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BACKGROUND Adolescents and young adults have health needs which are distinctly different from children and adults. A lack of education and training is reported by clinicians to be one of the main barriers to providing comprehensive developmentally appropriate care to young people, including the provision of confidential healthcare and taking a holistic approach. AIM This study documents the current provision of care to young people on an adult inpatient medical ward at a large tertiary teaching hospital in Auckland. METHODS Forty-three staff and 40 patients aged 16-24 years on an adult medical ward completed surveys, which were based on the Northern Regional Alliance, Northern Regional Youth Health Network Standards for Quality Care for Adolescents and Young Adults in Secondary or Tertiary Care. RESULTS Few staff (12%) had completed any specific training in looking after adolescent and young adult (AYA) patients. Confidentiality was not routinely discussed with young people by 50% of clinicians, and only 23% of staff reported that they see a young person alone as part of their consultation or admission. Less than half of young people reported receiving a comprehensive psychosocial assessment that included sexual health, mental health and suicide, and safety. CONCLUSIONS Key components of comprehensive developmentally appropriate healthcare were not regularly carried out by staff on an adult medical ward. These findings suggest that further education and training, and service improvements are needed in tertiary adult hospital settings. This article is protected by copyright. All rights reserved.

BACKGROUND Lack of validated and responsive outcome measures in the management of Frontal Fibrosing Alopecia (FFA) significantly limits our ability to assess disease progression and treatment response over time. OBJECTIVES The aim of this study was to understand how FFA extent and progression is currently assessed in UK specialist centres, validate components of the International FFA Cooperative Group (IFFACG) statement on FFA assessment, and identify pragmatic advice to improve FFA management in clinic. METHODS Consultant Dermatologists with a specialist interest in hair loss (n=17) were invited to take part. Preferred FFA assessment methods were explored using questionnaires and clinical scenarios. Participants were asked to identify and mark the current hairline in 10 frontal and 10 temporal hairline images, with assessment repeated 3 months later (to assess intra-individual variability) and 12 months later (to test whether inter-individual accuracy could be improved with simple instruction). RESULTS All 17 clinicians (100%) completed the questionnaire at each time interval. We identified a wide variation in assessment techniques between our experts. Measurements were perceived as the most accurate method of assessing frontal recession whereas photography was preferred for temporal recession. Inter-rater reliability between clinicians measuring the frontal hairline scenarios indicated a moderate strength of agreement (ICC 0.613; 95% CI: 0.398 to 0.848), yet intra-rater reliability was found to be poor with wide limits of agreement (-8.71mm to 9.92mm) on follow-up. Importantly, when clear guidance was provided on how the hairline should be identified (questionnaire 3), inter-rater reliability improved significantly, with an ICC 0.702 suggesting moderate agreement (95% CI: 0.508 to 0.890; p

Objective To determine men's satisfaction with and the potential acceptability of 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) when used for 28 days as an experimental, once-daily, oral hormonal male contraceptive (HMC). Study design We surveyed participants from a double-blind, randomized, placebo-controlled, phase 1 clinical trial, examining their experience with and willingness to use daily oral 11β-MNTDC for male contraception. Results Of 42 trial participants, 40 (30 11β-MNTDC, 10 placebo) completed baseline and end-of-treatment surveys. Based on a 28-day experience, few cited any baseline concerns about safety and drug adherence. Following treatment, nearly three-quarters (72.5%) of participants reported satisfaction with the study drug and nearly all (92.5%) would recommend the method to others. More than half of participants would be willing to pay for the study drug (62.5%) and indicated that the method exceeded initial expectations (53.9%). Nearly 90% reported that taking the pill was easy to remember and did not interfere with their daily routines. Approximately one-third of participants reported bothersome side effects (37% 11β-MNTDC vs. 20% placebo, p = 0.45). Given the option, 42% of participants would prefer a daily HMC pill over injectable regimens or a daily topical gel. Conclusion A majority of participants in this short-term trial of daily oral 11β-MNTDC reported satisfaction with the regimen, would recommend it to others, and would pay to use the drug as HMC despite some bothersome side effects. Implications Oral 11β-MNTDC would be an acceptable and preferable method among men desiring reversible hormonal male contraception (HMC). These data support further trials of novel oral HMCs such as 11β-MNTDC.

Background: The prevalence of stillbirth in many high income countries like Australia has remained unchanged for over 30 years. The 2018 Australian government Senate Select Committee on Stillbirth Research and Education highlighted the need for a public health campaign to encourage public conversations and increase awareness. However, there is little evidence about the community's knowledge and perceptions towards pregnancy and stillbirth, nor their aspirations for a public health campaign. Aims: To assess the general knowledge, perceptions, myths and attitudes towards stillbirth to inform future public health campaigns. Methods: Australian participants (n = 344; predominately women n = 294 (85.5%)) were recruited via Facebook.com. They completed a cross-sectional online survey designed to assess their knowledge of pregnancy and stillbirth, with additional questions on socio-demographic characteristics. Results: Stillbirth knowledge and awareness of incidence was low in this sample. Prominent myths, such as baby runs out of room in the uterus (n = 112, 33%) and baby slows down when preparing for labour (n = 24, 27%) were endorsed. Only 25% (n = 85) knew the prevalence of stillbirth in Australia (six per day). Almost two-thirds (n = 205; 62%) agreed that there needs to be a public health campaign, however one in five (n = 65; 20%) were concerned that talking about stillbirth with pregnant women may cause them to worry. Discussion and conclusion: Our findings reinforce the need for a targeted campaign, which educates the general population about the definition and prevalence of stillbirth, stillbirth risks and modifiable health behaviours. Appropriate messaging should target pregnant women during antenatal care as well as their support and care systems (family, friends, and care providers).53 Refereed/Peer-reviewed

Background We previously reported the Alopecia Areata Consensus of Experts study, which presented results of an international expert opinion on treatments for alopecia areata. Objective To report the results of the Alopecia Areata Consensus of Experts international expert opinion on diagnosis and laboratory evaluation for alopecia areata. Methods Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Consensus threshold was set at greater than or equal to 66%. Results Of 148 questions, expert consensus was achieved in 82 (55%). Round 1 consensus was achieved in 10 of 148 questions (7%). Round 2 achieved consensus in 47 of 77 questions (61%). The final face-to-face achieved consensus in 25 of 32 questions (78%). Consensus was greatest for laboratory evaluation (12 of 14 questions [86%]), followed by diagnosis (11 of 14 questions [79%]) of alopecia areata. Overall, etiopathogenesis achieved the least category consensus (31 of 68 questions [46%]). Limitations The study had low representation from Africa, South America, and Asia. Conclusion There is expert consensus on aspects of epidemiology, etiopathogenesis, clinical features, diagnosis, laboratory evaluation, and prognostic indicators of alopecia areata. The study also highlights areas where future clinical research could be directed to address unresolved hypotheses in alopecia areata patient care.

BackgroundThe health disadvantages faced by Australian Aboriginal peoples are evidenced in early life, although few studies have focused on the reasons for population-level inequalities in more severe adverse outcomes. This study aimed to examine the scale of disparity in severe neonatal morbidity (SNM) and mortality between Aboriginal and non-Aboriginal births and quantify the relative contributions of important maternal and infant factors.MethodA retrospective cohort study with singleton live births (≥32 weeks’ gestation) was conducted using Western Australia linked whole population datasets, from 1999 to 2015. Aboriginal status was determined based on the mothers’ self-reported ethnic origin. An Australian validated indicator was adapted to identify neonates with SNM. The Oaxaca-Blinder method was employed to calculate the contribution of each maternal and infant factor to the disparity in SNM and mortality.ResultsAnalyses included 425 070 births, with 15 967 (3.8%) SNM and mortality cases. The disparity in SNM and mortality between Aboriginal and non-Aboriginal births was 2.9 percentage points (95% CI 2.6 to 3.2). About 71% of this gap was explained by differences in modelled factors including maternal area of residence (23.8%), gestational age (22.2%), maternal age (7.5%) and antenatal smoking (7.2%).ConclusionsThere is a considerable disparity in SNM and mortality between Aboriginal and non-Aboriginal births in Western Australia with the majority of this related to differences in maternal sociodemographic factors, antenatal smoking and gestational age. Public health programmes targeting these factors may contribute to a reduction in early life health differentials and benefit Aboriginal population health through the life course.

