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Objective To investigate the relationship between maximal exercise capacity measured before severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalization due to coronavirus disease 2019 (COVID-19). Patients and Methods We identified patients (≥18 years) who completed a clinically indicated exercise stress test between 01 January 2016 and 29 February 2020 and had a test for SARS-CoV-2 (i.e., real-time reverse transcriptase polymerase chain reaction test) between 29 February 2020 and 31 May 2020. Maximal exercise capacity was quantified in metabolic equivalents of task (METs). Logistic regression was used to evaluate the likelihood that hospitalization secondary to COVID-19 is related to peak METs, with adjustment for 13 covariates previously identified as associated with higher risk for severe illness from COVID-19. Results We identified 246 patients (age= 59±12 years; 42% male; 75% black race) who had an exercise test and tested positive for SARS-CoV-2. Among these, 89 (36%) were hospitalized. Peak METs were significantly lower (P

Biotinidase deficiency disorder is a rare inherited metabolic disorder with typical neurological manifestations of hypotonia, developmental delay, rashes, seizures, hearing and vision impairment. We present two cases with different and unusual clinical profiles, whose neuroimaging resembled Neuromyelitis Optica Spectrum Disorder. Case 1 was initially treated with immunomodulation with steroids and intravenous immunoglobulins, with partial improvement. However reinvestigation for worsening of symptoms showed more extensive changes on spine magnetic resonance imaging. Raised lactate and alanine levels on repeat cerebrospinal fluid testing resulted in further investigations that revealed a biotinidase deficiency. Case 2 presented mainly with respiratory symptoms: a barium swallow suggested bulbar dysfunction. Neuroimaging of brain and spine was similar to that in case 1 and the child was promptly investigated for and confirmed to have biotinidase deficiency. Both cases responded to biotin supplementation. It is important to be cognisant of atypical neurological presentations of biotinidase deficiency including those that mimic immune mediated neurodemyelination disorders, as biotinidase deficiency is potentially treatable.

Pyridoxine‐dependent epilepsy (PDE) is a potentially treatable vitamin‐responsive epileptic encephalopathy. The most prevalent form of PDE is due to an underlying genetic defect in ALDH7A1 encoding Antiquitin (ATQ), an enzyme with α‐aminoadipic semialdehyde dehydrogenase (AASADH) activity which facilitates cerebral lysine degradation. Devastating outcomes including intellectual disability and significant developmental delays are still observed in 75% to 80% of pyridoxine responsive individuals with good seizure control, potentially attributable to the accumulation of toxic intermediates α‐aminoadipic semialdehyde (AASA) and its cyclic form Δ1‐piperideine‐6‐carboxylate (P6C) in plasma, urine and CSF. Thus, adjunct treatment strategies incorporating lysine restriction and arginine supplementation, separately or in combination with pyridoxine have been attempted to enhance seizure control and improve cognitive function. We describe a 4 year old girl with classical PDE who demonstrated significant improvements in clinical, neurological and developmental outcomes including absence of clinical seizures and cessation of antiepileptic medications since age 3 months, normalisation of EEG, significant improvement in the white matter signal throughout the cerebrum on neuroimaging and significant reduction in urine P6C and pipecolic acid levels post‐ combined therapy with lysine restricted diet in conjunction with pyridoxine and folinic acid. Lysine restriction was well tolerated with impressive compliance and plasma lysine levels remained within the lower reference ranges; mean level 70 μmol/L (ref range 52‐196 μmol/L). This case further emphasizes the benefit of early dietary intervention as an effective adjunct in the management of PDE.

IntroductionPerfluoroalkyl and polyfluoroalkyl substances (PFAS) are a diverse group of compounds that have been used in hundreds of industrial applications and consumer products including aqueous film-forming foam (AFFF) for many years. Multiple national and international health and environmental agencies have accepted that PFAS exposures are associated with numerous adverse health effects. Australian firefighters have been shown to have elevated levels of PFAS in their blood, specifically perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS), due to the historical use of AFFF. While PFAS concentrations decline over time once the source of exposure has been removed, their potential adverse health effects are such that it would be prudent to develop an intervention to lower levels at a faster rate than occurs via natural elimination rates.Methods and analysisThis is a randomised controlled trial of current and former Australian firefighters in the Metropolitan Fire Brigade/Fire Rescue Victoria, and contractors, with previous occupational exposure to PFAS and baseline elevated PFOS levels. The study is investigating whether whole blood donation every 12 weeks or plasma donation every 6 weeks will significantly reduce PFAS levels, compared with a control group. We have used covariate-adaptive randomisation to balance participants’ sex and blood PFAS levels between the three groups and would consider a 25% reduction in serum PFOS and PFHxS levels to be potentially clinically significant after 12 months of whole blood or plasma donation. A secondary analysis of health biomarkers is being made of changes between screening and week 52 in all three groups.Ethics and disseminationThis trial has been approved by Macquarie University Human Research Ethics Committee (reference number: 3855), final protocol V.2 dated 12 June 2019. Study results will be disseminated via peer-reviewed publications and presentations at conferences.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12619000204145).

Summary Background In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The ATAD3 locus is one such region in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomyopathy, respectively. Methods Whole-exome, whole-genome, and long-read DNA sequencing techniques combined with studies of RNA and quantitative proteomics were used to investigate 17 subjects from 16 unrelated families with suspected mitochondrial disease. Findings We report 6 different de novo duplications in the ATAD3 gene locus causing a distinctive presentation, including lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently, corneal clouding or cataracts and encephalopathy. The recurrent 68-kb ATAD3 duplications are identifiable from genome and exome sequencing but usually missed by microarrays. The ATAD3 duplications result in the formation of identical chimeric ATAD3A/ATAD3C proteins, altered ATAD3 complexes, and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue. Conclusions ATAD3 duplications appear to act in a dominant-negative manner and the de novo inheritance infers a low recurrence risk for families, unlike most pediatric mitochondrial diseases. More than 350 genes underlie mitochondrial diseases. In our experience, the ATAD3 locus is now one of the five most common causes of nuclear-encoded pediatric mitochondrial disease, but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies. Funding Australian NHMRC, US Department of Defense, US National Institutes of Health, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance, and Australian Mito Foundation.

