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Objective There is growing recognition of morbidity and mortality that can occur in patients with cranial diabetes insipidus (CDI) during hospitalisation, due to prescribing errors and dysnatraemia, often related to confusion between CDI and diabetes mellitus among non-specialists. We aimed to investigate this. Methods Data for each hospitalisation in patients with CDI attending Oxford University Hospital (OUH) were collected retrospectively. The same cohort were invited to complete a questionnaire by telephone. Results One hundred and nine patients were included, median age was 42 (range: 6–80) years. Route of desmopressin was tablet, melt and nasal spray in 74%, 7% and 17% of patients, respectively, while two patients used a combination of tablet and nasal spray. There were 85 admissions to OUH by 38 patients between 2012 and 2021. Daily measurement of serum sodium was performed in 39% of admissions; hyponatraemia and hypernatraemia occurred in 44 and 15% of admissions, respectively. Endocrine consultation was sought in 63% of admissions post-2018. Forty-five of 78 patients (58%) self-reported ≥1 admission to any hospital since diagnosis. Of these, 53% felt their medical team did not have a good understanding of the management of CDI during hospital admission. Twenty-four per cent reported delay in administration of desmopressin, while 44% reported confusion between CDI and diabetes mellitus, often leading to unnecessary blood glucose monitoring. Conclusion Dysnatraemia is common in hospitalised patients with CDI. More than half of patients perceived their medical team’s understanding of CDI to be poor when admitted with intercurrent illness. A coordinated approach, including early consultation of specialists, frequent serum sodium monitoring, and education of hospital specialists is needed to address this.

Introduction: Variants of the APOL1 gene are associated with chronic kidney disease (CKD) in people of African ancestry, although evidence for their impact in people with HIV are sparse. Methods: We conducted a cross-sectional study investigating the association between APOL1 renal risk alleles and kidney disease in people of African ancestry with HIV in the UK. The primary outcome was end-stage kidney disease (ESKD; estimated glomerular filtration rate [eGFR] of 2, chronic dialysis, or having received a kidney transplant). The secondary outcomes included renal impairment (eGFR 2), albuminuria (albumin-to-creatinine ratio [ACR] >30 mg/mmol), and biopsy-proven HIV-associated nephropathy (HIVAN). Multivariable logistic regression was used to estimate the associations between APOL1 high-risk genotypes (G1/G1, G1/G2, G2/G2) and kidney disease outcomes. Results: A total of 2864 participants (mean age 48.1 [SD 10.3], 57.3% female) were genotyped, of whom, 354 (12.4%) had APOL1 high-risk genotypes, and 99 (3.5%) had ESKD. After adjusting for demographic, HIV, and renal risk factors, individuals with APOL1 high-risk genotypes were at increased odds of ESKD (odds ratio [OR] 10.58, 95% CI 6.22–17.99), renal impairment (OR 5.50, 95% CI 3.81–7.95), albuminuria (OR 3.34, 95% CI 2.00–5.56), and HIVAN (OR 30.16, 95% CI 12.48–72.88). An estimated 49% of ESKD was attributable to APOL1 high-risk genotypes. Conclusion: APOL1 high-risk genotypes were strongly associated with kidney disease in people of African ancestry with HIV and accounted for approximately half of ESKD cases in this cohort.

This Brief examines the impact of Covid-19 on systems of government, emergency response and opposition members in legislatures and their ability to maintain democratic principles. Drawing on insights from five countries as case studies, Malaysia, New Zealand, Papua New Guinea, the Republic of Korea and Singapore, this Brief finds that emergency responses that restrict the capacity of the legislature erode the ability of opposition members to contribute. It also highlights that the role oppositions played during the pandemic varied based on the form of government—be it presidential or parliamentary.