Evidence about the association between maternal mental health disorders and stillbirth and infant mortality is limited and conflicting. We aimed to examine whether maternal prenatal mental health disorders are associated with stillbirth and/or infant mortality. MEDLINE, Embase, PsycINFO, and Scopus were searched for studies examining the association of any maternal prenatal (occurring before or during pregnancy) mental health disorder(s) and stillbirth or infant mortality. A random-effects meta-analysis was used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). The between-study heterogeneity was quantified using the I2 statistic. Subgroup analyses were performed to identify the source of heterogeneity. Of 4487 records identified, 28 met our inclusion criteria with 27 contributing to the meta-analyses. Over 60% of studies examined stillbirth and 54% of them evaluated neonatal or infant mortality. Thirteen studies investigated the association between maternal depression and anxiety and stillbirth/infant mortality, pooled OR, 1.42 (95% CI, 1.16–1.73; I2, 76.7%). Another 13 studies evaluated the association between severe maternal mental illness and stillbirth/infant mortality, pooled OR, 1.47 (95% CI, 1.28–1.68; I2, 62.3%). We found similar results for the association of any maternal mental health disorders and stillbirth/infant mortality (OR, 1.59; 95% CI, 1.43–1.77) and in subgroup analyses according to types of fetal/infant mortality. We found no significant evidence of publication bias. Maternal prenatal mental health disorders appear to be associated with a moderate increase in the risk of stillbirth and infant mortality, although the mechanisms are unclear. Efforts to prevent and treat these disorders may reduce the scale of stillbirth/infant deaths.

Purpose To investigate the proportion of severely growth-restricted singleton births

Importance A recent expert consensus exercise emphasized the importance of developing a global network of patient registries for alopecia areata to redress the paucity of comparable, real-world data regarding the effectiveness and safety of existing and emerging therapies for alopecia areata. Objective To generate core domains and domain items for a global network of alopecia areata patient registries. Evidence Review Sixty-six participants, representing physicians, patient organizations, scientists, the pharmaceutical industry, and pharmacoeconomic experts, participated in a 3-round eDelphi process, culminating in a face-to-face meeting at the World Congress of Dermatology, Milan, Italy, June 14, 2019. Findings Ninety-two core data items, across 25 domains, achieved consensus agreement. Twenty further noncore items were retained to facilitate data harmonization in centers that wish to record them. Broad representation across multiple stakeholder groups was sought; however, the opinion of physicians was overrepresented. Conclusions and Relevance This study identifies the domains and domain items required to develop a global network of alopecia areata registries. These domains will facilitate a standardized approach that will enable the recording of a comprehensive, comparable data set required to oversee the introduction of new therapies and harness real-world evidence from existing therapies at a time when the alopecia areata treatment paradigm is being radically and positively disrupted. Reuse of similar, existing frameworks in atopic dermatitis, produced by the Treatment of Atopic Eczema (TREAT) Registry Taskforce, increases the potential to reuse existing resources, creates opportunities for comparison of data across dermatology subspecialty disease areas, and supports the concept of data harmonization.

Background A systematic review failed to identify any systemic therapy used in alopecia areata (AA) where use is supported by robust evidence from high-quality randomized controlled trials. Objective To produce an international consensus statement on the use and utility of various treatments for AA. Methods Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Agreement of 66% or greater was considered consensus. Results In the first round, consensus was achieved in 22 of 423 (5%) questions. After a face-to-face meeting in round 3, overall, consensus was achieved for only 130 (33%) treatment-specific questions. There was greater consensus for intralesional treatment of AA (19 [68%]) followed by topical treatment (25 [43%]). Consensus was achieved in 45 (36%) questions pertaining to systemic therapies in AA. The categories with the least consensus were phototherapy and nonprescription therapies. Limitations The study included a comprehensive list of systemic treatments for AA but not all treatments used. Conclusion Despite divergent opinions among experts, consensus was achieved on a number of pertinent questions. The concluding statement also highlights areas where expert consensus is lacking and where an international patient registry could enable further research.

Background Perinatal mortality rates are typically higher in Aboriginal than non-Aboriginal populations of Australia. Objectives This study aimed to examine the pattern of stillbirth and neonatal mortality rate disparities over time in Western Australia, including an evaluation of these disparities across gestational age groupings. Methods All singleton births (>= 20 weeks gestation) in Western Australia between 1980 and 2015 were included. Linked data were obtained from core population health datasets of Western Australia. Stillbirth and neonatal mortality rates and percentage changes in the rates over time were calculated by Aboriginal status and gestational age categories. Results From 1980 to 2015, data were available for 930 926 births (925 715 livebirths, 5211 stillbirths and 2476 neonatal deaths). Over the study period, there was a substantial reduction in both the Aboriginal (19.6%) and non-Aboriginal (32.3%) stillbirth rates. These reductions were evident in most gestational age categories among non-Aboriginal births and in Aboriginal term births. Concomitantly, neonatal mortality rates decreased in all gestational age windows for both populations, ranging from 32.1% to 77.5%. The overall stillbirth and neonatal mortality rate differences between Aboriginal and non-Aboriginal birth decreased by 0.6 per 1000 births and 3.9 per 1000 livebirths, respectively, although the rate ratios (RR 2.51, 95% CI 2.14, 2.94) and (RR 2.94, 95% CI 2.24, 3.85), respectively reflect a persistent excess of Aboriginal perinatal mortality across the study period. Conclusions Despite steady improvements in perinatal mortality rates in Western Australia over 31/2 decades, the gap between Aboriginal and non-Aboriginal rates remains unchanged in relative terms. There is a continuing, pressing need to address modifiable risk factors for preventable early mortality in Aboriginal populations.

Funder: GlaxoSmithKline; funder-id: http://dx.doi.org/10.13039/100004330, Introduction: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. Methods: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. Results: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ−induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. Conclusion: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. Trial registration: NCT02723786.

Background Non-alcoholic fatty liver disease (NAFLD) is an emerging health problem, that can progress to non-alcoholic steatohepatitis (NASH) and cirrhosis with associated liver morbidity and mortality. The prevalence of NAFLD is estimated at 25%, with 2–3% of having NASH. It is linked with metabolic conditions, including poor diet and lifestyle changes are crucial in managing this condition. The bountiful supply of biscuits on NHS work areas means that staffs are exposed to poor diet at work. We conducted a study of the prevalence of NAFLD using Fibroscan (530, Compact, Echosense) in NHS staff in a district general hospital. Methods Data was collected at a Staff Wellness Programme from 2018 to 2020 where Fibroscan was performed. Patients were defined to have NAFLD if they had Controlled Attenuation Parameter (CAP) above 248dB/m. They were defined to have significant fibrosis if Liver Stiffness Measure (LSM) above 7.8 kilopascals (kPa). They were given leaflet with dietary and lifestyle advice and invited for repeat scanning at a later date. The use of CAP in detecting mild hepatic steatosis has a reported sensitivity of 87% and specificity of 91% Results A total of 74 staff (management and clinical) participated in the programme, 60 female and 14 male. Mean age 46.9 (range 25 to 70). 59.4% (n=44) had NAFLD with CAP >248 dB/m with 16.2% (n=12) also having associated fibrosis with LSM >7.8 kPA 15 patients who were identified as having NAFLD were re-scanned (mean 10.7 months) following advice on lifestyle changes. 80% (n= 12) had significant improvement in the CAP score with a mean reduction of 56.3dB/m (range 4–135). 20% (n=3) of patients whose CAP did not improve reported that their lifestyle had not changed much. Our data showed a baseline pre-intervention CAP 308.4 dB/m and LSM 6.5 kPa. Following intervention, this improved to CAP 268.9 dB/m and LSM 4.7 kPa. Most mentioned the easy understanding of Fibroscan, and being given a number representative of the liver fat may act as a ‘shock factor’ in motivating them for lifestyle change. Conclusion Although the numbers are small, this study suggests a higher prevalence of NAFLD in a district general hospital in comparison to the general populations (59.4% vs 25%). This study is limited by the non-random selection nature of our study populations, as people who signed up for Wellness Programme may have had a concern with their general health. However, it also showed a significant reduction in CAP and LSM score post-intervention, with simple lifestyle advise in a group of motivated healthcare workers. Most mentioned ‘Fibroscan with a number representative of the liver fat’, acts as a shock factor in motivating them for lifestyle changes. Fibroscan is a quick and easy tool, and in the right context, it can be used as a primary screening tool for NAFLD in the future.