Several initiatives at establishing a classification of inherited metabolic disorders have been published previously, some focusing on pathomechanisms, others on clinical manifestations, while yet another attempted a simplified approach of a comprehensive nosology. Some of these classifications suffered from shortcomings, such as lack of a mechanism for continuous update in light of a rapidly evolving field, or lack of widespread input from the metabolic community at large. Our classification-the International Classification of Inherited Metabolic Disorders, or International Classification of Inborn Metabolic Disorders (ICIMD)-includes 1450 disorders, and differs from prior approaches in that it benefited from input by a large number of experts in the field, and was endorsed by major metabolic societies around the globe. Several criteria such as pathway involvement and pathomechanisms were considered. The main purpose of the hierarchical, group-based approach of the ICIMD is an improved understanding of the interconnections between many individual conditions that may share functional, clinical, and diagnostic features. The ICIMD aims to include any primary genetic condition in which alteration of a biochemical pathway is intrinsic to specific biochemical, clinical, and/or pathophysiological features. As new disorders are discovered, we will seek the opinion of experts in the advisory board prior to inclusion in the appropriate group of the ICIMD, thus guaranteeing the continuing relevance of this classification via regular curation and expert advice.

AIM To determine whether information about a family history of hypercholesterolaemia or early cardiovascular disease was documented by paediatricians in children and adolescents with elevated low-density lipoprotein (LDL)-cholesterol levels. METHODS Retrospective chart review of all children with a LDL-cholesterol level ≥95th percentile (3.4 mmol/L) and ≥99th percentile (3.8 mmol/L) at a tertiary paediatric hospital in 2014. RESULTS Of 86 children with a LDL-cholesterol level ≥3.4 mmol/L, only 18 (20.9%) had documentation of a family history of hypercholesterolaemia or early cardiovascular disease. In those 18, 13 (72.2%) had a family history of hypercholesterolaemia and 11 (61.1%) a family history of early cardiovascular disease. Increasing the LDL-cholesterol cut-off level to ≥3.8 mmol/L (n = 46) did not improve documentation of a family history (9/46, 19.6%). CONCLUSIONS In patients with elevated LDL-cholesterol levels, paediatricians rarely document a positive or negative family history of hypercholesterolaemia or early cardiovascular disease. This represents a lost opportunity to diagnose children and adolescents with familial hypercholesterolaemia.

The purpose of this retrospective, observational study was to describe the relation between exercise workload during cardiac rehabilitation (CR), expressed as metabolic equivalents of task (METs), and prognosis among patients with coronary heart disease. We included patients with coronary heart disease who participated in CR between January 1998 and June 2007. METs were calculated from treadmill workload. Cox regression analysis was used to describe the relationship between METs and time to a composite outcome of all-cause mortality, nonfatal myocardial infarction, or heart failure hospitalization. Among 1,726 patients (36% women; median age 59 years [interquartile range, 52 to 66]), there were 467 events (27%) during a median follow-up of 5.8 years (interquartile range, 2.6 to 8.7). In analyses adjusted for age, sex, Charlson co-morbidity index, hypertension, diabetes, and CR referral diagnosis, METs were independently related to the composite outcome at CR start (Wald chi-square 43, hazard ratio 0.59 [95% confidence interval 0.51 to 0.70]) and CR end (Wald chi-square 47, hazard ratio 0.68 [95% confidence interval 0.61 to 0.76]). Patients exercising below 3.5 METs on exit from CR represent a high-risk group with 1- and 3-year event rates ≥7% and ≥18%, respectively. In conclusion, METs during CR is available at no additional cost and can be used to identify patients at increased risk for an event who may benefit from closer follow-up, extended length of stay in CR, and/or participation in other strategies aimed at maximizing adherence to secondary preventive behaviors and improving exercise capacity.

Silver-Russell syndrome (SRS OMIM 180860) is a rare, albeit well-recognized disorder characterized by severe intrauterine and postnatal growth retardation. It remains a clinical diagnosis with a molecular cause identifiable in approximately 60%-70% of patients. We report a 4-year-old Australian Aboriginal girl who was born at 32 weeks gestation with features strongly suggestive of SRS, after extensive investigation she was referred to our undiagnosed disease program (UDP). Genomic sequencing was performed which identified a heterozygous splice site variant in IGF2 which is predicted to be pathogenic by in-silico studies, paternal allelic origin, de novo status, and RNA studies on fibroblasts. We compare clinical findings with reported patients to add to the knowledge base on IGF2 variants and to promote the engagement of other Australian Aboriginal families in genomic medicine.

In patients with coronary heart disease, the exercise workload (i.e., metabolic equivalents of task, METs) at which patients exercise train upon entry and completion of cardiac rehabilitation (CR) are independently related to prognosis. Unknown is the association between exercise training workloads in CR and clinical outcomes in patients with heart failure (HF).Patients with HF who participated in an early outpatient CR program were used in this retrospective analysis. Exercise workloads upon entry and completion of CR were converted to METs. The primary outcome was all-cause mortality and the secondary outcome was HF hospitalization. Cox regression analysis was used to assess the adjusted risk between MET levels in CR and clinical outcomes.Among 707 patients, the median exercise training workload at the start and end of CR was 2.5 METs (IQR 2.1 to 3.1 METs) and 3.2 METS (IQR 2.7 to 4.1 METs), respectively, for men and 2.2 METs (IQR 1.9 to 2.6 METs) and 2.9 METS (IQR 2.3 to 3.4 METs), respectively, for women. There were 242 deaths and 266 HF hospitalizations. METs achieved at the end of CR had the strongest independent association with all-cause mortality (adjusted HR, 95% CI: 0.58, 0.48-0.70) and HF hospitalization (adjusted HR, 95% CI: 0.62, 0.52-0.74). Each 1 MET higher work load at the end of CR was associated with a 42% and 38% lower adjusted risk for all-cause mortality and HF hospitalization, respectively.In a diverse cohort of patients with chronic HF our data suggests that an easily accessible measure of exercise capacity (i.e., METs) that is collected during CR is independently associated with the adjusted risk for both all-cause mortality and HF-specific hospitalization. Training at MET levels3.5 METs identifies patients that might benefit from closer clinical surveillance and reinforced adherence to medical and lifestyle preventive strategies.

