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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

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).

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. TheWhole 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.We report six differentAustralian NHMRC, US Department of Defense, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance and Australian Mito Foundation.

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.

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.To examine the effect of blood or plasma donations on PFAS levels in firefighters in Australia.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.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.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.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.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.anzctr.org.au Identifier: ACTRN12619000204145.

Introduction Constipation is a common health problem, often self-diagnosed and self-managed with laxatives without healthcare professional involvement. To improve diagnosis and management, it is important to understand constipation prevalence, associated factors, and laxative utilisation among community-dwelling adults. Aim The research aimed to determine the prevalence of constipation and laxative use, to investigate factors associated with constipation and describe laxative utilisation in Australia. Methods The first part explored constipation and laxative use in the general adult population. A cross-sectional survey was conducted online using a large nationally representative sample. The study focused on constipation prevalence, associated factors and laxative utilisation as well as examining the impact of constipation definitions on prevalence. The second part explored constipation and laxative use in an older adult cohort. Using Australian Longitudinal Study of Ageing data, the prevalence of constipation, associated factors and laxative use were examined over time. Results The online survey was completed by 2,024 participants. The constipation definition had considerable impact on prevalence estimates. As per Rome III criteria, 24% of participants had chronic constipation. Ten factors were significantly associated with it. One third (37%) reported using laxatives for either constipation treatment or prevention with 56% using laxatives recommended by healthcare professionals. In the older adult study, 239 participants were followed for 11 years. Self-reported constipation (14% to 21%) and laxative use (6% to 15%) increased over this period. Conclusion Constipation and laxative use are common among community-dwelling adults. Increased healthcare professional involvement in diagnosis and management, particularly laxative choice and use, may improve health outcomes. Development of guidelines addressing laxative use for both treatment and prevention should be considered.

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.

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.

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.

I recently stumbled on an identity (Theorem 2) that related two types of permutations. It looked like one of those serendipitous pieces of mathematics that led to a simple enumerative result; mostly when this happens it leads joyously to an enumerative proof that was ‘blindingly’ obvious. Except in this case, it wasn’t, I don’t think.

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.

Pascal’s triangle is the most famous of all number arrays - full of patterns and surprises. One surprise is the fact that lurking amongst these binomial coefficients are the triangular and pyramidal numbers of ancient Greece, the combinatorial numbers which arose in the Hindu studies of arrangements and selections, together with the Fibonacci numbers from medieval Italy. New identities continue to be discovered, so much so that their publication frequently excites no one but the discoverer.

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.

This article sets out to explore some of the connections between two seemingly distinct mathematical objects: trigonometric functions and the integer sequences composed of the Fibonacci and Lucas numbers. It establishes that elements of Fibonacci/Lucas sequences obey identities that are closely related to traditional trigonometric identities. It then exploits this relationship by converting existing trigonometric results into corresponding Fibonacci/Lucas results. Along the way it uses mathematical tools that are not usually associated with either of these objects.

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.

Pascal's triangle, the Binomial expansion and the recurrence relation between its entries are all inextricably linked. In the normal course of events, the Binomial expansion leads to Pascal's Triangle, and thence to the recurrence relation between its entries. In this article we are going to reverse this process to make it possible to explore a particular type of generalisation of such interlinked structures, by generalising the recurrence relation and then exploring the resulting generalised ‘Pascal Triangle’ and ‘Binomial expansion’. Within the spectrum of generalisations considered, we find exactly four of particular significance: those concerned with the Binomial coefficients, the Stirling numbers of both kinds, and a lesser known set of numbers – the Lah numbers. We also examine the combinatorial properties of the entries in these triangles and a prime number divisibility property that they all share. Thereby, we achieve a remarkable synthesis of these different entities.

The Eulerian numbers are not strangers to readers of the Gazette but they are not normally associated with the subject of this article, despite the similarity of their names. This article seeks to use Eulerian numbers in generalised telescoping sums, a role that is a powerful extension of an established technique – the Euler summation formula.

I wanted to call this article, Counting permutations that contain a specified number of cycles of a given length but the Editor pointed out the problems this might cause the Production Editor - it simply wouldn't fit the running head. Hence the chosen title and the subject matter. There is a very well known result, nonetheless startling, about the relative frequency of derangements amongst the permutations of [r] = {1,2,3,… , r }.

This article started life as an investigation into certain aspects of the Fibonacci numbers, ‘morphed’ seamlessly into the structure of some infinite matrices and finally resolved into a general set of results that link structural aspects of Fibonacci numbers with trigonometric and hyperbolic functions. It is a surprising fact, but while I can find evidence that the link between these areas has been noted in the past, I can find no evidence that the link has been systematically developed.