INTRODUCTION Retrospective studies have reported an association between a single episode of significantly increased fetal movements (IFMs) and stillbirth after 28 weeks' gestation. This prospective study aimed to report the outcome of pregnancies associated with maternal perception of IFMs and determine whether this symptom is associated with adverse pregnancy outcome, a pathological intrauterine environment or placental dysfunction. MATERIAL AND METHODS Women reporting IFMs after 28 weeks' gestation were recruited from St Mary's Hospital, Manchester and Liverpool Women's Hospital, UK, between 1 November 2017 and 1 May 2019. Demographic and clinical information were obtained and an ultrasound scan was performed to assess fetal biometry, liquor volume and umbilical artery Doppler. Maternal serum samples were collected for analysis of placentally derived biomarkers using ELISA. After delivery, maternal and fetal outcome data were collected and placentas and umbilical cord blood were obtained for analysis using immunohistochemistry and ELISA, respectively. Placental and serum samples were matched by gestation and maternal characteristics to participants with normal fetal activity. RESULTS Seventy-seven women presented with IFM, representing 0.45% of the maternity population; 64 women consented to participate in the study, of which 7 (10.9%) experienced adverse pregnancy outcome: birthweight

ObjectivesTo assess the scale of ethnic inequalities in severe maternal morbidity (SMM) rates and quantify the contribution of maternal characteristics to these disparities.DesignRetrospective cohort study.SettingWhole-of-population linked administrative data from 2002 to 2015 in Western Australia.ParticipantsWomen with 410 043 birth events (includes all births from the same pregnancy) of 20 weeks’ or more gestation, including terminations for congenital anomalies.Primary and secondary outcome measuresWomen with SMM were identified based on a composite indicator of SMM using diagnosis and procedure codes developed for use in routinely collected data. Mothers were classified into seven ethnic groups, based on their reported ethnic origin. The associations between maternal ethnic origin and SMM were examined using a log-binomial model, which estimates risk ratios (RRs) and 95% CIs. The Blinder-Oaxaca decomposition technique was employed to partition the disparity in SMM between Aboriginal and Caucasian populations into ‘explained’ and ‘unexplained’ components.ResultsDuring the study period, 9378 SMM cases were documented. In the adjusted model, Aboriginal (RR 1.73, 95% CI 1.59 to 1.87), African (RR 1.64, 95% CI 1.43 to 1.89) and ‘other’ ethnicity (RR 1.49, 95% CI 1.37 to 1.63) women were at significantly higher risk of SMM compared with Caucasian women. Teenage and older mothers and socioeconomically disadvantaged women were also at greater risk of SMM. Differences in sociodemographic characteristics explained 33.2% of the disparity in SMM between Aboriginal and Caucasian women.ConclusionsThere are distinct disparities in SMM by ethnicity in Western Australia, with a greater risk among Aboriginal and African women. While improvements in SES and a reduction in teenage pregnancy can potentially support a sizeable reduction in SMM rate inequalities, future research should investigate other potential pathways and targeted interventions to close the ethnicity disparity.

Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) concentration n 3250) of Australian Aboriginal and Torres Strait Islander adults aged ≥18 years. We used data from the 2012–2013 Australian Aboriginal and Torres Strait Islander Health Survey (AATSIHS). Serum 25(OH)D concentrations were measured by liquid chromatography-tandem MS. Survey-weighted logistic regression models were used to determine the independent predictors of vitamin D deficiency. Approximately 27 % of adult AATSIHS participants were vitamin D deficient. Vitamin D deficiency was more prevalent in remote areas (39 %) than in non-remote areas (23 %). Independent predictors of vitamin D deficiency included assessment during winter (men, adjusted OR (aOR) 5·7; 95 % CI 2·2, 14·6; women, aOR 2·2; 95 % CI 1·3, 3·8) and spring (men, aOR 3·3; 95 % CI 1·4, 7·5; women, aOR 2·6; 95 % CI 1·5, 4·5) compared with summer, and obesity (men, aOR 2·6; 95 % CI 1·2, 5·4; women, aOR 4·3; 95 % CI 2·8, 6·8) compared with healthy weight. Statistically significant associations were evident for current smokers (men only, aOR 2·0; 95 % CI 1·2, 3·4), remote-dwelling women (aOR 2·0; 95 % CI 1·4, 2·9) and university-educated women (aOR 2·4; 95 % CI 1·2, 4·8). Given the high prevalence of vitamin D deficiency in this population, strategies to maintain adequate vitamin D status through safe sun exposure and dietary approaches are needed.

Background In the absence of treatment, endometrial hyperplasia (EH) can progress to endometrial cancer, particularly in the presence of histologic nuclear atypia. The development of EH results from exposure of the endometrium to oestrogen unopposed by progesterone. Oral progestogens have been used as treatment for EH without atypia, and in some cases of EH with atypia in women who wish to preserve fertility or who cannot tolerate surgery. EH without atypia is associated with a low risk of progression to atypia and cancer; EH with atypia is where the cells are structurally abnormal, and has a higher risk of developing cancer. Oral progestogen is not always effective at reversing the hyperplasia, can be associated with side effects, and depends on patient adherence. The levonorgestrel-intrauterine system (LNG-IUS) is an alternative method of administration of progestogen and may have some advantages over non-intrauterine progestogens. Objectives To evaluate the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in women with endometrial hyperplasia (EH) with or without atypia compared to medical treatment with non-intrauterine progestogens, placebo, surgery or no treatment. Search methods We searched the following databases: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO, and conference proceedings of 10 relevant organisations. We handsearched references in relevant published studies. We also searched ongoing trials in ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry, and other trial registries. We performed the final search in May 2020. Selection criteria Randomised controlled trials (RCTs) and cross-over trials of women with a histological diagnosis of endometrial hyperplasia with or without atypia comparing LNG-IUS with non-intrauterine progestogens, placebo, surgery or no treatment. Data collection and analysis Two review authors independently performed study selection, risk of bias assessment and data extraction. Our primary outcome measures were regression of EH and adverse effects associated with the LNG-IUS device (such as pelvic inflammatory disease, device expulsion, uterine perforation) when compared to treatment with non-intrauterine progestogens, placebo, surgery or no treatment. Secondary outcomes included hysterectomy, hormone-related adverse effects (such as bleeding/spotting, pelvic pain, breast tenderness, ovarian cysts, weight gain, acne), withdrawal from treatment due to adverse effects, satisfaction with treatment, and cost or resource use. We rated the overall quality of evidence using GRADE methods. Main results Thirteen RCTs (1657 women aged 22 to 75 years) met the inclusion criteria. Two studies had insufficient data for meta-analysis, thus the quantitative analysis included 11 RCTs. All trials evaluated treatment duration of six months or less. The evidence ranged from very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding and poor reporting of study methods), inconsistency and imprecision. LNG-IUS versus non-intrauterine progestogens Primary outcomes Regression of endometrial hyperplasia The LNG-IUS probably improves regression of EH compared with non-intrauterine progestogens at short-term follow-up (up to six months) (OR 2.94, 95% CI 2.10 to 4.13; I² = 0%; 10 RCTs, 1108 participants; moderate-quality evidence). This suggests that if regression of EH following treatment with a non-intrauterine progestogen is assumed to be 72%, regression of EH following treatment with LNG-IUS would be between 85% and 92%. Regression of EH may be improved by LNG-IUS compared with non-intrauterine progestogens at long-term follow-up (12 months) (OR 3.80, 95% CI 1.75 to 8.23; 1 RCT, 138 participants; low-quality evidence), Adverse effects associated with LNG-IUS There was insufficient evidence to determine device-related adverse effects; only one study reported on expulsion with insufficient data for analysis. Secondary outcomes The LNG-IUS may be associated with fewer hysterectomies (OR 0.26, 95% CI 0.15 to 0.46; I² = 19%; 4 RCTs, 452 participants; low-quality evidence), fewer withdrawals from treatment due to hormone-related adverse effects (OR 0.41, 95% CI 0.12 to 1.35; I² = 0%; 4 RCTs, 360 participants; low-quality evidence) and improved patient satisfaction with treatment (OR 5.28, 95% CI 2.51 to 11.10; I² = 0%; 2 RCTs, 202 participants; very low-quality evidence) compared to non-intrauterine progestogens. The LNG-IUS may be associated with more bleeding/spotting (OR 2.13, 95% CI 1.33 to 3.43; I² = 78%; 3 RCTs, 428 participants) and less nausea (OR 0.52, 95% CI 0.28 to 0.95; I² = 0%; 3 RCTs, 428 participants) compared to non-intrauterine progestogens. Data from single trials for mood swings and fatigue had a similar direction of effect as for bleeding/spotting, nausea and weight gain. There was insufficient evidence to determine cost or resource use. LNG-IUS versus no treatment Regression of endometrial hyperplasia One study demonstrated that the LNG-IUS is associated with regression of EH without atypia (OR 78.41, 95% CI 22.86 to 268.97; I² = 0%; 1 RCT, 190 participants; moderate-quality evidence) compared with no treatment. This study did not report on any other review outcome. Authors' conclusions There is moderate-quality evidence that treatment with LNG-IUS used for three to six months is probably more effective than non-intrauterine progestogens at reversing EH in the short term (up to six months) and long term (up to two years). Adverse effects (device-related and hormone-related) were poorly and incompletely reported across studies. Very low quality to low-quality evidence suggests the LNG-IUS may reduce the risk of hysterectomy, and may be associated with more bleeding/spotting, less nausea, less withdrawal from treatment due to adverse effects, and increased satisfaction with treatment, compared to non-intrauterine progestogens. There was insufficient evidence to reach conclusions regarding device-related adverse effects, or cost or resource use.

