Cardiac involvement in adults with Pompe disease

Background. Glycogen storage disease type II or Pompe disease is a neuromuscular disorder caused by deficiency of lysosomal acid α- glucosidase. Classic infantile Pompe disease results in massive left ventricular (LV) hypertrophy and failure. Although Pompe disease is often included in the differential diagnosis of LV hypertrophy the true frequency of cardiac involvement in adults with Pompe disease is not known. Methods. Forty-six consecutive adult patients (mean age 48 ± 12, 22 men) with Pompe disease were included. Each patient underwent a clinical examination, electrocardiography, and rest and low-dose dobutamine (in 20 patients) two-dimensional echocardiography including contrast and tissue Doppler imaging. Results. All patients had limited exercise tolerance; a rollator walking aid was used in seven patients (15%), a wheelchair in 13 patients (28%), and assisted ventilation in 14 patients (30%). Prior to this study, one patient was known with permanent atrial fibrillation, His-bundle ablation and a VVI pacemaker and another patient was known with fluid retention. The first patient had increased LV end-diastolic diameter, impaired LV ejection fraction, low systolic mitral annular velocities and diastolic dysfunction grade II. The patient with fluid retention was wheelchair bound and dependent on 24-h assisted ventilation and showed right ventricular and LV hypertrophy (septum 16 mm, posterior wall 15 mm). LV hypertrophy was not seen in any of the other patients. One woman of advanced age had isolated low systolic mitral annular velocities. Mean global systolic LV function, including contractile reserve, was not decreased in patients with Pompe disease. Eight patients (17%) had mild diastolic dysfunction grade I, related to hypertension in four and advanced age in seven. Conclusions. In adult patients with Pompe disease without objective signs of cardiac affection by 12-leads electrocardiography or physical examination, echocardiographic screening for LV hypertrophy seems not effective

Migraine with visual aura is a risk factor for incident atrial fibrillation: A cohort study

Objective Migraine with visual aura is associated with cardioembolic stroke risk. The aim of this study was to test association between migraine with visual aura and atrial fibrillation (AF), in the Atherosclerosis Risk in Communities study. Methods In the Atherosclerosis Risk in Communities study, a longitudinal, community-based cohort study, participants were interviewed for migraine history in 1993-1995 and were followed for incident AF through 2013. AF was adjudicated using ECGs, discharge codes, and death certificates. Multivariable Cox proportional hazards models were used to study the relation between migraine and its subtypes with incident AF, compared with controls without headaches. Mediation analysis was conducted to test whether AF was a mediator of migraine with visual aura-associated stroke risk. Results Of 11,939 participants assessed for headache and without prior AF or stroke, 426 reported migraines with visual aura, 1,090 migraine without visual aura, 1,018 nonmigraine headache, and 9,405 no headache. Over a 20-year follow-up period, incident AF was noted in 232 (15%) of 1,516 with migraine and 1,623 (17%) of 9,405 without headache. After adjustment for multiple confounders, migraine with visual aura was associated with increased risk of AF compared to no headache (hazard ratio 1.30, 95% confidence interval 1.03-1.62) as well as when compared to migraine without visual aura (hazard ratio 1.39, 95% confidence interval 1.05-1.83). The data suggest that AF may be a potential mediator of migraine with visual aura-stroke risk. Conclusions Migraine with aura was associated with increased risk of incident AF. This may potentially lead to ischemic strokes

Preliminary data on COVID-19 in patients with hemoglobinopathies : A multicentre ICET-A study

Objectives: This study aims to investigate, retrospectively, the epidemiological and clinical characteristics, laboratory results, radiologic findings, and outcomes of COVID-19 in patients with transfusion-dependent β thalassemia major (TM), β-thalassemia intermedia (TI) and sickle cell disease (SCD). Design: A total of 17 Centers, from 10 countries, following 9,499 patients with hemoglobinopathies, participated in the survey. Main outcome data: Clinical, laboratory, and radiologic findings and outcomes of patients with COVID-19 were collected from medical records and summarized. Results: A total of 13 patients, 7 with TM, 3 with TI, and 3 with SCD, with confirmed COVID-19, were identified in 6 Centers from different countries. The overall mean age of patients was 33.7±12.3 years (range:13-66); 9/13 (69.2%) patients were females. Six patients had pneumonia, and 4 needed oxygen therapy. Increased C-reactive protein (6/10), high serum lactate dehydrogenase (LDH; 6/10), and erythrocyte sedimentation rate (ESR; 6/10) were the most common laboratory findings. 6/10 patients had an exacerbation of anemia (2 with SCD). In the majority of patients, the course of COVID-19 was moderate (6/10) and severe in 3/10 patients. A 30-year-old female with TM, developed a critical SARS-CoV-2 infection, followed by death in an Intensive Care Unit. In one Center (Oman), the majority of suspected cases were observed in patients with SCD between the age of 21 and 40 years. A rapid clinical improvement of tachypnea/dyspnea and oxygen saturation was observed, after red blood cell exchange transfusion, in a young girl with SCD and worsening of anemia (Hb level from 9.2 g/dl to 6.1g/dl). Conclusions: The data presented in this survey permit an early assessment of the clinical characteristics of COVID 19 in different countries. 70% of symptomatic patients with COVID-19 required hospitalization. The presence of associated co-morbidities can aggravate the severity of COVID- 19, leading to a poorer prognosis irrespective of age