When I was offered the chance to become the President of the Association, I had no hesitation in accepting. How else could I react to the opportunity of joining such a distinguished list of predecessors? The list, which includes G. H. Hardy, Arthur Eddington and G. N. Watson contains almost all of the eminent UK mathematicians and educationalists of the twentieth century. So for the honour that you bestowed on me, thank you very much indeed. It wasn’t deserved, but it was hugely enjoyable and rewarding.

South Indian historical accounts, inscriptions, and literature describe many attempts at state formation and political independence by local elites between the collapse of Vijayanagara control of its heartland in the sixteenth century and the eighteenthcentury rise of British hegemony in the south. Most of these elites, known variously as "little kings," nayakas, and poligars, did not survive long in the political turmoil of the era. Those that did endure into the early nineteenth century were soon marginalized or removed from power by East India Company policies and direct military intervention. Archaeological site surveys, guided by contemporaneous East India Company manuscript maps, fort inventories, building plans, and other records, enable researchers to reconstruct and interpret major spatial patterns of the cultural landscapes of these small polities. This approach, which the authors are currently applying in their investigations of the Mysore kingdom, yields a fresh perspective of South Indian little kings and chiefs that complements the work of historians and contributes significantly to the understanding of the nature of these polities. This article describes a case study of the major spatial patterns of the Chitradurga poligars of central Karnataka, as they were in the late eighteenth and early nineteenth centuries. The results provide a fresh perspective on this poligar province and illustrate the significant interpretative value of contemporaneous colonial documents for archaeological site survey and spatial analyses in India.

I recently came across a very appealing result about the product of the lengths of the chords of a regular polygon with n sides inscribed in a unit circle. If one vertex is selected and the product of the chord lengths from that vertex to each of the others is evaluated, the result is just n. There is a simple proof. Consider such a polygon and denote its vertices by the points A0, A1, … , An. Suppose that O is the centre of the circle and the origin of the complex plane. The roots of the equationare just where ω is a primitive nth root of unity. Each of these roots represents one of the vertices. Suppose for convenience that the real number 1 is represented by A0.

This article grew out of a problem that I saw in an old textbook on sale in a second hand bookshop. It inspired a generalisation that leads to two sets of well known numbers (Bell and Stirling numbers), and then to a new result for one of them.

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.

This article examines the archaeological effects of two major geologic factors, eustatic sea-level rise and land subsidence, on the archaeological site distributions of low-energy coastlines. It describes an inexpensive, quick approach to identify these effects, which exploits the interpretive value of state-maintained archaeological site location files. The application of this approach to the Mississippi Gulf Coast suggests that coastal sites older than roughly 3500 B.P. were submerged or destroyed by eustatic sea-level rise; more recent sites were affected little by this process. Among subsidence factors, endogenic or deep-earth subsidence has had little impact on local site distributions. Exogenic or surficial subsidence processes, however, are sufficient to explain the temporal gradient of tidally inundated marsh sites.

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 …

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

You should never judge a book by its title - but I nearly always do. A mathematical colleague recommended a book to me Concrete Mathematics [1]. Just recently, someone else also referred me to the same book. Well a wink’s as good as a nod to a blind man and I now realise what a mistake I’d made; concrete is a conflation of ‘continuous’ and ‘discrete’. Like all good textbooks in mathematics, it distinguishes itself not just by the quality of its contents and presentation, but also by the superb collection of problems that it includes. One such problem - question 58 in Chapter 6 - inspired this article. There was a hint towards a generalised result, but there were no details. It did give a reference, [2, 3], but despite some efforts I found this unobtainable. Hence this article and my attempt to cover the same ground. The question posed in the book is concerned with the linear recurrence relations satisfied by the successive powers of Fibonacci numbers - so we start with the Fibonacci sequence itself.

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.

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. …

We examined associations between dietary fatty acids and progression of coronary artery disease (CAD) in 50 men receiving a lipid-lowering diet or usual care in the St Thomas' Atherosclerosis Regression Study. Nutrient intake was assessed by dietary history and computerized food tables. Progression of CAD over 39 mo, measured by a decrease in minimum absolute width of coronary segments (MinAWS) on angiography, was highly correlated with intakes of palmitic, stearic (18:0), palmitoleic, and elaidic (t-18:1) acids (P < 0.001); no protective effects were found with polyunsaturates. Total saturates and trans unsaturates explained 20% of variance in CAD progression. After adjustment for plasma cholesterol and other risk factors, change in MinAWS was most closely associated with intakes of 18:0 and t-18:1 fatty acids (P = 0.009). We suggest that progression of CAD in men is strongly related to intakes of both long-chain saturates and trans unsaturates, the effects of 18:0 and t-18:1 possibly being independent of plasma cholesterol concentration.