls were relocated and fed in yards with unrestricted access to hay and daily individual concentrate feeding for 125 d before SARA challenge. Semen was collected and assessed at 14-d intervals before the challenge to ensure acclimatization and the attainment of a stable spermiogram. The challenge treatments consisted of either a single oral dose of oligofructose (OFF; 6.5 g/kg BW) or an equivalent sham dose of water (Control). Locomotion, behavior, respiratory rate, and cardiovascular and gastrointestinal function were intensively monitored during the 24-h challenge period. Rumen fluid samples were retained for VFA, ammonia, and lactate analysis. After the challenge, semen was then collected every third day for a period of 7 wk and then once weekly until 12 wk, with associated blood collection for FSH, testosterone, inhibin, and cortisol assay. Percent normal sperm decreased in bulls dosed with OFF after the challenge period (P < 0.05) and continued to remain lower on completion of the study at 88 d after challenge. There was a corresponding increase in sperm defects commencing from 16 d after challenge. These included proximal cytoplasmic droplets (P < 0.001), distal reflex midpieces (P = 0.01), and vacuole and teratoid heads (P < 0.001). Changes in semen quality after challenge were associated with lower serum testosterone (P < 0.001) and FSH (P < 0.05). Serum cortisol in OFF bulls tended to be greater (P = 0.07) at 7 d after challenge. This study shows that SARA challenge causes a reduction in sperm quality sufficient to preclude bulls from sale as single sire breeding animals 3 mo after the event occurred.

Apolipoprotein (apo) A-IV, the third most abundant HDL-associated protein, is atheroprotective and shares similar properties as apoA-I. We have reported previously that apoA-I, the most abundant apolipoprotein in HDL, inhibits plaque disruption in a mouse model. We aimed at examining the effects of apoA-IV on markers of plaque stability in vivo.Plaques within brachiocephalic arteries of 16-week old apoE-knockout C57BL/6 mice were examined for changes in composition after 10 weeks on a high-fat diet (HFD). The animals received twice-weekly injections of human lipid-free apoA-IV (1 mg/kg, n = 31) or PBS (n = 32) during the 9th and 10th weeks of the HFD.In the apoA-IV treated mice, there were significantly fewer hemorrhagic plaque disruptions (9/31 vs. 18/32, p 0.05), thicker fibrous caps, smaller lipid cores, a lower macrophage:SMC ratio, less MMP-9 protein, more collagen, and fewer proliferating cells. In the plaques of mice given apoA-IV, MCP-1, VCAM-1, and inducible NOS were also significantly lower. Based on the percentage of cleaved PARP-positive and TUNEL-positive plaque nuclei, apoA-IV reduced apoptosis. in HMDMs, apoA-IV reduced MMP-9 mRNA expression by half, doubled mRNA levels of TIMP1 and decreased MMP-9 activity.ApoA-IV treatment is associated with a more stable plaque phenotype and a reduced incidence of acute disruptions in this mouse model.

Over the past two decades there have been significant advances in our understanding of both the anatomy and function of the melanopsin system. It has become clear that rather than acting as a simple irradiance detector the melanopsin system is in fact far more complicated. The range of behavioural systems known to be influenced by melanopsin activity is increasing with time, and it is now clear that melanopsin contributes not only to multiple non-image forming systems but also has a role in visual pathways. How melanopsin is capable of driving so many different behaviours is unclear, but recent evidence suggests that the answer may lie in the diversity of melanopsin light responses and the functional specialisation of photosensitive retinal ganglion cell (pRGC) subtypes. In this review, we shall overview the current understanding of the melanopsin system, and evaluate the evidence for the hypothesis that individual pRGC subtypes not only perform specific roles, but are functionally specialised to do so. We conclude that while, currently, the available data somewhat support this hypothesis, we currently lack the necessary detail to fully understand how the functional diversity of pRGC subtypes correlates with different behavioural responses, and ultimately why such complexity is required within the melanopsin system. What we are lacking is a cohesive understanding of how light responses differ between the pRGC subtypes (based not only on anatomical classification but also based on their site of innervation); how these diverse light responses are generated, and most importantly how these responses relate to the physiological functions they underpin.

