Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia

Recent advances in DNA sequencing have enabled mapping of genes for monogenic traits in families with small pedigrees and even in unrelated cases. We report the identification of disease-causing mutations in a rare, severe, skeletal dysplasia, studying a family of two healthy unrelated parents and two affected children using whole-exome sequencing. The two affected daughters have clinical and radiographic features suggestive of anauxetic dysplasia (OMIM 607095), a rare form of dwarfism caused by mutations of RMRP. However, mutations of RMRP were excluded in this family by direct sequencing. Our studies identified two novel compound heterozygous loss-of-function mutations in POP1, which encodes a core component of the RNase mitochondrial RNA processing (RNase MRP) complex that directly interacts with the RMRP RNA domains that are affected in anauxetic dysplasia. We demonstrate that these mutations impair the integrity and activity of this complex and that they impair cell proliferation, providing likely molecular and cellular mechanisms by which POP1 mutations cause this severe skeletal dysplasia. © 2011 Glazov et al.

Assessment of the severity of Ebola virus disease in Sierra Leone in 2014–2015

The current Ebola virus disease (EVD) epidemic in West Africa is unprecedented in scale, and Sierra Leone is the most severely affected country. The case fatality risk (CFR) and hospitalization fatality risk (HFR) were used to characterize the severity of infections in confirmed and probable EVD cases in Sierra Leone. Proportional hazards regression models were used to investigate factors associated with the risk of death in EVD cases. In total, there were 17 318 EVD cases reported in Sierra Leone from 23 May 2014 to 31 January 2015. Of the probable and confirmed EVD cases with a reported final outcome, a total of 2536 deaths and 886 recoveries were reported. CFR and HFR estimates were 74·2% [95% credibility interval (CrI) 72·6–75·5] and 68·9% (95% CrI 66·2–71·6), respectively. Risks of death were higher in the youngest (0–4 years) and oldest (≥60 years) age groups, and in the calendar month of October 2014. Sex and occupational status did not significantly affect the mortality of EVD. The CFR and HFR estimates of EVD were very high in Sierra Leone.

Corneal confocal microscopy : a novel noninvasive means to diagnose neuropathy in patients with Fabry disease

ABSTRACT: Neuropathy is a cause of significant disability in patients with Fabry disease, yet its diagnosis is difficult. In this study we compared the novel noninvasive techniques of corneal confocal microscopy (CCM) to quantify small-fiber pathology, and non-contact corneal esthesiometry (NCCA) to quantify loss of corneal sensation, with established tests of neuropathy in patients with Fabry disease. Ten heterozygous females with Fabry disease not on enzyme replacement therapy (ERT), 6 heterozygous females, 6 hemizygous males on ERT, and 14 age-matched, healthy volunteers underwent detailed quantification of neuropathic symptoms, neurological deficits, neurophysiology, quantitative sensory testing (QST), NCCA, and CCM. All patients with Fabry disease had significant neuropathic symptoms and an elevated Mainz score. Peroneal nerve amplitude was reduced in all patients and vibration perception threshold was elevated in both male and female patients on ERT. Cold sensation (CS) threshold was significantly reduced in both male and female patients on ERT (P < 0.02), but warm sensation (WS)and heat-induced pain (HIP) were only significantly increased in males onERT (P<0.01). However, corneal sensation assessed withNCCAwas significantly reduced in female (P < 0.02) and male (P < 0.04) patients on ERT compared with control subjects. According to CCM, corneal nerve fiber and branch density was significantly reduced in female (P < 0.03) and male (P < 0.02) patients on ERT compared with control subjects. Furthermore, the severity of neuropathic symptoms and the neurological component of the Mainz Severity Score Index correlated significantly with QSTand CCM. This study shows that CCM and NCCA provide a novel means to detect early nerve fiber damage and dysfunction, respectively, in patients with Fabry disease.