Methyl-CpG-binding protein 2 (MECP2) is a chromatin-associated protein that can both activate and repress transcription, playing an essential role in neuronal maturation. MECP2 is encoded by an X-linked gene (chromosome Xq28) with high expression in the brain, including the hypothalamic region. Loss-of-function mutations in MECP2 are usually associated with Rett syndrome, a rare genetic disorder characterized by normal early development followed by regression of acquired skills, such as purposeful hand movements and the ability to communicate, repetitive hand stereotypies, slowed brain growth, seizures, and intellectual disability with female predominance. Notably, early pubertal development (early thelarche, pubarche and, less often, menarche) has been demonstrated in girls with Rett syndrome. In this original study, a total of 329 CPP patients (308 girls and 21 boys) were investigated for MECP2 defects. Familial cases were identified in 38% of this CPP cohort. First, 129 CPP patients were enrolled for multigene sequencing studies (whole-exome sequencing n=58; targeted gene sequencing n=71) as part of genetic investigations based on large-scale approaches. Three rare heterozygous sequence variants predicted to be deleterious in MECP2 gene were identified in 5 girls from 4 unrelated families with CPP: the p.Arg97Cys de novo missense variant in two monozygotic twin sisters with CPP and microcephaly; the p.Ser176Arg de novo missense variant in one girl with sporadic CPP, obesity and autism; and the p.Ala6_Ala8dup insertion in two unrelated girls with sporadic CPP (one with a maternally inherited variant). To expand the investigation for potentially damaging sequence variants of MECP2, a larger multiethnic cohort of 200 CPP patients was further analyzed through Sanger sequencing. One rare heterozygous 3'UTR insertion in MECP2 (c.*36_*37insT) was identified in two unrelated girls with sporadic CPP (one with a maternally inherited variant and other with a de novo variant). None of these MECP2 variants have been previously reported in Rett syndrome cases. The girls with CPP associated with MECP2 defects did not manifest typical Rett syndrome. The three patients with more deleterious MECP2 variants, according to in silico prediction tools, had neurobehavioral phenotypes, likely corresponding to a genotype-phenotype correlation. Immunohistochemistry and immunofluorescence studies were performed in pubertal female mice. Abundant staining for Mecp2 was demonstrated in multiple hypothalamic nuclei (arcuate, suprachiasmatic, and paraventricular) and in the median eminence. Co-localization of Mecp2 and GnRH within GnRH neurons was suggested in double labelling experiments. Hence, Mecp2 expression was demonstrated in key hypothalamic nuclei responsible for GnRH regulation in female mice. In conclusion, we have identified rare dominant MECP2 defects in multiple unrelated girls with CPP with or without mild neurodevelopmental abnormalities, revealing a new X-linked form of premature reactivation of the hypothalamic-pituitary-gonadal axis. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m.

Objective: To investigate postgraduate student perceptions of face-to-face and distance education on a three-year programme in orthodontics. Design: Cross-sectional qualitative study. Setting: UCL Eastman Dental Institute, London. Participants: A total of 25 current postgraduate orthodontic students in the first, second and third years of training were included in this study. Methods: Postgraduate student perceptions were obtained by conducting online focus groups on Zoom Video Communications Inc. A focus group topic guide was developed, and a facilitator was trained to host the focus groups. There were separate focus groups for each year group, with a maximum of five participants in each group. The focus groups were audio recorded and transcribed verbatim. The transcripts were assessed by all members of the research team and analysed using a thematic content analysis, with a framework approach to identify themes and subthemes regarding perceptions of distance and face-to-face education. Results: A total of 25 students participated. Six key themes were identified relating to student perceptions of face-to-face and distance education: (1) social support network; (2) technology; (3) learning experience; (4) education environment; (5) interpersonal interactions; and (6) effective teaching/learning. There were perceived benefits and drawbacks for both modes of teaching delivery. In particular, students highlighted the importance of reliable technology, peer support and accessibility of educational resources for their academic learning. Students favoured a blended approach to learning where practical skills were taught in person and some theoretical aspects taught remotely. Conclusion: The results aid the understanding of how educational tools and digital technology can enrich the student academic experience. The results provide important information for the future development and delivery of orthodontic postgraduate education.

Puberty is a life-changing time in the life of a young person, with physical, psychological and social considerations. Amenorrhea is derived from Latin: a—‘not’, men—‘month’ and rhein—‘flow’, meaning absence of monthly flow. In medical terms, it is a symptom describing absence of menstruation. It can be classified as either primary or secondary. This article will focus solely on primary amenorrhea. Primary amenorrhea can induce great anxiety in both the patient and the family and often presents to the general paediatrician. A thorough history and examination and judicious use of investigations is crucial to ensure timely diagnosis and management.

Sickle cell trait (SCT) has been associated with chronic kidney disease (CKD) in African Americans, although evidence for its impact in Africans and people with HIV is currently lacking. We conducted a cross-sectional study investigating the association between SCT and kidney disease in people of African ancestry with HIV in the UK.The primary outcome was estimated glomerular filtration rate (eGFR) 60 ml/min per 1.73 mA total of 2895 participants (mean age 48.1 [SD 10.3], 57.2% female) were included, of whom 335 (11.6%) had SCT and 352 (12.2%) had eGFR 60 ml/min per 1.73 mOur results extend previously reported associations between SCT and kidney disease to people with HIV. In people of African ancestry with HIV, these associations were largely restricted to those with