Background: Vincristine is a chemotherapeutic agent frequently used in the treatment of childhood cancer. Peripheral neuropathy is an important side effect of Vincristine. We assessed the incidence, severity and type of peripheral neuropathy in children on Vincristine using clinical parameters and nerve conduction studies. Methods : Children with cancer treated with Vincristine were enrolled. Symptoms and signs of motor, sensory and autonomic peripheral neuropathy at baseline and at 3, 6 and 12 month follow up were documented. A modified total neuropathy score grading was undertaken. Nerve conduction studies (NCS) were undertaken and vitamin E levels measured at the time of these assessments. Results: 28 patients were enrolled over 12 months. 93% had evidence of neuropathy clinically and/or electrophysiologically. Weakness, pain and constipation were the most common symptoms and the most common sign was loss of ankle reflexes. The peripheral neuropathy was mild in most cases. Plasma levels of vitamin E remained in the normal range, however they dropped significantly from the baseline value. Conclusions: Peripheral neuropathy assessed clinically and electrophysiologically, occurs in the majority of children on Vincristine treatment. The neuropathy is sensory-motor and generally mild. There was a statistically significant drop in average vitamin E levels during treatment. Keywords: Vincristine, peripheral neuropathy, vitamin E

Background New approaches are required to address the needs of complex undiagnosed diseases patients. These approaches include clinical genomic diagnostic pipelines, utilizing intra- and multi-disciplinary platforms, as well as specialty-specific genomic clinics. Both are advancing diagnostic rates. However, complementary cross-disciplinary approaches are also critical to address those patients with multisystem disorders who traverse the bounds of multiple specialties and remain undiagnosed despite existing intra-specialty and genomic-focused approaches. The diagnostic possibilities of undiagnosed diseases include genetic and non-genetic conditions. The focus on genetic diseases addresses some of these disorders, however a cross-disciplinary approach is needed that also simultaneously addresses other disorder types. Herein, we describe the initiation and summary outcomes of a public health system approach for complex undiagnosed patients - the Undiagnosed Diseases Program-Western Australia (UDP-WA). Results Briefly the UDP-WA is: i) one of a complementary suite of approaches that is being delivered within health service, and with community engagement, to address the needs of those with severe undiagnosed diseases; ii) delivered within a public health system to support equitable access to health care, including for those from remote and regional areas; iii) providing diagnoses and improved patient care; iv) delivering a platform for in-service and real time genomic and phenomic education for clinicians that traverses a diverse range of specialties; v) retaining and recapturing clinical expertise; vi) supporting the education of junior and more senior medical staff; vii) designed to integrate with clinical translational research; and viii) is supporting greater connectedness for patients, families and medical staff. Conclusion The UDP-WA has been initiated in the public health system to complement existing clinical genomic approaches; it has been targeted to those with a specific diagnostic need, and initiated by redirecting existing clinical and financial resources. The UDP-WA supports the provision of equitable and sustainable diagnostics and simultaneously supports capacity building in clinical care and translational research, for those with undiagnosed, typically rare, conditions. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0619-z) contains supplementary material, which is available to authorized users.

Evidence suggests that, in the UK, the current three-year specialty training period in general practice is inadequate for equipping newly qualified GPs with mastery in all the necessary clinical and generic skills that would allow them to respond with optimum effect to the complexities and uncertainties of the generalist workplace. The North Western Deanery initiated an innovative pilot programme of extended (by 24 months) specialty training in general practice (GPST4-5). Nine ST3 trainees who had just 'graduated' from GPST, holding nMRCGP, were recruited, thereby formally deferring their application for a Certificate of Completion of Training (CCT). The programme was evaluated using established qualitative research techniques. Semi-structured interviews were conducted at fixed points and data were analysed for recurring discourses and themes using a framework thematic analysis. We obtained evidence of the benefits of extended specialty training in encouraging the development of clinical mastery alongside additional specialist skills, generalist and leadership competencies. We also identified the enabling factors for beneficial extended training, including workplace-based training under educational mentorship, combined with a blended learning programme and sustained expert- and peer-support.

Familial hypercholesterolaemia (FH) profoundly increases the risk of coronary artery disease (CAD). We investigated whether diet and a bile-acid sequestrant decrease coronary atherosclerosis in patients with FH.We identified 26 men with FH and CAD, participating in the St Thomas' Atherosclerosis Regression Study, who had been randomized to receive a fat-modified diet plus cholestyramine (8 g twice daily) (DC, n = 12) or usual care (UC, n = 14), and investigated the relative effects of these treatments on the angiographic progression of coronary atherosclerosis over 39 months. FH was defined as probable/definite according to Dutch Lipid Clinic Network criteria; mean FH score was 8.7 (range 6-15) and mean baseline low-density lipoprotein cholesterol (LDL-Ch) concentration was 5.4 (SD 1.4) mmol/L. Coronary atherosclerosis was assessed by serial quantitative angiography as the global changes in mean and minimum absolute width of segments (MAWS and MinAWS, respectively).Mean plasma LDL-Ch concentration fell by 35% with DC and remained significantly (p 0.001) lower during the trial at 3.78 (SD 0.98) mmol/L compared with UC at 4.89 (1.04). MAWS decreased by 0.252 (SEM 0.072) mm in the UC group and by 0.001 (0.065) mm in the DC group (p = 0.007), with corresponding reductions in MinAWS of 0.290 (0.087) mm and 0.013 (0.058) mm (p = 0.009); these changes were significant after adjusting for baseline variables, including coronary luminal dimensions and lipoprotein(a). Progression was observed in 7 patients (50%) on UC and 3 (25%) on DC (p = 0.19), with regression in no patients (0%) and 3 patients (25%) (p 0.05), respectively.This investigation, carried out in the pre-statin era, demonstrates that a prudent diet and cholestyramine could improve the course of coronary atherosclerosis in men with phenotypic FH through sustained reductions in LDL-Ch.