Facilitating needs based cancer care for people with a chronic disease : evaluation of an intervention using a multi-centre interrupted time series design

Background: Palliative care should be provided according to the individual needs of the patient, caregiver and family, so that the type and level of care provided, as well as the setting in which it is delivered, are dependent on the complexity and severity of individual needs, rather than prognosis or diagnosis. This paper presents a study designed to assess the feasibility and efficacy of an intervention to assist in the allocation of palliative care resources according to need, within the context of a population of people with advanced cancer. ---------- Methods/design: People with advanced cancer and their caregivers completed bi-monthly telephone interviews over a period of up to 18 months to assess unmet needs, anxiety and depression, quality of life, satisfaction with care and service utilisation. The intervention, introduced after at least two baseline phone interviews, involved a) training medical, nursing and allied health professionals at each recruitment site on the use of the Palliative Care Needs Assessment Guidelines and the Needs Assessment Tool: Progressive Disease - Cancer (NAT: PD-C); b) health professionals completing the NAT: PD-C with participating patients approximately monthly for the rest of the study period. Changes in outcomes will be compared pre-and post-intervention.---------- Discussion: The study will determine whether the routine, systematic and regular use of the Guidelines and NAT: PD-C in a range of clinical settings is a feasible and effective strategy for facilitating the timely provision of needs based care.

Corneal confocal microscopy : a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy

OBJECTIVE: The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies. ---------- RESEARCH DESIGN AND METHODS: A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM). ---------- RESULTS: Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = −0.475, P < 0.0001; NBD r = −0.511, P < 0.0001; and NFL r = −0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm2 with a sensitivity of 0.82 (95% CI 0.68–0.92) and specificity of 0.52 (0.40–0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm2 with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74). ---------- CONCLUSIONS: CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity. Established diabetic neuropathy leads to pain and foot ulceration. Detecting neuropathy early may allow intervention with treatments to slow or reverse this condition (1). Recent studies suggested that small unmyelinated C-fibers are damaged early in diabetic neuropathy (2–4) but can only be detected using invasive procedures such as sural nerve biopsy (4,5) or skin-punch biopsy (6–8). Our studies have shown that corneal confocal microscopy (CCM) can identify early small nerve fiber damage and accurately quantify the severity of diabetic neuropathy (9–11). We have also shown that CCM relates to intraepidermal nerve fiber loss (12) and a reduction in corneal sensitivity (13) and detects early nerve fiber regeneration after pancreas transplantation (14). Recently we have also shown that CCM detects nerve fiber damage in patients with Fabry disease (15) and idiopathic small fiber neuropathy (16) when results of electrophysiology tests and quantitative sensory testing (QST) are normal. In this study we assessed corneal sensitivity and corneal nerve morphology using CCM in diabetic patients stratified for the severity of diabetic neuropathy using neurological evaluation, electrophysiology tests, and QST. This enabled us to compare CCM and corneal esthesiometry with established tests of diabetic neuropathy and define their sensitivity and specificity to detect diabetic patients with early neuropathy and those at risk of foot ulceration.

A longitudinal study of health-related quality of life, fatigue and physical activity in chronic kidney disease patients

This study assessed the health-related quality of life (HRQoL), fatigue and physical activity levels of 28 persons with chronic kidney disease (CKD) on initial administration of an erythropoietin stimulating agent, and at 3 months, 6 months and 12 months. The sample comprised of 15 females and 13 males whose ages ranged from 31 to 84 years. Physical activity was measured using the Human Activity Profile (HAP): Self-care, Personal/Household work, Entertainment/Social, Independent exercise. Quality of life was measured using the SF-36 which gives scores on physical health (physical functioning, role-physical, bodily pain and general health) and mental health (vitality, social functioning, role-emotional and emotional well-being). Fatigue was measured by the Fatigue Severity Scale (FSS). Across all time points the renal sample engaged in considerably less HAP personal/household work activities and entertainment/social activities compared to healthy adults. The normative sample engaged in three times more independent/exercise activities compared to renal patients. One-way Repeated measures ANOVAs indicated a significant change over time for SF-36 scales of role physical, vitality, emotional well-being and overall mental health. There was a significant difference in fatigue levels over time [F(3,11) = 3.78, p<.05]. Fatigue was highest at baseline and lowest at 6 months. The more breathlessness the CKD patient reported, the fewer activities undertaken and the greater the reported level of fatigue. There were no significant age differences over time for fatigue or physical activity. Age differences were only found for SF-36 mental health at 3 months (t=-2.41, df=14, p<.05). Those younger than 65 years had lower emotional well-being compared to those aged over 65. Males had poorer physical health compared to females at 12 months. There were no significant gender differences on mental health at any time point. In the management of chronic kidney disease, early detection of a person’s inability to engage in routine activities due to fatigue is necessary. Early detection would enable timely interventions to optimise HRQoL and independent exercise.