Background and Purpose: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. Methods: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. Results: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09–1.21]; P =0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32–1.34]; P =0.25) among noncarriers. There was no significant interaction by genotype for major ischemia ( P =0.36) or stroke ( P =0.33). Conclusions: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00991029.

IntroductionMaternal mental health disorders such as anxiety and depression are major public health concerns. Evidence shows a link between maternal mental health disorders and preterm birth and low birth weight. However, the impacts of maternal mental health disorders on stillbirth and infant mortality have been less investigated and inconsistent findings have been reported. Thus, using the available literature, we plan to examine whether prenatal maternal mental health disorders impact the risk of stillbirth and infant mortality.Methods and analysisThis systematic review and meta-analysis will adhere to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and will be registered with the International Prospective Register of Systematic Reviews. Systematic searches will be conducted (from database inception to December 2019) in Medline, Embase, PsycINFO and Scopus for studies examining the association of prenatal mental health disorders and stillbirth and infant mortality. The search will be limited to studies published in English language and in humans only, with no restriction on the year of publication. Two independent reviewers will evaluate records and assess the quality of individual studies. The Newcastle–Ottawa scales and GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach will be used to assess the methodological quality and bias of the included studies. In addition to a narrative synthesis, a random-effects meta-analysis will be conducted when sufficient data are available. I2 statistics will be used to assess between-study heterogeneity in the estimated effect size.Ethics and disseminationAs it will be a systematic review and meta-analysis based on previously published evidence, there will be no requirement for ethical approval. Findings will be published in a peer-reviewed journal and will be presented at various conferences.PROSPERO registration number159834.

Background: Injectable hormonal male contraceptives (HMC) injectables appear safe and are effective in clinical trials, but global surveys suggest men would prefer an oral pill. 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is orally bioavailable and well-tolerated. When taken daily with food for 28 days, the drug decreases serum gonadotropins and testosterone without significant impact on mood. If ongoing studies demonstrate that daily 11β-MNTDC consistently suppresses spermatogenesis to Objective : To determine satisfaction with and acceptability of a daily oral 11β-MNTDC HMC pill Study Design: In a double-blind, randomized, placebo-controlled trial of a 28-day regimen of daily oral 11β-MNTDC at two academic medical centers, healthy male volunteers completed baseline and end-of-treatment surveys assessing their experience, satisfaction with, and willingness to use daily oral 11β-MNTDC. Results: Of 42 participants, 40 (30 11β-MNTDC, 10 placebo) completed end-of-treatment surveys. Respondents were primarily college-educated, sexually active white men between 21-40 years old. Less than 20% of participants cited initial concerns about safety and missing doses. Following treatment, nearly 90% of participants affirmed that taking the pill was easy to remember and did not interfere with their daily routine. Although one-third (37% 11β-MNTDC vs. 20% placebo, p=0.45) reported bothersome side effects, and 28% (30% 11β-MNTDC vs. 20% placebo, p=0.66) reported potential concerns about safety, these rates were neither statistically different in those taking active drug versus placebo nor associated with method satisfaction. The majority of participants reported satisfaction with the method (73% 11β-MNTDC vs. 70% placebo, p=0.84), that they would recommend it to others (90% 11β-MNTDC vs. 100% placebo, p=0.56), and that they would use the drug regimen as their primary contraceptive even if having to pay (67% 11β-MNTDC vs. 50% placebo, p=0.35). Half of participants (50% 11β-MNTDC vs. 67% placebo, p=0.51) affirmed that the method exceeded initial expectations. Respondents who reported being more likely to miss a dose were also more likely to report dissatisfaction with the study drug (p=0.03). Conclusion: The majority of participants in a 28-day trial of daily, oral 11β-MNTDC pills were satisfied with the regimen, would recommend the drug to others, and would pay to use the drug even when adverse or off-target effects (e.g. changes in libido and/or mood) were considered. If 11β-MNTDC is demonstrated to suppress spermatogenesis uniformly to very low levels, it would be acceptable to men desiring reversible contraception.

We present the case of a patient admitted to hospital in septic shock. He had a history of tricuspid valve infective endocarditis (IE) 6 months prior and regularly injected intravenous drugs. A bedside echo on arrival confirmed vegetations on his tricuspid valve, torrential tricuspid regurgitation and signs of significantly raised right-sided pressures. The admission chest radiograph showed consolidative changes in the lungs, suggestive of septic pulmonary emboli. He was commenced on antibiotics and treated in the high-dependency unit. He subsequently developed an acutely ischaemic right foot and nasal tip. Suspicions were raised of a paradoxical septic embolus through a right-to-left shunt, subsequently confirmed on bubble echo which showed passage of agitated saline between the atria. This was not apparent clinically or on echocardiogram during his previous episode of tricuspid valve IE, raising the possibility of the development of an acquired inter-atrial communication since his previous episode.

Aim To assess the comparative effects of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors, sulphonylureas (SUs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors on cardiometabolic risk factors in routine care. Materials and methods Using primary care data on 10 631 new users of SUs, SGLT2 inhibitors or DPP‐4 inhibitors added to metformin, obtained from the UK Clinical Practice Research Datalink, we created propensity‐score matched cohorts and used linear mixed models to describe changes in glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), systolic blood pressure (BP) and body mass index (BMI) over 96 weeks. Results HbA1c levels fell substantially after treatment intensification for all drugs: mean change at week 12: SGLT2 inhibitors: −15.2 mmol/mol (95% confidence interval [CI] –16.9, −13.5); SUs: −14.3 mmol/mol (95% CI –15.5, −13.2); and DPP‐4 inhibitors: −11.9 mmol/mol (95% CI –13.1, −10.6). Systolic BP fell for SGLT2 inhibitor users throughout follow‐up, but not for DPP‐4 inhibitor or SU users: mean change at week 12: SGLT2 inhibitors: −2.3 mmHg (95% CI –3.8, −0.8); SUs: −0.8 mmHg (95% CI –1.9, +0.4); and DPP‐4 inhibitors: −0.9 mmHg (95% CI –2.1,+0.2). BMI decreased for SGLT2 inhibitor and DPP‐4 inhibitor users, but not SU users: mean change at week 12: SGLT2 inhibitors: −0.7 kg/m2 (95% CI –0.9, −0.5); SUs: 0.0 kg/m2 (95% CI –0.3, +0.2); and DPP‐4 inhibitors: −0.3 kg/m2 (95% CI –0.5, −0.1). eGFR fell at 12 weeks for SGLT2 inhibitor and DPP‐4 inhibitor users. At 60 weeks, the fall in eGFR from baseline was similar for each drug class. Conclusions In routine care, SGLT2 inhibitors had greater effects on cardiometabolic risk factors than SUs. Routine care data closely replicated the effects of diabetes drugs on physiological variables measured in clinical trials.