Background and Purpose: Conditions associated with frailty are common in people experiencing stroke and may explain differences in outcomes. We assessed associations between a published, generic frailty risk score, derived from administrative data, and patient outcomes following stroke/transient ischemic attack; and its accuracy for stroke in predicting mortality compared with other measures of clinical status using coded data. Methods: Patient-level data from the Australian Stroke Clinical Registry (2009–2013) were linked with hospital admissions data. We used International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes with a 5-year look-back period to calculate the Hospital Frailty Risk Score (termed Frailty Score hereafter) and summarized results into 4 groups: no-risk (0), low-risk (1–5), intermediate-risk (5–15), and high-risk (>15). Multilevel models, accounting for hospital clustering, were used to assess associations between the Frailty Score and outcomes, including mortality (Cox regression) and readmissions up to 90 days, prolonged acute length of stay (>20 days; logistic regression), and health-related quality of life at 90 to 180 days (quantile regression). The performance of the Frailty Score was then compared with the Charlson and Elixhauser Indices using multiple tests (eg, C statistics) for predicting 30-day mortality. Models were adjusted for covariates including sociodemographics and stroke-related factors. Results: Among 15 468 adult patients, 15% died ≤90 days. The frailty scores were 9% no risk; 23% low, 45% intermediate, and 22% high. A 1-point increase in frailty (continuous variable) was associated with greater length of stay (OR adjusted , 1.05 [95% CI, 1.04 to 1.06), 90-day mortality (HR adjusted , 1.04 [95% CI, 1.03 to 1.05]), readmissions (OR adjusted , 1.02 [95% CI, 1.02 to 1.03]; and worse health-related quality of life (median difference, −0.010 [95% CI −0.012 to −0.010]). Adjusting for the Frailty Score provided a slightly better explanation of 30-day mortality (eg, larger C statistics) compared with other indices. Conclusions: Greater frailty was associated with worse outcomes following stroke/transient ischemic attack. The Frailty Score provides equivalent precision compared with the Charlson and Elixhauser indices for assessing risk-adjusted outcomes following stroke/transient ischemic attack.

Background: Clinical manifestations and treatment outcomes in children and adolescents with multiple endocrine neoplasia type 1 are not well characterized. Methods: We conducted a retrospective cohort study of 80 patients with multiple endocrine neoplasia type 1 who commenced tumor surveillance at ≤18 years of age. Results: Fifty-six patients (70%) developed an endocrine tumor by age ≤18 years (median age = 14 years, range = 6–18 years). Primary hyperparathyroidism occurred in >80% of patients, with >70% undergoing parathyroidectomy, in which less-than-subtotal (70% had nonfunctioning tumors, >35% had insulinomas, and 55% undergoing surgery. Pituitary tumors developed in >30% of patients, and ∼35% were macroprolactinomas. Tumor occurrence in male patients and female patients was not significantly different. Genetic analyses revealed 38 germline MEN1 mutations, of which 3 were novel. Conclusions: Seventy percent of children aged ≤18 years with multiple endocrine neoplasia type 1 develop endocrine tumors, which include parathyroid tumors for which less-than-subtotal parathyroidectomy should be avoided; pancreaticoduodenal neuroendocrine tumors that may metastasize; and pituitary macroprolactinomas.

ObjectiveTo compare the processes and outcomes of care in patients who had a stroke treated in urban versus rural hospitals in Australia.DesignObservational study using data from a multicentre national registry.SettingData from 50 acute care hospitals in Australia (25 urban, 25 rural) which participated in the Australian Stroke Clinical Registry during the period 2010–2015.ParticipantsPatients were divided into two groups (urban, rural) according to the Australian Standard Geographical Classification Remoteness Area classification. Data pertaining to 28 115 patients who had a stroke were analysed, of whom 8159 (29%) were admitted to hospitals located within rural areas.Primary and secondary outcome measuresRegional differences in processes of care (admission to a stroke unit, thrombolysis for ischaemic stroke, discharge on antihypertensive medication and provision of a care plan), and survival analyses up to 180 days and health-related quality of life at 90–180 days.ResultsCompared with those admitted to urban hospitals, patients in rural hospitals less often received thrombolysis (urban 12.7% vs rural 7.5%, pConclusionsRural access to recommended components of acute stroke care was comparatively poorer; however, this did not appear to impact health outcomes at approximately 6 months.

