The criminalization of women with postpartum psychosis: "a call for action" for judicial change.

PURPOSE: To prevent the incarceration and influence outcomes when criminal culpability is linked to postpartum psychosis. METHODS: Infanticide, neonaticide and filicide are most often linked with postpartum psychosis, which affects 1-2 women per 1,000 births or 4,000 women each year in the United States. Multiple genetic, hormonal and psychosocial factors surrounding childbirth result in a 1 to 4% risk of infanticide in women with postpartum psychosis. The authors seek to increase awareness of postpartum psychosis and postpartum depression in state legislatures. Others are working to have it recognized in the Diagnostic and Statistical Manual of Mental Disorders (DSM) as a specific illness. Specific postpartum legislation for those charged with crimes related to maternal mental illness is necessary. RESULTS: In Illinois, the very first criminal law in the nation recognizing the pernicious effects of this illness went into effect in 2018. The authors and others are attempting to cause similar or broader legislation to be brought in other states. Several women have been released from extended incarceration utilizing this law. CONCLUSIONS: This temporary mental illness can lead to tragic outcomes when hospitalization and crisis intervention is delayed or the illness is misdiagnosed. The legal/judicial system has not utilized the growing body of scientific developments that medical researchers have discovered in recent decades. The lack of a unique diagnostic classification in the DSM and the lack of postpartum criminal laws, lead to mentally ill mothers in the U.S. receiving excessively harsh sentences when prosecuted, evidenced both in trial and sentencing.

Exercise training workloads in cardiac rehabilitation are associated with clinical outcomes in patients with heart failure.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 levels <3.5 METs identifies patients that might benefit from closer clinical surveillance and reinforced adherence to medical and lifestyle preventive strategies.

Silver Russel syndrome in an aboriginal patient from Australia.

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.

Documenting family history in children with hypercholesterolaemia: A lost opportunity.

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.

Prognostic value of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. The Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX) project.

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 (VO2), percent predicted maximum oxygen uptake (ppMVO2), minute ventilation to carbon dioxide production slope (VE/VCO2 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 ß-blockade therapy, ppMVO2 was the strongest predictor of the end point (Wald χ(2) = 15.0, hazard ratio per 10%, P < .001), followed by peak VO2 (Wald χ(2) = 11.8, P = .001). VE/VCO2 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 VO2 and ppMVO2 in patients with HFpEF. Additional studies are needed to define optimal cut points to identify low- and high-risk patients.

Effects of ultraviolet light on human serum 25-hydroxyvitamin D and systemic immune function.

BACKGROUND: Many immune-mediated diseases are associated with low levels of vitamin D and sunlight. UV light or supplementation with vitamin D can increase regulatory T-cell activity and prevent animal models of autoimmune disease. Increasing population vitamin D levels may therefore alleviate the burden of human immune-mediated disease. OBJECTIVE: To determine the responses of circulating 25-hydroxyvitamin D [25(OH)D] levels, regulatory T-cell numbers, and immune function to UV light exposure in patients being treated for skin disease. METHODS: Twenty-four subjects with skin disease from the North of Scotland were recruited between December and March. At baseline, and after 2 and 4 weeks of narrowband UV light exposure, we measured peripheral blood 25(OH)D level, numbers of regulatory T cells (CD4(+)CD25(hi)FoxP3(+)), and T-cell proliferative and cytokine responses to anti-CD3/CD28 stimulation. RESULTS: Median (interquartile range) narrowband UV-B received during the study was 39.1 (30.9) as standard erythema dose, comparable to a quarter of the median summer sunlight exposure received locally. This increased the 25(OH)D level from a mean ± SD of 34 ± 17 nmol/L to 58 ± 16 nmol/L after 2 weeks and 78 ± 19 nmol/L after 4 weeks. The mean proportion of circulating regulatory T cells increased from 0.5% to 1.6% CD3(+) cells, which significantly correlated with the increased 25(OH)D level. UV treatment was also followed by reduced proliferative and IL-10 responses to anti-CD3/CD28 independent of the 25(OH)D level. CONCLUSION: Narrowband UV light reduces systemic immune responsiveness via the induction of regulatory T cells. Light and 25(OH)D levels may affect particular immune functions independently. The levels of serum 25(OH)D over which these effects are apparent should guide future interventions.

Enhanced interpretation of newborn screening results without analyte cutoff values.

PURPOSE: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. METHODS: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. RESULTS: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. CONCLUSION: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.

Ethnic and gender differences in rates of congenital adrenal hyperplasia in Western Australia over a 21 year period.

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.

Effect of Plasma and Blood Donations on Levels of Perfluoroalkyl and Polyfluoroalkyl Substances in Firefighters in Australia: A Randomized Clinical Trial.