Background Although cardiopulmonary exercise (CPX) testing in patients with heart failure and reduced ejection fraction is well established, there are limited data on the value of CPX variables in patients with HF and preserved ejection fraction (HFpEF). We sought to determine the prognostic value of select CPX measures in patients with HFpEF. Methods This was a retrospective analysis of patients with HFpEF (ejection fraction ≥ 50%) who performed a CPX test between 1997 and 2010. Selected CPX variables included peak oxygen uptake (VO 2 ), percent predicted maximum oxygen uptake (ppMVO 2 ), minute ventilation to carbon dioxide production slope (V E /VCO 2 slope) and exercise oscillatory ventilation (EOV). Separate Cox regression analyses were performed to assess the relationship between each CPX variable and a composite outcome of all-cause mortality or cardiac transplant. Results We identified 173 HFpEF patients (45% women, 58% non-white, age 54 ± 14 years) with complete CPX data. During a median follow-up of 5.2 years, there were 42 deaths and 5 cardiac transplants. The 1-, 3-, and 5-year cumulative event-free survival was 96%, 90%, and 82%, respectively. Based on the Wald statistic from the Cox regression analyses adjusted for age, sex, and β-blockade therapy, ppMVO 2 was the strongest predictor of the end point (Wald χ 2 = 15.0, hazard ratio per 10%, P 2 (Wald χ 2 = 11.8, P = .001). V E /VCO 2 slope (Wald χ 2 = 0.4, P = .54) and EOV (Wald χ 2 = 0.15, P = .70) had no significant association to the composite outcome. Conclusion These data support the prognostic utility of peak VO 2 and ppMVO 2 in patients with HFpEF. Additional studies are needed to define optimal cut points to identify low- and high-risk patients.

Aim: To evaluate the incidence, sex distribution, ethnicity, age at diagnosis, clinical presentation and morbidity of all childhood-onset congenital adrenal hyperplasia (CAH) cases in Western Australia (WA) between 1990 and 2010, a state where newborn screening for CAH is not in place. Methods: The total number of all known CAH cases was identified. Case files were reviewed retrospectively to determine clinical details. Classical CAH (C-CAH) was defined as patients presenting before 6 months of age and non-classical (NC-CAH) as presenting after 6 months. Results: Of the 41 CAH cases (26 female) born in WA, 5(12.2%) were of Aboriginal ethnicity. CAH was due to 21-hydroxylase deficiency in 40 cases. Of those with 21-hydroxylase deficiency, 37 were C-CAH (25 female) and 3 NC-CAH (all male). The incidence of C-CAH in WA was estimated to be 0.67 per 10 000 live births (1:14 869). The incidence rate ratio of Aboriginal compared with non-Aboriginal C-CAH was 2.45 (95% confidence interval 0.96–6.29). The mean age of diagnosis of C-CAH cases was lower in females (8.9 ± 2.5 days) compared to males (23.4 ± 9.8 days). Among these males, 72.7% presented initially with adrenal crisis. Conclusion: The estimated incidence of classical CAH is similar to composite worldwide data. The increased female-to-male ratio is not in keeping with the expected sex distribution seen in a recessively inherited disease. The delayed diagnosis in males, with a significant proportion presenting with adrenal crisis, could be avoided with newborn screening. The higher rate of CAH in patients with Aboriginal ethnicity is a novel observation.

Urea cycle disorders (UCDs) are rare causes of hyperammonemic encephalopathy in adults. Most UCDs present in childhood and, if unrecognized, are rapidly fatal. Affected individuals who survive to adulthood may remain undiagnosed because of clinicians' unawareness of the condition or atypical presentations. We describe the case of a 49-year-old man who initially presented with a stroke and developed hyperammonemic encephalopathy over a period of 8 months. A diagnosis of carbamoyl phosphate synthetase type 1 deficiency was made, and the patient was referred for liver transplantation. One year after liver transplantation, the patient had normal plasma ammonia concentrations and had returned to work. Liver Transpl, 2011. © 2011 AASLD.

Several plasma lipoprotein disorders are classic modifiable risk factors for atherosclerotic cardiovascular disease, and they arise from various causes. Other forms of lipoprotein disorder are associated with pathological consequences such as acute pancreatitis. Like many other risk factors, most lipoprotein disorders are the result of gene–environment interactions. Furthermore, lipoprotein disorders may be secondary to other disease states. The pattern of lipid disturbance and its clinical consequences are best understood in terms of disruption to the normal metabolism of lipoproteins, levels of which may increase or decrease accordingly. This article reviews the framework of the classification of lipoprotein disorders in order to consolidate a clinical approach that is based on the etiology and pathophysiology of the underlying metabolic disturbance.

Refsum's Disease is an inherited metabolic disorder in which a metabolite of branched chain fatty acids accumulates due to lack of appropriate oxidative enzymes. Patients have elevated plasma phytanic acid levels and high concentrations of phytanic acid in a variety of tissues leading to progressive tissue damage. Besides retinal degeneration or retinal dystrophy associated with adult onset retinitis pigmentosa, additional symptoms include chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, anosmia, ichthyosis, as well as skeletal, cardiac, hepatic, and renal abnormalities. Current management includes avoidance of dietary sources of branched chain fatty acids and regular plasmapheresis to prevent accumulation of these compounds to ameliorate progressive neurological deficits. Two brothers with Refsum's disease who experienced progressive symptoms despite optimal diet and plasmapheresis were commenced on a novel therapy. We report the effect of the intestinal lipase inhibitor, Orlistat, which led to significant reduction (P-value<0.001on 2-sample unpairedt-test) of mean preplasmapheresis phytanic acid levels with retardation of the progression of most of their dermatological and neurological symptoms.