Background A combination of safety concerns and labeling changes impacted use of erythropoiesis-stimulating agents (ESAs) in renal anemia. Data regarding contemporary utilization in pre-dialysis chronic kidney disease (CKD) are lacking. Methods Electronic healthcare records and medical claims data of pre-dialysis CKD patients were aggregated from a large US managed care provider (2011–13). ESA use patterns, characteristics, and outcomes of ESA-treated/untreated patients were quantified. Results At baseline, 109/32,308 patients (0.3%) were ESA users. Treated patients were older, had more advanced CKD (58.8% vs 5.4% with stage 4/5 vs 3) and greater prevalence of comorbid diabetes, hypertension, heart failure, and peripheral vascular disease. An additional 266 patients initiated ESA: hemoglobin at initiation was 8–10 g/dL in 193 of these and >10 g/dL in the remainder; 61.7% had stage 4/5 CKD; prevalence of cardiovascular disease was high (50.8% heart failure; 25.2% prior myocardial infarction; 24.1% prior stroke). During follow-up, rates of death and cardiovascular events were higher in baseline ESA users and ESA naives versus non-users. Conclusions ESA use in pre-dialysis CKD patients was exceedingly rare and directed disproportionately to older, sicker patients; these patients had high rates of death and cardiovascular events. These data provide context for contemporary use of ESA in pre-dialysis CKD. Electronic supplementary material The online version of this article (10.1186/s12882-018-0925-2) contains supplementary material, which is available to authorized users.

Hanna Jokinen tutkimusryhmän jäsenenä (VICCCS Grp) Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2. Methods: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. Results: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. Discussion: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration. (C) 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Background: Pazopanib (P) and trabectedin (T) are approved targeted treatments for metastatic soft tissue sarcoma (mSTS). Our objective was to evaluate the efficacy (from clinical trials [CT]) and effectiveness (from real-world studies [RW]) of P and T in second line (2L+) mSS. Methods: This meta-analysis included all English language studies assessing P or T efficacy/effectiveness in patients with 2L+ mSS, 1999 onwards, identified by a systematic literature review. Outcomes were overall response rate (ORR) representing the proportion of patients who have achieved CR or PR during the study and median overall survival (mOS) in months (mos) from start of study medication. Proportions from studies were pooled using generalized linear mixed models to account for small sample sizes, zero events and random site effects. Medians were combined using the weighted median of the medians method with 95% confidence intervals from an inverted sign test. Results: 16 studies with 405 patients with 2L+ mSS met the inclusion criteria. Response was measured variably across studies (CT: RECIST v1.0, v1.1; RW: modified RECIST or clinician assessment). ORR estimates were higher in RW than CTs (Table). OS results were consistent across CTs and RW (Table). Conclusions: This is the first study to provide estimates for patients with mSS in the 2L+ setting, distinct from mSTS and pool outcomes of targeted therapies. RW estimates of ORR for both treatments were higher than those observed in trials likely due to variable definition of response and in underlying prognostic factors. mOS was consistent across both types of studies and was similar to mOS seen on placebo (10.7 mos in PALETTE study) suggesting a high unmet need in this population. Funding: GSK (213368). Outcomes with pazopanib (P) and trabectedin (T) in clinical trials (CT) and real-world (RW) studiesPTP & T pooledORR-ALL (%)N=6, n=96, 18.9 (8.5, 41.8)N=7, n=162, 12.3 (8.0, 18.9)N=13, n=258, 14.7 (9.2, 23.4)ORR-CT (%)N=1, n=38, 13.2 (2.4, 23.9)†N=3, n=57, 7.0 (2.7, 18.1)N=4, n=95, 9.5 (5.1, 17.6)ORR-RW (%)N=5, n=58, 20.2 (7.4, 54.8)N=4, n=105, 15.2 (9.7, 23.9)N=9, n=163, 17.7 (9.9, 31.5)mOS-ALL (mos)N=4, n=96, 10.3 (8.7, 13.8)N=4, n=165, 9.9 (1.5, 13.9)N=8, n=261, 9.9 (9.2, 13.9)mOS-CT (mos)ND*ND*N=3, n=113, 10.3 (8.7, 13.9)mOS-RW (mos)ND*ND*N=5, n=148, 9.9 (9.2, 13.9)*Not done due to small sample size; †results of study since N=1. N=number of studies; n=number of patients. Estimates presented with 95% confidence intervals. Citation Format: Charlotte Carroll, Nashita Patel, Necdet B. Gunsoy, Dan Parks, Heide A. Stirnadel-Farrant, Shibani Pokras. Meta-analysis of pazopanib and trabectedin in 2L+ metastatic synovial sarcoma (2L+ mSS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2630.

Background A growing body of literature highlights that racial discrimination has negative impacts on child health, although most studies have been limited to an examination of direct forms of racism using cross-sectional data. We aim to provide further insights on the impact of early exposure to racism on child health using longitudinal data among Indigenous children in Australia and multiple indicators of racial discrimination. Methods We used data on 1239 Indigenous children aged 5–10 years from Waves 1–6 (2008–2013) of Footprints in Time, a longitudinal study of Indigenous children across Australia. We examined associations between three dimensions of carer-reported racial discrimination (measuring the direct experiences of children and vicarious exposure by their primary carer and family) and a range of physical and mental health outcomes. Analysis was conducted using multivariate logistic regression within a multilevel framework. Results Two-fifths (40%) of primary carers, 45% of families and 14% of Indigenous children aged 5–10 years were reported to have experienced racial discrimination at some point in time, with 28–40% of these experiencing it persistently (reported at multiple time points). Primary carer and child experiences of racial discrimination were each associated with poor child mental health status (high risk of clinically significant emotional or behavioural difficulties), sleep difficulties, obesity and asthma, but not with child general health or injury. Children exposed to persistent vicarious racial discrimination were more likely to have sleep difficulties and asthma in multivariate models than those with a time-limited exposure. Conclusions The findings indicate that direct and persistent vicarious racial discrimination are detrimental to the physical and mental health of Indigenous children in Australia, and suggest that prolonged and more frequent exposure to racial discrimination that starts in the early lifecourse can impact on multiple domains of health in later life. Tackling and reducing racism should be an integral part of policy and intervention aimed at improving the health of Australian Indigenous children and thereby reducing health disparities between Indigenous and non-Indigenous children. Electronic supplementary material The online version of this article (doi:10.1186/s12939-017-0612-0) contains supplementary material, which is available to authorized users.

Aim The burden of chronic kidney disease (CKD) is growing rapidly around the world. However, there is limited information on the overall regional prevalence of CKD, as well as the prognostic implications and treatment patterns in Asian region. We have established the Asian Renal Collaboration (ARC) with the goal of consolidating region-wide data regarding CKD. Methods This collaborative project will synthesize data and perform meta-analyses of observational studies conducted in Asia. Studies will be identified through a systematic literature search including abstracts, proceedings of meetings, electronic databases such as MEDLINE and EMBASE. Personal enquiry among collaborators and experts in the region will identify additional studies, or other data sources such as registries. Both cross-sectional and longitudinal studies that describe the prevalence of CKD and its complications will be included, as will longitudinal studies that describe important clinical outcomes for people with CKD. Individual participant data will be sought, where possible, from each of the studies included in the collaboration for baseline parameters and subsequent outcomes, in order to maximize flexibility and consistency of data analyses. Conclusions This study is an initiative offering a unique opportunity to obtain information about the prevalence and manifestations of CKD in Asia, as well as its risk factors. The ARC will also provide insights into important outcomes including progression of CKD, CKD complications, cardiovascular disease and death. These findings will improve our understanding of kidney disease in Asia, and thus help inform service provision, preventive care and further research across the region.

Unfortunately, after publication, we found errors in the extraction of data on gestational diabetes and threatened miscarriage.

Purpose Despite numerous calls to improve training in adolescent health, there is little known about the prevalence or effectiveness of specialized training in adolescent health. Methods A two-stage random sampling cluster design was used to collect nationally representative data from 8,500 students from 91 high schools. Student data were linked to data from a survey of school health clinicians from participating schools on their level of training in youth health. Multilevel models accounting for demographic characteristics of students were used to estimate the association between nurses and physicians training in youth health and health outcomes among students. Results Almost all nurses and physicians reported some training in youth health, either having attended lectures or study days in youth health (n = 60, 80%) or completed postgraduate papers in youth health (n = 13, 17.3%). Students in schools where the nurses and physicians had received postgraduate training in youth health were less likely than students from schools with clinicians having attended lectures or study days in youth health to report emotional and behavior difficulties (11.8 vs. 12.7, p = .002) and binge drinking (19.6% vs. 24.9%, p = .03). There were no significant associations between depressive symptoms, suicide risk, cigarette, marijuana, contraception use, or motor vehicle risk behaviors among students and level of training among clinicians in their schools' health service. Conclusions Postgraduate training in youth health among nurses and physicians in school health services is associated with fewer students reporting mental health difficulties and binge alcohol use. These findings support specialized training in youth health for clinicians working predominantly with young people.