Risk factors for malnutrition in community-dwelling people with Parkinson’s disease

In the elderly, the risks for protein-energy malnutrition from older age, dementia, depression and living alone have been well-documented. Other risk factors including anorexia, gastrointestinal dysfunction, loss of olfactory and taste senses and early satiety have also been suggested to contribute to poor nutritional status. In Parkinson’s disease (PD), it has been suggested that the disease symptoms may predispose people with PD to malnutrition. However, the risks for malnutrition in this population are not well-understood. The current study’s aim was to determine malnutrition risk factors in community-dwelling adults with PD. Nutritional status was assessed using the Patient-Generated Subjective Global Assessment (PG-SGA). Data about age, time since diagnosis, medications and living situation were collected. Levodopa equivalent doses (LDED) and LDED per kg body weight (mg/kg) were calculated. Depression and anxiety were measured using the Beck’s Depression Inventory (BDI) and Spielberger Trait Anxiety questionnaire, respectively. Cognitive function was assessed using the Addenbrooke’s Cognitive Examination (ACE-R). Non-motor symptoms were assessed using the Scales for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT) and Modified Constipation Assessment Scale (MCAS). A total of 125 community-dwelling people with PD were included, average age of 70.2±9.3(35-92) years and average time since diagnosis of 7.3±5.9(0–31) years. Average body mass index (BMI) was 26.0±5.5kg/m2. Of these, 15% (n=19) were malnourished (SGA-B). Multivariate logistic regression analysis revealed that older age (OR=1.16, CI=1.02-1.31), more depressive symptoms (OR=1.26, CI=1.07-1.48), lower levels of anxiety (OR=.90, CI=.82-.99), and higher LDED per kg body weight (OR=1.57, CI=1.14-2.15) significantly increased malnutrition risk. Cognitive function, living situation, number of prescription medications, LDED, years since diagnosis and the severity of non-motor symptoms did not significantly influence malnutrition risk. Malnutrition results in poorer health outcomes. Proactively addressing the risk factors can help prevent declines in nutritional status. In the current study, older people with PD with depression and greater amounts of levodopa per body weight were at increased malnutrition risk.

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010 : a systematic analysis for the Global Burden of Disease Study 2010

Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient −0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding Bill & Melinda Gates Foundation.

The human μ-opioid receptor gene polymorphism (A118G) is associated with head pain severity in a clinical cohort of female migraine with aura patients