Low plasma levels of high-density-lipoprotein cholesterol (HDL-C) and high triglyceride (TG) are strongly associated with cardiovascular disease (CVD). Clinical recognition of this high-risk population demands accurate measurement of HDL-C, whereas cost and clinical demand dictate that optimal HDL-C measurement requires fully automated methods that avoid manual precipitation. Commercial techniques use specific reagents to selectively expose and "directly" measure cholesterol in HDL. However, these "direct" methods may experience interference from the cholesterol content of triglyceride-rich-lipoproteins (TRL), leading to analytical overestimation of HDL-C, with subsequent underestimation of low-density-lipoprotein cholesterol (LDL-C) and of CVD risk.The aim of this study was to develop a method to overcome this interference.Serum/Li+-heparin plasma samples from consecutive patients were analyzed for HDL-C by the comparison of three generations of the Roche Diagnostics, HDL-C assay on a Hitachi-917 or Modular-PPE analyzer. HDL-C measurement was performed before and after removal of TRL by ultracentrifugation ("direct" HDL-C and HDL-UC, respectively). We examined the effect of TG on the relationship between HDL-UC and "direct" HDL-C. Analysis of variance multiregression analysis was performed for each generation of the commercial assay.We observed progressive TG interference that increased "direct" HDL-C by 10% to 15% or more in moderately hypertriglyceridemic samples (600 mg/dL). Predictive equations were derived for each generation of the assay to estimate HDL-C in the absence of TRL.This study casts doubt on the specificity of "direct" HDL-C assays in the presence of hypertriglyceridemia. The use of assay-specific correction formulae to adjust for interference from TRL reduces the overestimation of HDL-C that influences CVD risk calculation, treatment, and follow-up of patients.

OBJECTIVE: Tandem mass spectrometry is widely applied to routine newborn screening but there are no long-term studies of outcome. We studied the clinical outcome at six years of age in Australia. METHODS: In a cohort study, we analyzed the outcome at 6 years for patients detected by screening or by clinical diagnosis among >2 million infants born from 1994 to 1998 (1 017 800, all unscreened) and 1998 to 2002 (461 500 screened, 533 400 unscreened) recording intellectual and physical condition, school placement, other medical problems, growth, treatment, diet, and hospital admissions. Results were analyzed separately for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and other disorders, and grouped patients as those who presented clinically or died in the first 5 days of life; patients presented later or diagnosed by screening, and those with substantially benign disorders. RESULTS: Inborn errors, excluding phenylketonuria, were diagnosed in 116 of 1 551 200 unscreened infants (7.5/100 000 births) and 70 of 461 500 screened infants (15.2/100 000 births). Excluding MCADD, 21 unscreened patients with metabolic disorders diagnosed after 5 days of life died or had a significant intellectual or physical handicap (1.35/100 000 population) compared with 2 of the screened cohort (0.43/100 000; odds ratio: 3.1 [95% CI: 0.73–13.32]). Considering the likely morbidity or mortality among the expected number of never-diagnosed unscreened patients, there would be a significant difference. Growth distribution was normal in all cohorts. CONCLUSION: Screening by tandem mass spectrometry provides a better outcome for patients at 6 years of age, with fewer deaths and fewer clinically significant disabilities.

Two types of end-point measurement are presently available in clinical trials of the effect of treatment of hyperlipidaemia on cardiovascular disease; these are the incidence of clinical events and the arteriographic assessment of progression or regression of atherosclerosis. These approaches are briefly reviewed. In the present trial, 25 hyperlipidaemic men with symptomatic femoral atherosclerosis underwent biplanar femoral arteriography at baseline. They were then randomised into treatment and usual-care groups; treatment was individualized, comprising a lipid-lowering diet with cholestyramine, nicotinic acid or clofibrate as appropriate for the lipoprotein disorder. Mean cholesterol and triglyceride levels were 19% and 37% lower in the treatment group. Arteriography was repeated after a mean period of 19 months. With attention to blinding of observers, changes in arteriograms were quantitated using computerised image analysis and visual methods, and expressed both by patient and by arterial segment. All end-points were in conformity and showed a lower rate of progression of arterial disease in the treatment group, and a higher frequency of segmental regression in treated patients. In this small trial of patients with functionally-significant atherosclerosis, effective treatment of hyperlipidaemia favourably affected the course of the arterial disease.

BackgroundReattribution is frequently taught to general practitioners (GPs) as a structured consultation that provides a psychological explanation for medically unexplained symptoms.AimsTo determine if practice-based training of GPs in reattribution changes doctor–patient communication, thereby improving outcomes in patients with medically unexplained symptoms of 3 months' duration.MethodCluster randomised controlled trial in 16 practices, 74 GPs and 141 patients with medically unexplained symptoms of 6 hours of reattribution training v. treatment as usual.ResultsWith training, the proportion of consultations mostly consistent with reattribution increased (31 v. 2%, P=0.002). Training was associated with decreased quality of life (health thermometer difference −0.9, 95% CI −1.6 to −0.1; P=0.027) with no other effects on patient outcome or health contacts.ConclusionsPractice-based training in reattribution changed doctor–patient communication without improving outcome of patients with medically unexplained symptoms.

We describe two half-siblings with monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency, a defect on ketone body utilization, that has only recently been identified (van Hasselt et al., N Engl J Med, 371:1900–1907, 2014) as a cause for recurrent ketoacidoses. Our index patient is a boy with non-consanguineous parents who had presented acutely with impaired consciousness and severe metabolic ketoacidosis following a 3-day history of gastroenteritis at age 5 years. A 12.5-year-old half-brother who shared the proband’s mother also had a previous history of recurrent ketoacidoses. Results of mutation and enzyme activity analyses in proband samples advocated against methylacetoacetyl-coenzyme A thiolase (“beta-ketothiolase”) and succinyl-coenzyme A: 3-oxoacyl coenzyme A transferase (SCOT) deficiencies. A single heterozygous c.982C>T transition in the SLC16A1 gene resulting in a stop mutation (p.Arg328Ter) was detected in both boys. It was shared by their healthy mother and by the proband’s half-sister, but was absent in the proband’s father. MCT1 deficiency may be more prevalent than is apparent, as clinical manifestations can occur both in individuals with bi- and monoallelic mutations. It may be an important differential diagnosis in recurrent ketoacidosis with or without hypoglycemia, particularly in the absence of any specific metabolic profiles in blood and urine. Early diagnosis may enable improved disease management. Careful identification of potential triggers of metabolic decompensations in individuals even with single heterozygous mutations in the SLC16A1 gene is indicated.