Background Synovial sarcoma (SS) is a rare and aggressive soft tissue sarcoma which primarily affects the extremities of arms and legs. It also occurs in head and neck, trunk, lungs and pleura. Brennan et al. (2016) reported a SS incidence rate of 1.4 per million in 2009 in England. There are no other population-based studies providing the burden of SS in Europe (EU). In addition, the age- and gender- specific distribution of SS patient population have not been published. The objective of this study was to estimate the incidence, prevalence and mortality of SS in 2019 for the EU28 countries. Methods Data from the United States (US) Surveillance, Epidemiology, and End Results (SEER) 18 Registries, Nov. 2018 (2000-2016) was analyzed using SEER*Stat software (v8.3.5) to calculate the incidence, prevalence and mortality of SS (overall, and by age groups and gender) for 2019. The estimated age-standardized incidence rate of SS, based on this SEER analysis in the US, was similar to that reported by Brennan et al. (2016). These rates were applied to the overall, and age- and gender-specific 2019 EU28 population to estimate the burden of SS in EU28. Results In the EU28 countries in 2019, there will be an estimated 993 incident cases of SS, 3,550 prevalent patients and 520 deaths. Most (74%) of the prevalent patients with SS will be 20-64 years old, and only 17% will be 65 years and older. Approximately 40% of patients newly diagnosed with SS will be of ages 20-44 years, and 32% of ages 45-64 years. There will be a low occurrence ( Conclusions SS is a rare disease. Life expectancy of patients with SS is lower than the general population in EU28 due to high mortality in the 20-64 year age group. SS also occurs among children. Population-based studies are needed to better characterize SS patient population for improving patient care and survival in EU28. Legal entity responsible for the study The authors. Funding GlaxoSmithKline. Disclosure N. Joseph: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S. St. Laurent: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S. Zheng: Full / Part-time employment: GlaxoSmithKline. H. Stirnadel-Farrant: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. C. Dharmani: Full / Part-time employment: GlaxoSmithKline.

Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA.To obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA.This analysis pooled individual patient-level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019.In the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset.The primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage.The study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 [6.5%] vs 458 of 5035 [9.1%]; hazard ratio [HR], 0.70 [95% CI, 0.61-0.81]; P .001), mainly within the first 21 days (263 of 5016 [5.2%] vs 391 of 5035 [7.8%]; HR, 0.66 [95% CI, 0.56-0.77]; P .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant.In this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.

The aim of this systematic review was to evaluate the associations between pre-pregnancy body mass index and gestational weight gain and placental abruption. Relevant studies were identified from PubMed, EMBASE, Scopus and CINAHL. Unpublished findings from analyses of linked population-based data sets from Western Australia (2012–2015, n = 114,792) were also included. Studies evaluating pre-pregnancy body mass index and/or gestational weight gain and placental abruption were included. Two independent reviewers evaluated studies for inclusion and quality. Data including odds ratios (ORs) and 95% confidence intervals (CIs) were extracted and analysed by random effects meta-analysis. 21 studies were included, of which 15 were eligible for meta-analyses. The summary ORs for the association of being underweight, overweight and obese, and placental abruption, compared to normal weight women, were 1.4 (95% CI 1.1, 1.7), 0.8 (95% CI 0.8, 0.9) and 0.8 (95% CI 0.7, 0.9), respectively. These findings remained unchanged when each study was eliminated from the analysis and in subgroup analyses. Although data were scarce, women with gestational weight gain below the Institute of Medicine recommendations appeared to be at greater risk of abruption compared with women who had optimal weight gain. Mothers that are underweight prior to or in early pregnancy are at a moderately increased risk of placental abruption.

Background In women with prolactinoma medical treatment with dopamine agonists (DA) can restore fertility. A number of studies have established the safety of DA during pregnancy and the impact of pregnancy and lactation on remission of prolactinoma. However, the total number of reported cases remains modest and further evidence is needed. Aims To evaluate the safety of DA during pregnancy and remission of prolactinoma after pregnancy and lactation. Materials and methods Retrospective cohort study (2002-2014) of 57 pregnancies in 47 women with prolactinoma who received DA. Neonatal and pregnancy complications were recorded. Prolactin levels and treatment data were collected at the time of diagnosis, pre-conception, during pregnancy and lactation, and post-partum (up to 114 months). Results DA treatment was stopped a median of 4.5 weeks after conception in 49 pregnancies (86%). There were 49 live births (86% of pregnancies) and six miscarriages. Six pregnancies had an adverse neonatal outcome including two with congenital malformations. Following 26% of pregnancies women achieved remission after birth or lactation, and 25% of women were in remission at last follow-up. Remission was associated with older maternal age (P = 0.036), a lower prolactin level at diagnosis (P = 0.037), and a smaller adenoma at diagnosis (P = 0.045). Conclusions Successful pregnancy and lactation is common after DA treatment for prolactinoma. Fetal exposure in the first four weeks of pregnancy appears to be generally safe. Encouragingly, post-partum and after lactation a quarter of women had a normal prolactin level without medical treatment.

Introduction: Misclassification of outcome events can potentially lead to biased treatment effect estimates. Efforts to avoid endpoint misclassification in large-scale multicenter randomized clinical trials such as POINT have included an independent adjudication committee blinded to study treatments to standardize assessment of outcomes and reduce risk of ascertainment bias of main study endpoints. Debate continues about the scientific value of such committees and whether independent assessments improve reliability of study results, particularly when compared to the considerable time and resources consumed by the process. Methods: An independent adjudication committee adjudicated 467 primary and secondary efficacy outcomes and major and minor bleeding events, including the primary efficacy endpoint, a composite of new ischemic vascular events: ischemic stroke, myocardial infarction or ischemic vascular death at 90 days. The impact of the adjudicated endpoint process was studied by comparing the primary results using site-assessed endpoints versus adjudicator-assessed endpoints. Time from randomization to first endpoint of interest was calculated using the log-rank test and the hazard ratio and 95% CI were computed using a Cox proportional hazards model. Rate of agreement between site-assessed and adjudicator-assessed outcomes was also calculated. All analyses were completed according to the intention-to-treat principle. Results: The primary results of POINT have been published. The hazard ratios (HRs) (95% confidence interval [CI]) for clopidogrel versus aspirin therapy for the primary composite endpoint were 0.75 (0.59-0.95) for adjudicator-assessed events and 0.76 (0.60-0.95) for investigator-assessed events. Agreement between the composite endpoint for adjudicated-assessed and investigator-assessed events was 90.7%. Conclusion: Independent endpoint adjudication did not significantly impact estimates of the primary efficacy treatment effect in POINT compared to site-assessed endpoints. If misclassification of outcome events is infrequent, and careful site selection, study design and outcome definitions are in place, independent adjudication may have no meaningful impact on estimates of treatment effect.

Introduction: An online process for eliciting and assessing information from stroke patients to prescreen for stroke recovery studies holds potential to accelerate enrollment, but the validity of using self-reported information for online pre-screening is uncertain. Methods: Among patients in the UCSF Stroke Recovery Initiative, a nationwide, online participant recruitment registry of stroke patients that have expressed an interest in stroke recovery studies (strokerecoveryinitiative.ucsf.edu; NCT03318432), we compared self-reported information on stroke subtype (ischemic vs. hemorrhagic), location (MCA, cerebellar, brainstem), and functional status (modified Rankin Scale) elicited online to final validated responses as determined by follow-up semi-structured telephone interviews. We used descriptive statistics and Cohen’s kappa to evaluate the concordance of self-reported information against validated responses. Results: A total of 1,283 of the 3,959 participants in the recruitment registry were selected for semi-structured telephone follow-up (mean age 56; 55% male; average of 2.6 years after the index stroke). There was moderate agreement between self-report and telephone-validated responses for stroke subtype (84.4% agreement, kappa=0.68 for ischemic stroke; 83.0% agreement, 0.70 for hemorrhagic stroke) and similar performance for stroke location (86.1% agreement, kappa=0.75 for MCA location; 81.1% agreement, 0.66 for cerebellar location; 86.9% agreement, 0.78 for brainstem location). Agreement for the modified Rankin Scale for functional status was somewhat lower overall (66.7% agreement, kappa=0.53) but self-reported scores were within 1 point of the validated score 94% of the time. Conclusion: Using self-reported information to prescreen patients for stroke recovery studies requires a permissive approach to basic eligibility criteria to flag potentially-eligible candidates for additional follow-up. The efficiency and high-throughput of an online prescreening process would benefit from having studies with eligibility criteria that are developed with an efficient prescreening process in mind as well as high-throughput pre-screening instruments that are optimized for self-report.