This secondary analysis of a randomized clinical trial examines the effect of androgen deprivation therapy (ADT) during radiotherapy in patients who were classified as having either favorable intermediate-risk or unfavorable intermediate-risk prostate cancer.

333 Background: High-risk, localized prostate cancer has a poor prognosis. We hypothesized that adj docetaxel (D) and prednisone and long-term (24 mos) androgen suppression (AS) and radiation therapy (RT) would improve overall survival (OS) and tested this in NRG/RTOG 0521. Results with med follow-up of 5.7 yrs were reported (JCO 37:1159, 2019), showing a benefit of D (HR=0.69, 90% CI: 0.49-0.97, 1-sided p=0.034). Med follow-up is now 10.4 yrs and we report updated results for OS and metastasis (DM). Methods: NRG/RTOG 0521 opened 12/05 and closed 8/09 with targeted accrual of 600 and designed to detect a HR of 0.49, based on improvement in 4-yr OS from 86 to 93%. With 0.05 1-sided type I error and 90% power >78 deaths were required. Pts were stratified by predefined risk groups. Group 1: Gl 9-10, any T; Group 2: Gl 8, PSA

Purpose Fluorouracil plus cisplatin and radiation twice a day (FCT) is an established chemoradiation (CRT) regimen for selective bladder-sparing treatment of muscle-invasive bladder cancer. Gemcitabine and once daily radiation (GD) is a well-supported alternative. The current trial evaluates these regimens. Methods Patients with cT2-4a muscle-invasive bladder cancer were randomly assigned to FCT or GD. Patients underwent transurethral resection and induction CRT to 40 Gy. Patients who achieved a complete response (CR) received consolidation CRT to 64 Gy and others underwent cystectomy. We administered adjuvant gemcitabine/cisplatin chemotherapy. The primary end point was the rate of freedom from distant metastasis at 3 years (DMF3). The trial was not statistically powered to compare regimens, but to assess whether either regimen exceeded a DMF3 benchmark of 75%. Toxicity and efficacy end points, including CR and bladder-intact distant metastasis free survival at 3 years (BI-DMFS3), were assessed. Results From December 2008 to April 2014, 70 patients were enrolled, of which 66 were eligible for analysis, 33 per arm. Median follow-up was 5.1 years (range, 0.4 to 7.8 years) for eligible living patients. DMF3 was 78% and 84% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. Postinduction CR rates were 88% and 78%, respectively. Of 33 patients in the FCT arm, 21 (64%) experienced treatment-related grade 3 and 4 toxicities during protocol treatment, with 18 (55%), two (6%), and two patients (6%) experiencing grade 3 and 4 hematologic, GI, and genitourinary toxicity, respectively. For the 33 patients in the GD arm, these figures were 18 (55%) overall and 14 (42%), three (9%) and two patients (6%), respectively. Conclusion Both regimens demonstrated DMF3 greater than 75%. There were fewer toxicities observed in the GD arm. Either gemcitabine and once daily radiation or a cisplatin-based regimen could serve as a base for future trials of systemic therapy.

This paper evaluates the use of accelerometers for continuous monitoring of respiratory rate (RR), which is an important vital sign in post-intensive care patients or those inside the intensive care unit (ICU). The respiratory rate can be estimated from accelerometer and photoplethysmography (PPG) signals for patients following ICU discharge. Due to sensor faults, sensor detachment, and various artifacts arising from motion, RR estimates derived from accelerometry and PPG may not be sufficiently reliable for use with existing algorithms. This paper described a case study of 10 selected patients, for which fewer RR estimates have been obtained from PPG signals in comparison to those from accelerometry. We describe an algorithm for which we show a maximum mean absolute error between estimates derived from PPG and accelerometer of 2.56 breaths/min. Our results obtained using the 10 selected patients are highly promising for estimation of RR from accelerometers, where significant agreements have been observed with the PPG-based RR estimates in many segments and across various patients. We present this research as a step towards producing reliable RR monitoring systems using low-cost mobile accelerometers for monitoring patients inside the ICU or on the ward (post-ICU).