Nonketotic hyperglycinaemia (NKH) is an autosomal recessive disorder of glycine metabolism caused by a deficiency in the mitochondrial glycine cleavage enzyme. The majority of cases are caused by mutations in the P-protein, one of the four components of the glycine cleavage enzyme, also known as glycine decarboxylase (GLDC). Previous studies searching for causative mutations in NKH patients have only looked for a limited number of specific mutations or only screened part of the gene, and in many cases either no mutation or only one mutation was found, which is of limited use for prenatal diagnosis. In this study, we describe the screening of the entire GLDC gene in 3 NKH families by D-HPLC analysis of all 25 exons, identifying two point mutations and two large deletions (exon 8 and exons 2-15) using a combination of D-HPLC analysis, long range PCR, Southern blot and sequencing. For complete prenatal testing both mutations need to be identified, and we suggest that screening of the entire gene as well as deletional analysis should be considered in those subjects where only one mutation has been identified.

Purpose: The rationale for ‘professional education and development’ (PED) courses is to support general practitioners, enabling them to access a range of theoretical and practical skills within a supportive schema. It aims to identify whether and how a regional PED course has had a beneficial impact upon participants. Methods: The study comprised a qualitative investigation of participants’ assessed coursework portfolios. The content of each portfolio gives individual accounts of the impact of the course on personal and practice development. Permission to access extant portfolios was obtained from 16 recent alumni of the course. The anonymous written material was analysed by the research team for recurring discourses and themes using a thematic framework analysis. Results: Seven major thematic categories were extrapolated from the data: leadership, resilience, quality improvement, change management, development of new services, educational expertise, and patient safety. In each category, we found evidence that the course enabled development of practitioners by enhancing knowledge and skills which had a positive impact upon their self-perceived effectiveness and motivation. Conclusion: Extended specialty training is on the horizon but such courses may still serve a valuable purpose for current trainees and the existing general practitioners workforce which will be responsible for leading the shift towards community-based service delivery.

The World Health Organization (WHO) has recommended measurement of neonatal thyroid-stimulating hormone (TSH) as a marker of population iodine status. A population is considered iodine sufficient when3% of neonatal blood samples collected 3-4 days after birth have TSH concentrations5 mIU/L. However, changes in technology and clinical practices have opened the WHO criteria to various interpretations.This study aimed to investigate the effects of time of sampling, weight, and sex on neonatal TSH concentrations by analyzing neonatal TSH data, based on the WHO criteria for population iodine sufficiency.We analyzed the Western Australian (WA) Newborn Screening Program records for 198,826 babies born in WA between 2005 and 2011, to determine the relationship between neonatal TSH concentrations and time of sampling, weight, and sex.The proportion of TSH results above the WHO cut-off was higher for samples collected 48-72 h after birth rather than later, for males, for birth weights below 2500 g, and when a cut-off of 5.0 mIU/L was used.Following changes in newborn screening protocols and earlier collection of blood samples, the WHO criteria appear inappropriate. We recommend that WHO revise current guidelines regarding use of neonatal TSH for monitoring population iodine status.

A modified diet has been advocated for the past 50 years for prevention of cardiovascular disease. The evidence has in the past been largely epidemiological and experimental, with relatively limited support from clinical trials. However a major element of this strategy, reduction in intake of saturated fats, has recently been called into question; the evidence for and against this view is critically reviewed. A Cochrane review, and recent trials, have advanced our understanding of the role of diet and of optimal dietary recommendation strategy. Here we consider these advances in the light of established knowledge.

Worldwide, cardiovascular diseases are now the most common cause of death and a substantial source of chronic disability and health costs. In the light of new data from clinical trials and a fuller understanding of risk factors, the International Task Force for the Prevention of Coronary Heart Disease, in cooperation with the International Atherosclerosis Society, prepared a revised and comprehensive statement regarding the scientific basis of the primary and secondary prevention of cardiovascular disease. The following is a short account of the clinical implications of this statement. It is best read in conjunction with the full document, which can be found at http://www.chd-taskforce.com Assessing a patient’s overall or global risk of cardiovascular disease is the first step in preventive care, for it enables the physician to identify and provide the appropriate level of treatment for risk factors. Much can be learned from measuring even a few risk factors. The fuller the knowledge of the patient’s risk status, the sounder the treatment decisions. Initial costs may be offset by long-term rational treatment. The goals of treatment and, hence, the extent of dietary change and the need for (and choice and dosage of) drug treatment all depend on global risk assessment. Two methods for determining global risk follow. Note and tabulate the following risk factors, including those laboratory investigations that are available. ### Age, Sex, and Menopausal Status Risk increases progressively with adult age, and coronary heart disease (CHD) is most common after the age of 60 years. In premenopausal women, CHD is rare (except in those who use oral contraceptives and smoke). After menopause, risk increases steeply, approaching that of men after the age of 70 years. ### History of Cardiovascular Disease The risk of further CHD events or stroke is much higher in persons with a history of myocardial infarction, angina, stroke, or intermittent claudication and in those who have ischemic …

Context About 40% of British General Practitioners (GPs) train formally in a psychiatric post as part of their general practice training, but such training may not fully meet the needs of future GPs. A specific course in psychiatry for family doctors has run in Manchester for more than a decade. Method Semi-structured interviews conducted with GP registrars before attending the Manchester course in psychiatry with questionnaire follow-up afterwards to ascertain (a) the training ‘wants’ of GP registrars and (b) whether the course was providing them. Results GP registrars most frequently wanted training in communication skills, how to access the resources that are available to GPs, the detection of psychiatric illness, drug treatment and the management of aggression. The course was successful in satisfying the first three but failed in the last two. There was trend for those who attended Manchester Medical School, which scored significantly higher on number of topics covered at undergraduate level, to perceive a greater need for training than those who attended other medical schools. However, there was no evidence to link self-perception of greater need with having already worked in general practice during postgraduate training. Conclusions More attention needs to be paid to how to address the specific mental health skills training requirements of GP registrars both within the attachment in psychiatry and during the practice year. Preliminary research is required to devise teaching packages before they are entirely satisfactory for GP education.