We introduce Ego4D, a massive-scale egocentric video dataset and benchmark suite. It offers 3,670 hours of daily-life activity video spanning hundreds of scenarios (household, outdoor, workplace, leisure, etc.) captured by 931 unique camera wearers from 74 worldwide locations and 9 different countries. The approach to collection is designed to uphold rigorous privacy and ethics standards with consenting participants and robust de-identification procedures where relevant. Ego4D dramatically expands the volume of diverse egocentric video footage publicly available to the research community. Portions of the video are accompanied by audio, 3D meshes of the environment, eye gaze, stereo, and/or synchronized videos from multiple egocentric cameras at the same event. Furthermore, we present a host of new benchmark challenges centered around understanding the first-person visual experience in the past (querying an episodic memory), present (analyzing hand-object manipulation, audio-visual conversation, and social interactions), and future (forecasting activities). By publicly sharing this massive annotated dataset and benchmark suite, we aim to push the frontier of first-person perception. Project page: https://ego4d-data.org/, Comment: To appear in the Proceedings of the IEEE/CVF Conference on Computer Vision and Pattern Recognition (CVPR), 2022. This version updates the baseline result numbers for the Hands and Objects benchmark (appendix)

Puberty is an important transitional time between childhood and adulthood, incorporating many physical, psychological and emotional changes. The development of secondary sexual characteristics is controlled by the hypothalamic–pituitary–gonadal (HPG) axis. Problems occurring in puberty can be frightening and worrying for both the young person and their carers/parents. In this chapter, we will look specifically at problems in puberty relating to the malfunction of the HPG axis, presenting with hypogonadotropic hypogonadism.

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the pathogen responsible for Coronavirus Disease 2019 (COVID-19). Whilst most children and young people develop mild symptoms, recent reports suggest a novel paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Case definition and classification are preliminary, treatment is empiric and disease-associated outcomes are unclear. Here, we report 29 patients with PIMS-TS who were diagnosed, admitted and treated in the English North West between March and June 2020. Consistent with patterns observed internationally, cases peaked approximately 4 weeks after the initial surge of COVID-19-like symptoms in the UK population. Clinical symptoms included fever (100%), skin rashes (72%), cardiovascular involvement (86%), conjunctivitis (62%) and respiratory involvement (21%). Some patients had clinical features partially resembling Kawasaki disease (KD), toxic shock syndrome and cytokine storm syndrome. Male gender (69%), black, Asian and other minority ethnicities (BAME, 59%) were over-represented. Immune modulating treatment was used in all, including intravenous immunoglobulin (IVIG), corticosteroids and cytokine blockers. Notably, 32% of patients treated with IVIG alone went into remission. The rest required additional treatment, usually corticosteroids, with the exception of two patients who were treated with TNF inhibition and IL-1 blockade, respectively. Another patient received IL-1 inhibition as primary therapy, with associated rapid and sustained remission. Randomized and prospective studies are needed to investigate efficacy and safety of treatment, especially as resources of IVIG may be depleted secondary to high demand during future waves of COVID-19.

Background Clinical prediction rules, such as CHA2DS2-VASc, HATCH and HAVOC have been used in the prediction of stroke and transient ischemic attack (TIA) in those with atrial fibrillation (AF). Currently the ESC guidelines recommend the use of the CHA2DS2-VASc score to help determine which patients with AF would most benefit from anticoagulation. In recent years there has been a trend to use CHA2DS2-VASc for stroke prediction even in the non-AF population, with similar C-statistic (0.61–0.76) in comparison to AF cohorts. Similarly, natriuretic peptides have gained interest as a marker of cardiovascular risk, including cardioembolic stroke. Purpose We compared CHA2DS2-VASc, HA2TCH and HAVOC for prediction of stroke/TIA in patients without a history of atrial fibrillation or flutter and hypothesised that adding natriuretic peptides would improve clinical risk prediction for stroke or TIA in the STOP-HF population. Methods The study included 1156 patients without known AF enrolled in the STOP HF follow-up study between 2006 and 2017. The end-point measured was Stroke/TIA. Baseline NTproBNP levels(NP), CHA2DS2-VASc, HAVOC and HATCH scores were recorded for all patients. Logistical regression analysis and receiver operating characteristic curve were used to estimate odds ratio and the diagnostic accuracy of the NP and clinical prediction scores for Stroke/TIA, respectively. Results The mean age (SD) was 65.8 (10.1) years, 579 (50.5%) were female, prominent co-morbidities were hypertension and diabetes (table 1). The median NTproBNP was 93 pg/ml (IQR:53- 189). The endpoint of stroke/TIA occurred in 44 (3.8%) of the population. Patients experiencing stroke/TIA over follow up were older, more likely to have baseline vascular and thromboembolic disease and higher baseline NTproBNP levels than those who did not experience stroke/TIA during follow up. The median scores for the CHA2DS2-VASc, HAVOC, HATCH were also higher at baseline higher in the new onset TIA/Stroke group. All the clinical prediction scores as well as NTproBNP predicted Stroke/TIA (table 2). All clinical prediction scores remained significant predictors of Stroke/TIA after multivariate adjustment. NP prediction was no longer significant (table 2). The HATCH score significantly outperformed the other scores with a c statistic of 0.76 (95% CI, 0.69 - 0.78) (figure 1 & 2). The c-statistic for the CHA2DS2-VASc and HAVOC scores were 0.69 (95% CI, 0.61- 0.77) and 0.66 (95% CI, 0.57- 0.74), respectively. Addition of NP did not improve the discriminatory power of any of the scores. Conclusion All the clinical scores predicted Stroke/TIA in patients without known AF. However, the HATCH score significantly outperformed the CHA2DS2-VASc and HAVOC scores. Baseline NP levels, neither predicted Stroke/TIA, nor enhanced the prediction power of the clinical scores. Further evaluation of the HA2TCH score will delineate its potential value in clinical practice.