Migraine is a painful and debilitating, neurovascular disease. Current migraine head pain treatments work with differing efficacies in migraineurs. The opioid system plays an important role in diverse biological functions including analgesia, drug response and pain reduction. The A118G single nucleotide polymorphism (SNP) in exon 1 of the μ-opioid receptor gene (OPRM1) has been associated with elevated pain responses and decreased pain threshold in a variety of populations. The aim of the current preliminary study was to test whether genotypes of the OPRM1 A118G SNP are associated with head pain severity in a clinical cohort of female migraineurs. This was a preliminary study to determine whether genotypes of the OPRM1 A118G SNP are associated with head pain severity in a clinical cohort of female migraineurs. A total of 153 chronic migraine with aura sufferers were assessed for migraine head pain using the Migraine Disability Assessment Score instrument and classified into high and low pain severity groups. DNA was extracted and genotypes obtained for the A118G SNP. Logistic regression analysis adjusting for age effects showed the A118G SNP of the OPRM1 gene to be significantly associated with migraine pain severity in the test population (P = 0.0037). In particular, G118 allele carriers were more likely to be high pain sufferers compared to homozygous carriers of the A118 allele (OR = 3.125, 95 % CI = 1.41, 6.93, P = 0.0037). These findings suggest that A118G genotypes of the OPRM1 gene may influence migraine-associated head pain in females. Further investigations are required to fully understand the effect of this gene variant on migraine head pain including studies in males and in different migraine subtypes, as well as in response to head pain medication.

Chlamydia muridarum lung infection in infants alters hematopoietic cells to promote allergic airway disease in mice

Background Viral and bacterial respiratory tract infections in early-life are linked to the development of allergic airway inflammation and asthma. However, the mechanisms involved are not well understood. We have previously shown that neonatal and infant, but not adult, chlamydial lung infections in mice permanently alter inflammatory phenotype and physiology to increase the severity of allergic airway disease by increasing lung interleukin (IL)-13 expression, mucus hyper-secretion and airway hyper-responsiveness. This occurred through different mechanisms with infection at different ages. Neonatal infection suppressed inflammatory responses but enhanced systemic dendritic cell:T-cell IL-13 release and induced permanent alterations in lung structure (i.e., increased the size of alveoli). Infant infection enhanced inflammatory responses but had no effect on lung structure. Here we investigated the role of hematopoietic cells in these processes using bone marrow chimera studies. Methodology/Principal Findings Neonatal (<24-hours-old), infant (3-weeks-old) and adult (6-weeks-old) mice were infected with C. muridarum. Nine weeks after infection bone marrow was collected and transferred into recipient age-matched irradiated naïve mice. Allergic airway disease was induced (8 weeks after adoptive transfer) by sensitization and challenge with ovalbumin. Reconstitution of irradiated naïve mice with bone marrow from mice infected as neonates resulted in the suppression of the hallmark features of allergic airway disease including mucus hyper-secretion and airway hyper-responsiveness, which was associated with decreased IL-13 levels in the lung. In stark contrast, reconstitution with bone marrow from mice infected as infants increased the severity of allergic airway disease by increasing T helper type-2 cell cytokine release (IL-5 and IL-13), mucus hyper-secretion, airway hyper-responsiveness and IL-13 levels in the lung. Reconstitution with bone marrow from infected adult mice had no effects. Conclusions These results suggest that an infant chlamydial lung infection results in long lasting alterations in hematopoietic cells that increases the severity of allergic airway disease in later-life.

Quality of life, fatigue and activity in Australians with chronic kidney disease : a longitudinal study

Aims and objectives This study sought to determine the relationship between health related quality of life (HRQoL), fatigue and activity levels of people with anaemia secondary to chronic kidney disease (CKD) over a 12 month period following the introduction of an erythropoietin stimulating agent (ESA). Background CKD occurs in five stages and it is a complex chronic illness which severely impacts on an individual’s HRQoL, and ability to perform everyday activities. Fatigue is also a common symptom experienced by people with CKD. Design and methods Using a longitudinal repeated measures design, 28 people with CKD completed the SF-36, human activity profile and fatigue severity scale at the commencement of an ESA and then at 3, 6 and 12 months. Results Over a 12 month period, people reported a significant change in HRQoL in relation to role physical, vitality, mental health/emotional well-being and overall mental health. However activity levels did not significantly improve during that time. Both the amount of breathlessness and level of fatigue were highest at baseline and declined over time. Both fatigue and breathlessness were correlated with less reported general health over time. Conclusion Renal nurses, in dialysis units and CKD outpatient clinics, have repeated and frequent contact with people with CKD over long periods of time, and are in an ideal position to routinely assess fatigue and activity levels and to institute timely interventions. Early detection would enable timely nursing interventions to optimise HRQoL and independent activity. Relevance to Clinical Practice Drawing on rehabilitation nursing interventions could assist renal nurses to minimize the burden of fatigue and its impact on simple everyday activities and a person’s quality of life. These interventions are important for people who are living at home and could assist in lowering the burden on home support services.