ObjectiveTo determine the relationship between serum ferritin and malnutrition in newly assessed patients at a paediatric eating disorders clinic.DesignThis was a prospectively assessed clinical cohort study.SettingIntake assessment clinic of a tertiary eating disorders service for children and adolescents.MethodsClinical, anthropometric and laboratory features of children and adolescents were systematically measured. The relationship of serum ferritin to other clinical, anthropometric and laboratory measures was determined using linear regression.ResultsA total of 121 female patients aged 9.5–17.6 years were included, with body mass index (BMI) z score −5.7 to 1.9 (median −1.3). Using multiple regression, serum ferritin was inversely associated with BMI z score (regression coefficient (β)=−0.234, 95% CI −0.413 to −0.055) and serum insulin-like growth factor 1 (IGF-1) (β=−0.476, 95% CI −0.884 to −0.068) and positively associated with alanine aminotransferase (β=0.357, 95% CI 0.055 to 0.659, controlling for age, pubertal stage and serum iron).ConclusionsIn malnourished adolescents with eating disorders increased serum ferritin is associated with lower BMI z score and serum IGF-1.

Clinical management of the lipoprotein abnormalities associated with diabetes mellitus requires effective laboratory assessment. Lipoprotein abnormalities vary according to the aetiology of the diabetes, but both type 1 and type 2 diabetes may result in quantitative and/or qualitative changes in lipoproteins. Routine assessment is based on assays that are readily available thanks to high-throughput automated analytical techniques. Preanalytical considerations, such as the need to fast and analytical performance of individual assays, should be considered in the context of the requirements for clinical decision-making. In particular, the risk of macrovascular complications of diabetes can be anticipated by consideration of major cardiovascular risk factors including total cholesterol (TC), fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C), from which additional indicators such as low-density lipoprotein cholesterol (LDL-C) and non-HDL cholesterol (NHDL-C) may be derived.

Abstract To explore possible mechanisms whereby the triglyceride-rich lipoproteins IDL and VLDL may promote atherosclerosis, fractional loss of these lipoproteins from the intima–inner media was measured in vivo in genetically hyperlipidemic rabbits of the St Thomas’s Hospital strain and compared with the fractional loss of LDL, HDL, and albumin. These rabbits exhibit elevated plasma levels of VLDL, IDL, and LDL. In each rabbit, two aliquots of the same macromolecule, one iodinated with 125 I and the other with 131 I, respectively, were injected intravenously on average 24 and 3 hours, respectively, before removal of the aortic intima–inner media. The fractional loss from the intima–inner media of newly entered macromolecules was then calculated. The average fractional losses for VLDL, IDL, LDL, HDL, and albumin in lesioned aortic arches were 0.1%/h (n=4), −0.2%/h (n=3), 1.8%/h (n=4), 11.4%/h (n=3), and 26.3%/h (n=1), respectively; in nonlesioned aortic arches fractional losses for IDL, LDL, HDL, and albumin were 1.7%/h (n=1), 0.6%/h (n=2), 14.6%/h (n=3), and 25.9%/h (n=3). In both lesioned and nonlesioned aortic arches, the logarithms of these fractional loss values were inversely and linearly dependent on the diameter of the macromolecules ( R 2 =.57, P =.001 and R 2 =.84, P

Glycerol kinase deficiency occurs either as a relatively benign isolated enzyme deficiency, or as part of a syndrome resulting from a microdeletion in the p21 region of the X chromosome associated with congenital adrenal hypoplasia and/or Duchenne muscular dystrophy. Developmental delay is a consistent feature of the microdeletion syndrome but not of the isolated enzyme defect. We report a case of isolated glycerol kinase deficiency in a neonate presenting with hypotonia, apnea, mild developmental delay, and glyceroluria, without evidence of adrenal insufficiency or myopathy. A mild communicating hydrocephalus was noted on magnetic resonance imaging brain scan. It is important, therefore, to exclude glyceroluria in infants being investigated for apnea and hypotonia. (J Child Neurol 1994;9:70-73).

Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance presenting in infancy with renal salt wasting and failure to thrive. Here, we present the case of a 6-week-old baby girl who presented with mild hyponatraemia and dehydration with a background of severe failure to thrive. At presentation, urinary sodium was not measurably increased, but plasma aldosterone and renin were increased, and continued to rise during the subsequent week. Despite high calorie feeds the infant weight gain and hyponatraemia did not improve until salt supplements were commenced. Subsequently, the karyotype was reported as 46,XX,inv (4)(q31.2q35). A search of the OMIM database for related genes at or near the inversion breakpoints, showed that the mineralocorticoid receptor gene (NR3C2) at 4q31.23 was a likely candidate. Further FISH analysis showed findings consistent with disruption of the NR3C2 gene by the proximal breakpoint (4q31.23) of the inversion. There was no evidence of deletion or duplication at or near the breakpoint. This is the first report of a structural chromosome disruption of the NR3C2 gene giving rise to the classical clinical manifestations of pseudohypoaldosteronism type 1 in an infant.

Objective Training in communication can change clinician behaviors, but brief training may function by altering attitudes rather than teaching new skills. We used data from a trial of mental health training for office-based primary care to determine indicators of uptake that predicted parent and child outcomes. Methods Clinicians (n = 50) were randomized to be controls or receive training. Uptake was determined comparing pre- and post-training visits with standardized patients (SPs) coded for skills and patient centeredness. Clinical outcomes were assessed by recruiting and following 403 children/youth ages 5–16 making visits to participants. At 6 months, change in mental health was assessed by parent and youth reports using the Strengths and Difficulties Questionnaire. Results Trained clinicians used more agenda setting, time, and anger management skills than controls and showed increased patient centeredness toward SP parents, but not adolescents. Increased patient-centeredness toward parents predicted improvement in child/youth symptoms and functioning (rated by parents), and improvement in youth-rated symptoms. Increased skills alone were not associated with improvement, but patients of clinicians above the mean for both skill and patient-centeredness change improved most.