Puberty is the physiological sequence of events when secondary sexual characteristics develop, reproductive capacity is achieved, and final adult stature reached. The outward signs usually develop over 3 to 5 years, with significant variation both in the age that puberty starts and the pace at which development proceeds. The events that lead to the triggering of puberty remain uncertain, but clinical presentations may arise because the process is abnormally early (precocious puberty) or abnormally late (delayed or absent puberty). Several variants of the normal processes may also present for clinical assessment, for example, premature isolated thelarche (breast development) or adrenarche (pubic and axillary hair development), which do not require treatment.

Background Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. Early intervention for those with high cardiovascular risk is crucial in improving patient outcomes. Traditional prevention strategies for CVD have focused on conventional risk factors, such as overweight, dyslipidaemia, diabetes, and hypertension, which may reflect the potential for cardiovascular insult. Natriuretic peptides (NPs), including B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP), are well-established biomarkers for the detection and diagnostic evaluation of heart failure. They are of interest for CVD prevention because they are secreted by the heart as a protective response to cardiovascular stress, strain, and damage. Therefore, measuring NP levels in patients without heart failure may be valuable for risk stratification, to identify those at highest risk of CVD who would benefit most from intensive risk reduction measures. Objectives To assess the effects of natriuretic peptide (NP)-guided treatment for people with cardiovascular risk factors and without heart failure. Search methods Searches of the following bibliographic databases were conducted up to 9 July 2019: CENTRAL, MEDLINE, Embase, and Web of Science. Three clinical trial registries were also searched in July 2019. Selection criteria We included randomised controlled trials enrolling adults with one or more cardiovascular risk factors and without heart failure, which compared NP-based screening and subsequent NP-guided treatment versus standard care in all settings (i.e. community, hospital). Data collection and analysis Two review authors independently screened titles and abstracts and selected studies for inclusion, extracted data, and evaluated risk of bias. Risk ratios (RRs) were calculated for dichotomous data, and mean differences (MDs) with 95% confidence intervals (CIs) were calculated for continuous data. We contacted trial authors to obtain missing data and to verify crucial study characteristics. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, two review authors independently assessed the quality of the evidence and GRADE profiler (GRADEPRO) was used to import data from Review Manager to create a 'Summary of findings' table. Main results We included two randomised controlled trials (three reports) with 1674 participants, with mean age between 64.1 and 67.8 years. Follow-up ranged from 2 years to mean 4.3 years.For primary outcome measures, effect estimates from a single study showed uncertainty for the effect of NP-guided treatment on cardiovascular mortality in patients with cardiovascular risk factors and without heart failure (RR 0.33, 95% CI 0.04 to 3.17; 1 study; 300 participants; low-quality evidence). Pooled analysis demonstrated that in comparison to standard care, NP-guided treatment probably reduces the risk of cardiovascular hospitalisation (RR 0.52, 95% CI 0.40 to 0.68; 2 studies; 1674 participants; moderate-quality evidence). This corresponds to a risk of 163 per 1000 in the control group and 85 (95% CI 65 to 111) per 1000 in the NP-guided treatment group.When secondary outcome measures were evaluated, evidence from a pooled analysis showed uncertainty for the effect of NP-guided treatment on all-cause mortality (RR 0.90, 95% CI 0.60 to 1.35; 2 studies; 1354 participants; low-quality evidence). Pooled analysis indicates that NP-guided treatment probably reduces the risk of all-cause hospitalisation (RR 0.83, 95% CI 0.75 to 0.92; 2 studies; 1354 participants; moderate-quality evidence). This corresponds to a risk of 601 per 1000 in the control group and 499 (95% CI 457 to 553) per 1000 in the NP-guided treatment group. The effect estimate from a single study indicates that NP-guided treatment reduced the risk of ventricular dysfunction (RR 0.61, 95% CI 0.41 to 0.91; 1374 participants; high-quality evidence). The risk in this study's control group was 87 per 1000, compared with 53 (95% CI 36 to 79) per 1000 with NP-guided treatment. Results from the same study show that NP-guided treatment does not affect change in NP level at the end of follow-up, relative to standard care (MD -4.06 pg/mL, 95% CI -15.07 to 6.95; 1 study; 1374 participants; moderate-quality evidence). Authors' conclusions This review shows that NP-guided treatment is likely to reduce ventricular dysfunction and cardiovascular and all-cause hospitalisation for patients who have cardiovascular risk factors and who do not have heart failure. Effects on mortality and natriuretic peptide levels are less certain. Neither of the included studies were powered to evaluate mortality. Available evidence shows uncertainty regarding the effects of NP-guided treatment on both cardiovascular mortality and all-cause mortality; very low event numbers resulted in a high degree of imprecision in these effect estimates. Evidence also shows that NP-guided treatment may not affect NP level at the end of follow-up.As both trials included in our review were pragmatic studies, non-blinding of patients and practices may have biased results towards a finding of equivalence. Further studies with more adequately powered sample sizes and longer duration of follow-up are required to evaluate the effect of NP-guided treatment on mortality. As two trials are ongoing, one of which is a large multi-centre trial, it is hoped that future iterations of this review will benefit from larger sample sizes across a wider geographical area.