Importance: Elevated levels of blood perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been associated with a range of adverse health outcomes. Firefighters have been exposed to PFASs in firefighting foams and have previously been shown to have higher PFAS levels in blood samples than the general population. No interventions have been shown to reduce PFAS levels. Objective: To examine the effect of blood or plasma donations on PFAS levels in firefighters in Australia. Design, Setting, and Participants: This 52-week, open-label, randomized clinical trial enrolled participants from May 23 to August 23, 2019. Participants were 285 Fire Rescue Victoria staff or contractors with serum levels of perfluorooctane sulfonate (PFOS) of 5 ng/mL or more who were eligible to donate blood, had not donated blood in the 3 months prior to randomization, and were able to provide written informed consent. Analysis was performed on an intention-to-treat basis from May to July 2021. Interventions: Firefighters with baseline PFOS levels of 5 ng/mL or more were randomly assigned to donate plasma every 6 weeks for 12 months, donate blood every 12 weeks for 12 months, or be observed only. Main Outcomes and Measures: The primary end points were changes in the serum PFOS and perfluorohexane sulfonic acid (PFHxS) levels after 12 months of plasma or blood donations or after observation only. Secondary end points included changes in serum PFAS levels from week 52 to week 64, changes in other PFASs, and changes in complete blood count, biochemistry, thyroid function, and lipid profile from screening to week 52. Results: A total of 285 firefighters (279 men [97.9%]; mean [SD] age, 53.0 [8.4] years) were enrolled; 95 were randomly assigned to donate plasma, 95 were randomly assigned to donate blood, and 95 were randomly assigned to be observed. The mean level of PFOS at 12 months was significantly reduced by plasma donation (-2.9 ng/mL; 95% CI, -3.6 to -2.3 ng/mL; P < .001) and blood donation (-1.1 ng/mL; 95% CI, -1.5 to -0.7 ng/mL; P < .001) but was unchanged in the observation group. The mean level of PFHxS was significantly reduced by plasma donation (-1.1 ng/mL; 95% CI, -1.6 to -0.7 ng/mL; P < .001), but no significant change was observed in the blood donation or observation groups. Analysis between groups indicated that plasma donation had a larger treatment effect than blood donation, but both were significantly more efficacious than observation in reducing PFAS levels. Conclusions and Relevance: Plasma and blood donations caused greater reductions in serum PFAS levels than observation alone over a 12-month period. Further research is needed to evaluate the clinical implications of these findings. Trial Registration: anzctr.org.au Identifier: ACTRN12619000204145.

Late-onset carbamoyl phosphate synthetase 1 deficiency in an adult cured by liver transplantation.

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.

Structural chromosome disruption of the NR3C2 gene causing pseudohypoaldosteronism type 1 presenting in infancy.

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.

Study protocol for a randomised controlled trial examining the effect of blood and plasma donation on serum perfluoroalkyl and polyfluoroalkyl substance (PFAS) levels in firefighters.

INTRODUCTION: Perfluoroalkyl 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 ANALYSIS: This 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 DISSEMINATION: This 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 NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000204145).

Inverse Relationship of Maximal Exercise Capacity to Hospitalization Secondary to Coronavirus Disease 2019.

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). METHODS: We identified patients (≥18 years) who completed a clinically indicated exercise stress test between January 1, 2016, and February 29, 2020, and had a test for SARS-CoV-2 (ie, real-time reverse transcriptase polymerase chain reaction test) between February 29, 2020, and May 30, 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<.001) among patients who were hospitalized (6.7±2.8) compared with those not hospitalized (8.0±2.4). Peak METs were inversely associated with the likelihood of hospitalization in unadjusted (odds ratio, 0.83; 95% CI, 0.74-0.92) and adjusted models (odds ratio, 0.87; 95% CI, 0.76-0.99). CONCLUSION: Maximal exercise capacity is independently and inversely associated with the likelihood of hospitalization due to COVID-19. These data further support the important relationship between cardiorespiratory fitness and health outcomes. Future studies are needed to determine whether improving maximal exercise capacity is associated with lower risk of complications due to viral infections, such as COVID-19.

Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus.

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 six 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, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance and Australian Mito Foundation.

Biotinidase deficiency presenting as Neuromyelitis Optica Spectrum Disorder.

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.

Beneficial outcome of early dietary lysine restriction as an adjunct to pyridoxine therapy in a child with pyridoxine dependant epilepsy due to Antiquitin deficiency.

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.

Initiating an undiagnosed diseases program in the Western Australian public health system.

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.

Turning theory into practice: rationale, feasibility and external validity of an exploratory randomized controlled trial of training family practitioners in reattribution to manage patients with medically unexplained symptoms (the MUST).

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.

Angiographic progression of coronary atherosclerosis in patients with familial hypercholesterolaemia treated with non-statin therapy: Impact of a fat-modified diet and a resin.

BACKGROUND AND AIMS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.