Introduction: Across 269 international sites, the POINT trial randomly assigned 4881 patients with minor ischemic stroke or high-risk transient ischemic attack to receive either clopidogrel at a loading dose of 600 mg on day 1 followed by 75 mg per day, plus aspirin at a dose of 50-325 mg per day or the same range of doses of aspirin alone. Dual antiplatelet therapy significantly reduced the incidence of major ischemic events, but also significantly increased the incidence of major hemorrhage. Clopidogrel is a prodrug that requires metabolism by the cytochrome P450 complex to act on the P2Y12 platelet receptor. CYP2C19 (cytochrome P450 family 2 subfamily C polypeptide 19) variants are associated with variable rates of metabolism of clopidogrel and thus pharmacogenomic effects may be clinically relevant. Methods: Genomic DNA was extracted from peripheral blood monocytes using the standard protocols. Genotyping for CYP2C19 *2, *3 and *17 alleles (rs4244285, rs4986893 and rs12248560) defines metabolizer/activator status and was performed using custom TaqMan Allelic Discrimination Assays on a QuantStudio™ 7 Flex Real-Time PCR System. Results: As of June 28, 2018, a total of 445 trial participants had DNA available for analysis. CYP2C19 allele genotyping demonstrated approximately one quarter of subjects (n=127; 28.6%) would be defined as poor or Intermediate metabolizers of clopidogrel. Conclusions: Based on targeted cytochrome P 450 genotyping, about one quarter of POINT patients have reduced clopidogrel activation. Additional genotyping is ongoing. We plan to present results assessing whether the treatment effect of clopidogrel is limited to those with CYP2C19 genotypes associated with normal drug metabolism.

Background and Purpose— In randomized stroke trials, central adjudication of a trial’s primary outcome is regularly implemented. However, recent evidence questions the importance of central adjudication in randomized trials. The aim of this review was to compare outcomes assessed by central adjudicators with outcomes assessed by site investigators. Methods— We included randomized stroke trials where the primary outcome had undergone an assessment by site investigators and central adjudicators. We searched MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, and Google Scholar for eligible studies. We extracted information about the adjudication process as well as the treatment effect for the primary outcome, assessed both by central adjudicators and by site investigators. We calculated the ratio of these treatment effects so that a ratio of these treatment effects >1 indicated that central adjudication resulted in a more beneficial treatment effect than assessment by the site investigator. A random-effects meta-analysis model was fitted to estimate a pooled effect. Results— Fifteen trials, comprising 69 560 participants, were included. The primary outcomes included were stroke (8/15, 53%), a composite event including stroke (6/15, 40%) and functional outcome after stroke measured on the modified Rankin Scale (1/15, 7%). The majority of site investigators were blind to treatment allocation (9/15, 60%). On average, there was no difference in treatment effect estimates based on data from central adjudicators and site investigators (pooled ratio of these treatment effects=1.02; 95% CI, [0.95–1.09]). Conclusions— We found no evidence that central adjudication of the primary outcome in stroke trials had any impact on trial conclusions. This suggests that potential advantages of central adjudication may not outweigh cost and time disadvantages in stroke studies if the primary purpose of adjudication is to ensure validity of trial findings.

A group of experienced vets argue that the lack of control of endemically TB-infected communities of badgers has resulted in a bovine TB dilemma that is worse now than it was 50 years ago.

Background Endoscopic retrograde cholangiopancreatography (ERCP) is an essential tool in the management of pancreaticobiliary pathology. It is technically demanding and has the potential to cause significant morbidity and mortality. Several trials have identified small centres and lower hospital volume as risk factors for lower success rates and higher complication rates. Taranaki Base Hospital (TBH) is a provincial hospital with a catchment of 100 000, providing its population with an on-site ERCP service. Transporting patients to the nearest tertiary centre would incur significant costs to both the patient and district health board. Aims To determine the outcomes of performing ERCP at TBH and compare these with published figures. To determine if it is a safe and effective option for patients in this region. Methods An ambi-directional study of all ERCP procedures at TBH between January 2011 and December 2015 was conducted. Patient demographics, procedure indication and procedural details were captured via ProVation® MD and endoscopist's notes. Complications were identified through patient's notes and recorded if occurring within 30 days of the procedure. All complications were graded mild, moderate or severe based on a grading system described by Cotton et al. Results A total of 445 procedures were performed. Bile duct cannulation rate was 92.3% and therapeutic success rate was 89.9%. Complications occurred in 8.99% of patients and ERCP-specific mortality was 0.22%. Haemorrhage occurred in 1.35% of patients, pancreatitis in 5.2% and perforation in 0.45%. Success and complication rates are similar to other published studies. Conclusion ERCP can be safely and successfully performed in a provincial centre.

Used to detect liver disease and injury, baseline liver chemistry distributions were evaluated by age and gender in children without known liver disease. Baseline liver chemistries [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL)] were analyzed from 24 randomized controlled pediatric clinical trials. Using quantile regression, liver chemistry distributions were examined by age and gender; upper limit normal (ULN) ranges were compared to the 97.5th percentiles of the distributions for the specified ages and genders. 5410 subjects without known liver disease (0-18 years; 60% male) were studied. The median ALT varied little with age. In males age 5-18, the ALT 97.5th percentile increased from 34 to 63 IU/L. In both genders, the median and 97.5th percentile AST decreased with age. After age 9, ALP decreased. TBIL increased with age. Despite most liver chemistry 97.5th percentiles changing substantively with age and gender, the reference lab ULN generally changed minimally and did not correlate with the 97.5th percentile. Gender and age specific 97.5th percentile data should therefore be considered for the reference laboratory ULN in children to more accurately detect liver injury and disease.

e23577 Background: Soft tissue sarcoma (STS) is a rare malignancy with an annual incidence rate of < 5 cases per 100,000 persons; outcomes for metastatic STS (mSTS) are poor. A targeted literature review was conducted to quantify the efficacy/effectiveness of current mSTS therapies. Methods: A structured search based on the population, intervention, comparator, outcome, study type (PICOS) framework was performed on articles (2009–2019) in MEDLINE, Embase, and Cochrane Central. Limited congress searches (ESMO, AACR, ASCO 2016–2018/2019) were also conducted. Clinical trials (CT) and observational studies (Obs) involving patients (pts, any age) with advanced mSTS receiving any pharmacological intervention were included. After screening, selected efficacy (CT) or effectiveness (Obs) endpoints (including progression-free survival [PFS], overall survival [OS], overall response rate, and duration of response) stratified by line of treatment (LOT, if available) were extracted. Results: Overall, 85 studies (56 CT, 29 Obs) met inclusion criteria; study size was 20–4,274 pts. PFS and OS (from 70 studies) were reported for pts with mSTS treated with a wide range of interventions including doxorubicin, trabectedin, pazopanib, and gemcitabine. Across any LOT, median PFS ranged 1.5–9.3 months in CT and 2.1–11.0 months in Obs; ranges were 5.7─28.8 months and 7.0─38.6 months, respectively, for OS. Median PFS and OS were generally lower with later (vs initial) LOT; few studies assessed ≥4 LOT (Table). Outcome data (any LOT) for trabectedin and pazopanib (the only approved targeted mSTS treatments) are shown in Table. Conclusions: This review of the efficacy/effectiveness of current treatments highlights the unmet clinical need for therapies that improve survival outcomes in pts with mSTS. Results may be influenced by small sample size, pt population, and care improvements over the period studied. [Table: see text]