Background Elevated B-type NP (BNP) in asymptomatic patients with cardiac abnormalities can provide a protective, endogenous response to fibro-inflammation. The PARABLE study is investigating the hypothesis that augmenting BNP pharmacologically with the neutral endopepdidase inhibitor sacubitril can modulate progression of LAVI over 18 months measured using cardiac Magnetic Resonance Imaging (cMRI). In addition, all patients in PARABLE undergo Doppler-echocardiography at baseline, 9 months and 18 months. The purpose of this report is to evaluate overall, blinded progression of cardiac structural and functional abnormalities over 9 months in the first 100 and 18 months in the first 74 patients. Methods PARABLE is an investigator-led, prospective, randomised, double blind, double dummy, phase II trial comparing treatment with sacubitril/valsartan versus valsartan. PARABLE will enroll 250 patients aged over 40 years with hypertension and/or diabetes, with BNP from 20–280 pg/mL or NTproBNP from 100 to 1000 pg/mL) and LAVI above 28 mL/m2. Excluded are patients with a history of heart failure, left ventricular systolic dysfunction, haemodynamically significant mitral and/or aortic valve disease, persistent atrial fibrillation, hepatic dysfunction and severe chronic kidney disease. The primary endpoint is change in LAVI measured by cMRI over 18 months. We evaluated blinded Doppler-echocardiographic measures of left ventricular structure, systolic function and diastolic function at baseline, 9 months and 18 months. Results In the first 100 patients to complete the study, 35% were female, average age 72.7±8.0 years, 94% had hypertension and 22% had Type 2 diabetes. Sub-population blood pressure was 136/78±21/13 mmHg, heart rate was 63.5±10.8 bpm and body mass index was 28.8±4.9 kg/m2. Other baseline medical history included dyslipidaemia (83%), coronary artery disease (52%), other vascular disease (5%), stroke/TIA (10%), paroxysmal atrial fibrillation n (7%) and chronic kidney disease (2%). Median BNP was 79 pg/mL [interquartile range (IQR) 47, 117] and Baseline Doppler-echocardiography showed average ejection fraction was 68.5±6.5%, LVMI was 113.3±28.2%, E/e’ was 11.3±3.2 and LAVI was 34.3±4.9 mL/m2. There were no significant changes from baseline in Doppler-echocardiography measures at 9 months. At 18 months, in the subgroup who had completed the study, the only observed change was a significant increase in LAVI from 34.0±4.6 mL/m2 to 36.0±5.0 mL/m2 (p Conclusions Participants in the PARABLE clinical trial with elevated BNP and LAVI at baseline show significant progression of LAVI abnormalities over an 18-month time period. The PARABLE study is on target to define the impact of preserving circulating BNP using sacubitril on LAVI progression as a personalised therapy for prevention of progression of left ventricular diastolic dysfunction.