The epidemiology of invasive group A streptococcal disease in Victoria, Australia

Objective To estimate the incidence and severity of invasive group A streptococcal infection in Victoria, Australia. Design Prospective active surveillance study. Setting Public and private laboratories, hospitals and general practitioners throughout Victoria. Patients eople in Victoria diagnosed with group A streptococcal disease notified to the surveillance system between 1 March 2002 and 31 August 2004. Main outcome measure Confirmed invasive group A streptococcal disease. Results We identified 333 confirmed cases: an average annualised incidence rate of 2.7 (95% CI, 2.3-3.2) per 100000 population per year. Rates were highest in people aged 65 years and older and those younger than 5 years. The case-fatality rate was 7.8%. Streptococcal toxic shock syndrome occurred in 48 patients (14.4%), with a case-fatality rate of 23%. Thirty cases of necrotising fasciitis were reported; five (17%) of these patients died. Type 1 (23%) was the most frequently identified emm sequence type in all, age groups. All tested isolates were susceptible to penicillin and clindamycin. Two isolates (4%) were resistant to erythromycin. Conclusion The incidence of invasive group A streptococcal disease in temperate Australia is greater than previously appreciated and warrants greater public health attention, including its designation as a notifiable disease.

Utilising hospital data to inform product safety prioritisation : the application of RAPEX severity rankings in ICD-coded burn data

Background The implementation of the Australian Consumer Law in 2011 highlighted the need for better use of injury data to improve the effectiveness and responsiveness of product safety (PS) initiatives. In the PS system, resources are allocated to different priority issues using risk assessment tools. The rapid exchange of information (RAPEX) tool to prioritise hazards, developed by the European Commission, is currently being adopted in Australia. Injury data is required as a basic input to the RAPEX tool in the risk assessment process. One of the challenges in utilising injury data in the PS system is the complexity of translating detailed clinical coded data into broad categories such as those used in the RAPEX tool. Aims This study aims to translate hospital burns data into a simplified format by mapping the International Statistical Classification of Disease and Related Health Problems (Tenth Revision) Australian Modification (ICD-10-AM) burn codes into RAPEX severity rankings, using these rankings to identify priority areas in childhood product-related burns data. Methods ICD-10-AM burn codes were mapped into four levels of severity using the RAPEX guide table by assigning rankings from 1-4, in order of increasing severity. RAPEX rankings were determined by the thickness and surface area of the burn (BSA) with information extracted from the fourth character of T20-T30 codes for burn thickness, and the fourth and fifth characters of T31 codes for the BSA. Following the mapping process, secondary data analysis of 2008-2010 Queensland Hospital Admitted Patient Data Collection (QHAPDC) paediatric data was conducted to identify priority areas in product-related burns. Results The application of RAPEX rankings in QHAPDC burn data showed approximately 70% of paediatric burns in Queensland hospitals were categorised under RAPEX levels 1 and 2, 25% under RAPEX 3 and 4, with the remaining 5% unclassifiable. In the PS system, prioritisations are made to issues categorised under RAPEX levels 3 and 4. Analysis of external cause codes within these levels showed that flammable materials (for children aged 10-15yo) and hot substances (for children aged <2yo) were the most frequently identified products. Discussion and conclusions The mapping of ICD-10-AM burn codes into RAPEX rankings showed a favourable degree of compatibility between both classification systems, suggesting that ICD-10-AM coded burn data can be simplified to more effectively support PS initiatives. Additionally, the secondary data analysis showed that only 25% of all admitted burn cases in Queensland were severe enough to trigger a PS response.