P of atherosclerotic cardiovascular disease (CVD) by management of its major risk factors is remarkably effective. Yet it remains a dominant source of morbidity, mortality and healthcare expenditure. In the 1970s and 1980s, Australia was one of the first countries in which CVDmortality decreased; but the downward trend had all but ceased in younger Australians by 2000–2004 [1]. Recent economic analysis demonstrates that the direct cost of acute coronary syndromeevents continues to rise in A i a s

This study assessed nonfasting cholesterol and triglyceride in plasma and in lipoproteins as predictors of the extent of aortic atherosclerosis in 2 similar groups of rabbits from the St. Thomas's Hospital strain; the lipoprotein classes studied in the 2 groups were very low (VLDL), intermediate (IDL), low (LDL), and high density lipoprotein (HDL), and Sf greater than 60 lipoprotein, Sf 12-60 lipoprotein, LDL and HDL, respectively. These rabbits exhibit elevated plasma levels of VLDL, IDL, and LDL, with plasma cholesterol and triglyceride of up to 23 mmol/l and 7 mmol/l, respectively, and with up to 100% of the aortic intima bearing atherosclerosis-like lesions. In group 1 rabbits (n = 25), univariate linear regression showed that cholesterol in plasma, LDL, IDL and in VLDL each were positively associated with the extent of aortic atherosclerosis. In group 2 rabbits (n = 20), cholesterol in plasma, LDL and Sf 12-60, but not in Sf greater than 60 lipoprotein, was consistently positively associated with the extent of aortic atherosclerosis. Neither plasma triglyceride, triglyceride in lipoprotein fractions nor HDL cholesterol was associated consistently with the extent of atherosclerosis. Using step-up multiple linear regression among lipoprotein lipids, IDL and Sf 12-60 lipoprotein cholesterol were the most powerful independent predictors of the extent of aortic atherosclerosis in the 2 groups of rabbits. LDL cholesterol was the only other independent predictor. The results suggest that remnant lipoproteins, whether defined as IDL or Sf 12-60 lipoprotein, play an important causal role in atherosclerosis under conditions where plasma levels of these lipoproteins are elevated.

Although familial hypercholesterolemia is eminently treatable, the majority of cases go undetected, and this disorder remains a major challenge for preventive medicine. In this timely Viewpoint, Gerald Watts, Barry Lewis, and David Sullivan discuss how new genetic screening initiatives, together with a co-operative approach to treatment, could result in a quantum leap for coronary disease prevention.

Human lung endothelin converting enzyme has been isolated in nearly homogeniously pure form. The enzyme is a zinc containing neutral metalloproteinase which is strongly inhibited by phosphoramidon. The enzyme has a subunit mass of about 100 kda and apparent masses of about 232 and 440 kda by gel filtration.

Background The evidence for the effectiveness of reattribution training are limited, and optimal service delivery is not yet established. Objectives The objectives of this study were to establish the feasibility and to optimize the service delivery and design of a definitive randomized controlled trial (RCT) of reattribution training for patients with medically unexplained symptoms (MUSs) in routine primary care. Methodology The study was of a cluster RCT design with the practice as the unit of randomization. Health facilitator (HF)-delivered reattribution training was compared with no reattribution training. The primary outcome measure used is doctor–patient communication in the consultation. Quantitative and qualitative methods identify barriers to effectiveness. The acceptability and feasibility of the intervention were established by attendance rates and postal survey after completion of training. Results Sixteen practices and 70 family practitioners (FPs) were recruited with representative practice and FP characteristics. Six hours of HF reattribution training to FPs in the workplace proved feasible and acceptable with all 35 FPs completing the training. Feedback from 27 (77%) FPs who received training indicated that 25 (93%) FPs believed that specific and relevant learning achievements were made, 22 (82%) felt more confident and 21 (77%) thought the training was useful. Conclusion HF-delivered reattribution training to whole practices is feasible and acceptable, and its effectiveness is measurable in routine primary care.

The paper by Stein et al. [1] contains important lessons for other healthcare organisations on the development and implementation of a teaching programme to improve clinician– patient communication. The development is based on sound educational principles although these are not overtly expressed in the paper. Implementation uses a ‘top down’ cascade and faculty development that could form the basis of an integrated approach to teaching a skill set required across medical specialities. The paper, therefore, is significant

Some 50% of the world's population resides in Asia, including ≈1000 million in China, a similar number in the Indian subcontinent, and >200 million in Indonesia. This region is undergoing unprecedented economic growth, rapid technological changes, urbanization, and major changes in lifestyle. The very high CHD death rates in Singapore (the most economically developed country in the region), which are similar to those of the United States and Australia, provide a warning that Asia may expect a surge in CHD.1 2 3 The dramatic rise in CHD experienced in eastern Europe must be prevented in Asia. To achieve acceptable and effective CHD prevention programs requires a thorough knowledge of the region, recognizing in particular the diversity of its countries. These range in size from compact urbanized places (Singapore and Hong Kong) to vast countries such as India and China, each with marked regional differences. The demography is equally varied: in the Philippines, for example, 60% of the population are younger than 19 years, whereas in Japan and Hong Kong, there is an increasing proportion of elderly people, and life expectancies at birth are among the longest in the world, eg, 75.1 years for men and 80.3 years for women in Hong Kong in 1993.4 The degree of economic development varies greatly. It is advanced in Japan, Korea, Taiwan, Hong Kong, and Singapore and is changing rapidly in China, Philippines, Malaysia, Thailand, Indonesia, and India. Nearby Australia and New Zealand, with predominantly Caucasian populations, are increasingly economically interdependent with Asia. They have achieved substantial reductions in CHD death rates from very high rates in the late 1960s because of the favorable lifestyle changes encouraged by their national heart foundations and supported by their respective governments. Established clinical guidelines such as those of the NCEP, the International Task Force on …

A suggestion of racial discrimination in a professional licensing examination is a serious matter.1 We are surprised to see it in the paper in the BMJ by Esmail and Roberts2 when the corresponding GMC report using the same data explicitly states that the same authors found no bias in the clinical skills assessment (CSA) of the examination for membership of the Royal College of General Practitioners (MRCGP).3 It is misleading at best to suggest that discrimination in the CSA is the cause of differential pass rates when the paper presents no such evidence. Table 1 shows that black and minority ethnic (BME) candidates who are international medical graduates (IMG) and/or from the European Economic Area (EEA) also seem to do less well than white IMG/EEA candidates in the GMC’s Professional and Linguistic Assessment Board (PLAB) part 2 examination. …