Aims: This study sought to review the literature for clinical prediction models for the diagnosis of patients with chronic heart failure in the community and to validate the models in a novel cohort of patients with a suspected diagnosis of chronic heart failure. Methods and results: MEDLINE and Embase were searched from 1946 to Q4 2017. Studies were eligible if they contained at least one multivariable model for the diagnosis of chronic heart failure applicable to the primary care setting. The CHARMS checklist was used to evaluate models. We also validated models, where possible, in a novel cohort of patients with a suspected diagnosis of heart failure referred to a rapid access diagnostic clinic. In total, 5310 articles were identified with nine articles subsequently meeting the eligibility criteria. Three models had undergone internal validation, and four had undergone external validation. No clinical impact studies have been completed to date. Area under the curve (AUC) varied from 0.74 to 0.93 and from 0.60 to 0.65 in the novel cohort for clinical models alone with AUC up to 0.89 in combination with electrocardiogram and B-type natriuretic peptide (BNP). The AUC for BNP was 0.86 (95% confidence interval 83.3–88.6%). Conclusions: This review demonstrates that there are a number of clinical prediction rules relevant to the diagnosis of chronic heart failure in the literature. Clinical impact studies are required to compare the use of clinical prediction rules and biomarker strategies in this setting.

BackgroundMonitoring of hormonal control represents a key part of the management of congenital adrenal hyperplasia (CAH). Monitoring strategies remain suboptimal because they rely on frequent blood tests and are not specific for adrenal-derived hormones. Recent evidence suggests the crucial role of adrenal-specific 11-oxygenated-C19 androgens in the pathogenesis of CAH.ObjectiveTo establish a correlation between plasma and salivary adrenal-specific androgens in CAH as a noninvasive monitoring strategy.DesignThis prospective cross-sectional study recruited patients between 2015 and 2018.SettingMulticenter study including 13 tertiary centers in the United Kingdom.ParticipantsSeventy-eight children with CAH and 62 matched healthy controls.MethodsUsing liquid chromatography–tandem mass spectrometry, plasma and salivary concentrations of five steroids were measured: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11-hydroxyandrostenedione (11OHA4), and 11-ketotestosterone (11KT). The correlation between plasma and salivary steroids was analyzed to assess their use in clinical practice.ResultsStrong correlations between plasma and salivary steroid concentrations in patients with CAH were detected: 17OHP (rs = 0.871; P < 0.001), A4 (rs = 0.931; P < 0.001), T (rs = 0.867; P < 0.001), 11OH4A (rs = 0.876; P < 0.001), and 11KT (rs = 0.944; P < 0.001). These results were consistent for patient subgroups based on sex and age. Analysis of patient subgroups based on 17OHP concentrations established clear correlations between plasma and salivary concentrations of the adrenal-specific androgen 11KT.ConclusionsThe current study identified tight correlations between plasma and saliva for the adrenal-derived 11-oxygenated C19 androgen 11KT, as well as 17OHP and A4, which are widely used for monitoring treatment in CAH. This combination of steroid hormones will serve as an improved noninvasive salivary test for disease monitoring in patients with CAH.

Simple Summary In the summer of 2019–2020, a series of more than 15,000 bushfires raged across Australia in a catastrophic event called Australia’s Black Summer. An estimated 3 billion native animals, and whole ecosystems, were impacted by the bushfires, with many endangered species pushed closer to extinction. Zoos Victoria was part of a state-led bushfire response to assist wildlife, alongside government, non-government organisations, and key partners. Here, we detail the role of Zoos Victoria in wildlife triage and welfare, threatened species evacuation and recovery, media and communications, and fundraising during and after the fires. We provide case studies on the triage, care, release, and monitoring of injured koalas (Phascolarctos cinereus); the evacuation and return of endangered eastern bristlebirds (Dasyornis brachypterus) and brush-tailed rock wallabies (Petrogale penicillata); and the development of nutritionally suitable supplementary food and emergency feeding of critically endangered mountain pygmy-possums (Burramys parvus). We share our strategies for future resilience and readiness for similar catastrophic events, as well as the development of triage protocols, emergency response kits, emergency enclosures, captive breeding programs, and nature-based healing for communities directly affected by the fires. We hope that by outlining these contributions from a zoo-based conservation organisation, other zoos and wildlife organisations, both nationally and internationally, may be assisted or encouraged to commit resources and build expertise to assist wildlife in catastrophic events. Abstract Modern zoos are increasingly taking a leading role in emergency management and wildlife recovery. In the face of climate change and the predicted increase in frequency and magnitude of catastrophic events, zoos provide specialised expertise to assist wildlife welfare and endangered species recovery. In the 2019–2020 Australian bushfire season, now called Australia’s Black Summer, a state government-directed response was developed, assembling specialised individuals and organisations from government, non-government organisations, research institutions, and others. Here, we detail the role of Zoos Victoria staff in wildlife triage and welfare, threatened species evacuation and recovery, media and communications, and fundraising during and after the fires. We share strategies for future resilience, readiness, and the ability to mobilise quickly in catastrophic events. The development of triage protocols, emergency response kits, emergency enclosures, and expanded and new captive breeding programs is underway, as are programs for care of staff mental health and nature-based community healing for people directly affected by the fires. We hope this account of our response to one of the greatest recent threats to Australia’s biodiversity, and steps to prepare for the future will assist other zoos and wildlife organisations around the world in preparations to help wildlife before, during, and after catastrophic events.