Background: Several novel therapies for multiple myeloma (MM) have been approved in recent years. While these therapies have demonstrated improvement in real-world tumor responses and progression-free survival, the cost burden of late-line relapsed refractory MM is not well understood. The objective of this retrospective cohort analysis of US claims data was to examine total, MM-related, and adverse event (AE)-related healthcare costs for patients with MM at different lines of treatment (LOTs), with a focus on patients at third (3L) or later (4L+) LOT. Methods: The study identified an incident cohort of treatment-naïve patients with MM aged ≥18 years from the PharMetrics Plus (IQVIA™, Durham, NC) database of US commercial claims and included patients had a first diagnosis of MM (Index date) between January 1, 2012 and December 31, 2016 and received ≥1 MM therapy during the ≥1-year follow-up period. Endpoints included all-cause and MM-related costs per patient per month (PPPM), common AEs, AE-related costs per episode, and proportion of patients requiring AE-related hospitalization. Descriptive analyses were conducted based on LOT (first-line [1L], second-line [2L], 3L and 4L+) which was defined using all MM drugs of interest observed within 28 days of use of the first MM drug, whereas end of a LOT was identified using a 90-day gap in the therapy regimen or use of a new agent outside the 28-day window. All-cause and MM-related costs were compared between patients indexed from 2012-2014 and 2015-2017 (ranges based on the availability of new MM drugs) using a univariate generalized model with log link and gamma distribution. Results: Of the 2,120 patients in the incident cohort, 799 (37.7%) and 390 (18.4%) patients received 3L and 4L+ treatments, respectively. Mean (standard deviation) age at initial MM diagnosis was 58.9 (8.9) and 58.8 (8.6) years for patients progressing to 3L and 4L+. Patients at 3L or 4L+ had greater use of novel therapies (29.2% and 66.9%, respectively) vs patients at 1L (1.4%) and 2L (12.0%). Mean all-cause and MM-related total costs PPPM were higher in 3L and 4L+ vs the mean costs for the entire cohort (Table 1). Costs were significantly greater in patients indexed later (2015-2017) vs earlier (2012-2014) during the study (before inflation adjustments). The most frequent AEs after initial MM diagnosis included hematologic AEs (anemia [79.3%], neutropenia [40.9%], and thrombocytopenia [38.2%]), pneumonia (32.6%), and bone pain (72.9%). The median duration of most AEs was short (1.0-5.0 days). The AE-related cost per episode of these AEs was high and increased during later lines of therapy, largely driven by increased inpatient and outpatient costs (Table 2). Costs were highest across lines of therapy for anemia, neutropenia and pneumonia. Conclusion: Patients in 3L and 4L+ of MM treatment incurred high healthcare costs that followed a typical cost distribution ranging from $18,000 to $22,000 PPPM (median values), with several patients incurring much higher costs that swung mean values substantially upward ($89,000 and $40,000 PPPM, respectively). Costs of managing AEs followed a similar distribution but were somewhat similar across LOTs, with median values ranging from $2,000 to $4,500 per episode and mean values exceeding $30,000 per episode. Additional research should focus on better understanding patients with high cost values, and other costs of managing MM and associated AEs that were not addressed in this analysis. Acknowledgments: Medical writing assistance was provided by Mary E. Morgan PhD at Fishawack Indicia Ltd UK and funded by GlaxoSmithKline. Programming was provided by Kainan Sun, an employee of IQVIA. This study (HO-18-18615) was funded by GlaxoSmithKline. Disclosures Felber: GlaxoSmithKline: Employment, Equity Ownership. Chen:IQVIA: Employment; GSK: Research Funding. Willson:GSK: Equity Ownership; GSK: Employment. Bell:GlaxoSmithKline: Equity Ownership; GlaxoSmithKline: Employment. Simard:GlaxoSmithKline (former employee): Employment; Medtronic (current employee): Employment. Nunna:GSK: Research Funding; IQVIA: Employment. Dharmani:GSK: Employment. Stirnadel-Farrant:GSK: Employment, Equity Ownership. Wang:GSK: Employment; BMS: Equity Ownership. Bruno:GSK: Employment; BMS: Equity Ownership.

Introduction: Cardiovascular (CV) morbidity and mortality are excessively high among hemodialysis (HD) patients. Anemia is a common complication of chronic kidney disease (CKD) and a known risk factor for CV events. To understand the impact of the recent regulatory and guideline changes in anemia management, we examined regional CV event rates in high-risk and erythropoiesis-stimulating agent (ESA)−hyporesponsive HD patients. Methods: A prospective cohort study including 16,560 HD patients, 8660 CV high-risk, and 884 hyporesponsive to ESAs, from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 4 (2009−2011) and phase 5 (2012−2015) was conducted to quantify all-cause mortality, major adverse cardiovascular events (MACE), and MACE plus heart failure and thromboembolic events (MACE+). Results: The MACE+ rates (per 100 patient-years) were highest in North America (NA) (19.4; 95% CI = 18.2−20.7), followed by Europe (EU) (17.4; 95% CI = 16.6−18.1) and lowest in Japan (7.5; 95% CI = 6.9−8.1). When restricted to the high CV risk population, rates increased by 36% in NA, 45% in EU, and 72% in Japan. Mortality accounted for >74% of MACE+ events. MACE+ rates in ESA-hyporesponsive patients and high CV risk patients were similar in NA and EU cohorts. There were minimal differences in outcomes between the DOPPS phases 4 and 5. Conclusion: Cardiovascular event rates are high in the HD population, vary by geographic region, and are substantially higher in high CV risk patients and ESA-hyporesponsive patients; however, the rates appear not to be affected by anemia guideline changes. The findings from this study will be essential to contextualize the design of future CV anemia-related outcome studies and clinical trials. Keywords: cardiovascular events, cohort study, DOPPS, ESA hyporesponsivness, hemodialysis

Background: The development of kidney disease is a serious complication among people with type 2 diabetes mellitus, associated with substantially increased morbidity and mortality. We aimed to summarise the current evidence for the relationship between treatments for type 2 diabetes and long-term kidney outcomes, by conducting a systematic search and review of relevant studies. Methods: We searched Medline, Embase and Web of Science, between 1st January 1980 and 15th May 2018 for published clinical trials and observational studies comparing two or more classes of oral therapy for type 2 diabetes. We included people receiving oral antidiabetic drugs. Studies were eligible that; (i) compared two or more classes of oral therapy for type 2 diabetes; (ii) reported kidney outcomes as primary or secondary outcomes; (iii) included more than 100 participants; and (iv) followed up participants for 48 weeks or more. Kidney-related outcome measures included were Incidence of chronic kidney disease, reduced eGFR, increased creatinine, ‘micro’ and ‘macro’ albuminuria. Results: We identified 15 eligible studies, seven of which were randomised controlled trials and eight were observational studies. Reporting of specific renal outcomes varied widely. Due to variability of comparisons and outcomes meta-analysis was not possible. The majority of comparisons between treatment with metformin or sulfonylurea indicated that metformin was associated with better renal outcomes. Little evidence was available for recently introduced treatments or commonly prescribed combination therapies. Conclusions: Comparative evidence for the effect of treatments for type 2 diabetes on renal outcomes, either as monotherapy or in combination is sparse.

For hypertensive women in CHIPS (Control of Hypertension in Pregnancy Study), we assessed whether the maternal benefits of tight control could be achieved, while minimizing any potentially negative effect on fetal growth, by delaying initiation of antihypertensive therapy until later in pregnancy. For the 981 women with nonsevere, chronic or gestational hypertension randomized to less-tight (target diastolic blood pressure, 100 mm Hg), or tight (target, 85 mm Hg) control, we used mixed-effects logistic regression to examine whether the effect of less-tight (versus tight) control on major outcomes was dependent on gestational age at randomization, adjusting for baseline factors as in the primary analysis and including an interaction term between gestational age at randomization and treatment allocation. Gestational age was considered categorically (quartiles) and continuously (linear or quadratic form), and the optimal functional form selected to provide the best fit to the data based on the Akaike information criterion. Randomization before (but not after) 24 weeks to less-tight (versus tight) control was associated with fewer babies with birth weight P interaction =0.005), but more preterm birth ( P interaction =0.043), and no effect on perinatal death or high-level neonatal care >48 hours ( P interaction =0.354). For the mother, less-tight (versus tight) control was associated with more severe hypertension at all gestational ages but particularly so before 28 weeks ( P interaction =0.076). In women with nonsevere, chronic, or gestational hypertension, there seems to be no gestational age at which less-tight (versus tight) control is the preferred management strategy to optimize maternal or perinatal outcomes. Clinical Trial Registration— URL: https://www.isrctn.com . Unique identifier: ISRCTN71416914.