Introduction: Impaired Quality of Life (QoL) in Congenital Adrenal Hyperplasia (CAH) has been demonstrated in adults, but research in children has yielded variable results. We investigated the impact of CAH on QoL of children and adolescents alongside clinical health outcomes (biometric and biochemical profiles). Method: We collected data from 14 tertiary UK centres to explore current health status of 8-18 year olds with CAH. QoL was assessed by using three different questionnaires; strengths and difficulties questionnaire (SDQ), Paediatric Quality of life (PedsQL) and Self-image profile (SIP), the former two completed by both patients and their parents. Height, weight and blood pressure were converted to age and sex adjusted z-scores. Serum markers included 17OH-progesterone (17OHP), androstenedione (D4), testosterone (T) and 11-ketotestosterone (11KT). Statistical Analysis: Statistical analysis comprised of principal component analysis (PCA) followed by multivariate analysis of variance (MANOVA), and post hoc regression. Results: Of the 107 CAH patients included in the study, median age 12.4 years (IQR 10.0-15.1), 55% were female and 104 completed at least 1 questionnaire. Adequate data for PCA was available from 73/107. Three Principal Components (PCs) with observed eigenvalues > 1 explained 71% of the total variance in the observed variables. PC1 reflected ‘disease control’ comprising 17OHP, D4, T and 11KT. PC2 reflected ‘biometrics’ comprising age, and height and weight z-score. PC3 reflected ‘blood pressure’, comprising systolic and diastolic z-score. PC1 correlated with outcomes in the parent and patient SDQ as well as parent PedsQL. PC2 and PC3 did not correlate with QoL. Regression analysis revealed higher scores (indicating lower QoL) in the SDQ domain of emotional problems and PedsQL domain of emotional health in patients where biomarkers suggested good control or overtreatment. Post hoc regression analysis revealed a rise in Androstenedione of 10nmol/L equated to an improved SDQ emotional problems score of 0.5 points and an improved PedsQL emotional health score of 3 points. Conclusion: The study found an interrelation between QoL and biomarkers of disease control in CAH. There were more emotional problems with higher levels of androgen suppression. Biochemical control within normal ranges did not predict emotional problems. However, unexpectedly, patients with very high levels of androgens were highlighted as reporting fewer problems with their emotional QoL. Further research into QoL in CAH and optimal levels of biochemical control will further understanding.

Introduction: The association between congenital adrenal hyperplasia (CAH) and increased morbidity and mortality in adult life has been well established, however, limited knowledge exists regarding the onset of co-morbidities during childhood. Objective: To establish the health status of children and young persons (CYP) with CAH in the United Kingdom. Methods: This cross-sectional multi-center study involved 14 tertiary endocrine units across the United Kingdom. We recruited 107 patients aged 8-18 years with 21-hydroxylase deficiency and 83 matched controls. We collected and analyzed demographic, clinical, and metabolic data, as well as psychological questionnaires (Strengths and Difficulties [SDQ], Paediatric Quality of Life [PedsQL]and Self-Image Profile [SIP]). Results: The majority of patients (62.2%) were diagnosed within the first month of life, most commonly presenting with ambiguous genitalia (32.7%) or salt losing crisis (25.2%). After diagnosis, 37.3% of patients required admission for adrenal crisis, 11.2% presenting three or more episodes. Of the female patients, 57.6% had undergone urogenital examination under anesthesia and 35.5% had genital surgery. Most CAH patients received glucocorticoid (GC) replacement therapy with hydrocortisone (HC) (94.3%) and the rest with prednisolone, with a mean for relative GC doses of 13.3 (±3.7) mg/m2 per day HC-equivalent. 76.6% of patients received treatment with fludrocortisone, with a mean dose of 105.0 (±50.2) µg/m2 per day. Comparing height-Standard Deviation Score (SDS), patients under 12 years were taller (p=0.011) and patients aged 12-18 years shorter (p=0.031) than controls. Bone age was advanced in patients, with a mean difference from the chronological age of 1.9 (±2.2) years. CAH patients were more frequently overweight (26.4%) or obese (22.6%) compared to controls (10.8% and 10.8% respectively, p