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. Methods: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model—a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates—with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality—which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. Findings: The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2–100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1–290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1–211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4–48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3–37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7–9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. Interpretation: Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. Funding: Bill & Melinda Gates Foundation

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions. Funding: Bill & Melinda Gates Foundation

MS Lesions Detection in MRI Using Grouping Artificial Immune Networks

A dual-channel 3D MRI segmentation technique based on grouping artificial immune networks (GAIN) is introduced to detect MS lesion in MR images. The technique demonstrates the ability of artificial immune networks to handle MS lesions detection in T1- and T2-weighted brain MRI. The GAIN-based MRI segmentation technique was evaluated using simulated MS brain images from the McConnell Brain Imaging Centre, Montreal Neurological Institute of McGill University. 3D anisotropic filtering is used to handle noise artifacts in the simulated 3D MRI data sets. Experimental results demonstrated that dual channel MS segmentation approach exhibited high accuracy in segmenting the simulated MS brain data and an even higher accuracy when compared to techniques based on single channel 3D MRI data sets in terms of the Dice coefficient, an objective measure of overlap

Bone disease in β thalassemia patients: past, present and future perspectives

Bone disorders in patients with thalassemia major (TM) and intermedia (TI) constitute complex conditions that result from various factors affecting the growing skeleton. Although much progress has been made in our understanding of the natural history, pathogenesis and clinical manifestations of β- and δβ-thalassemia, bone manifestations remain a puzzle for the clinician. In this review, we outline the key points in the current literature on the pathogenesis and management of bone disease in patients with TM and TI who were conventionally treated in recent decades with frequent blood transfusions and iron chelation. Prevention, early recognition and treatment are the most effective strategies for the management of bone disease in these patients. However, further studies are required to maintain optimal bone health for both TM and TI patients. Studying bone disease in patients with non-transfusion dependent TI, which seems to worsen considerably with age, is important to delineate the effect of the disease itself on bone health without the intervening factors of transfusions, iron intoxication and chelation. © 2017 Elsevier Inc

The Management of Permanent Primary Hypoparathyroidism in Children and Adolescents: A Complex Task

Management of hypoparathyroidism (hypoPT), depends on the etiology and the severity of hypocalcemia. Treatment goals include control of hypocalcemic symptoms preserving serum calcium in the low-normal range and phosphate in the high normal range. While correction of serum calcium to low-normal range does not fully correct mineral and bone metabolism it may be associated with increased risk of complications such as nephrolithiasis, nephrocalcinosis and soft tissue calcifications. Therefore, it is imperative to find out ways to individualize treatment of patients with hypoPT to achieve the best prognosis while minimizing complications. Replacement therapy with recombinant human PTH (rhPTH) was recently tested for optimizing treatment of hypoPT in a small number of patients. For children and adolescents, further studies are needed to evaluate the long-term effects and safety of rhPTH. In this short review we summarize current knowledge on the management of hypoPT and debate our gaps on the long-term management of children and adolescents with hypoPT. Copyright© of YS Medical Media ltd

The juvenile fibromyalgia syndrome (JFMS): A poorly defined disorder

Summary. Juvenile fibromyalgia syndrome (JFMS) is a chronic condition characterized by symptoms of chronic diffuse musculoskeletal pain and multiple painful tender points on palpation. It is often accompanied by fatigue, disorders of sleep, chronic headaches, irritable bowel syndrome, and subjective soft tissue swelling. The complexity of the presenting clinical picture in JPFS has not been sufficiently defined in the literature. Similarities to adult fibromyalgia syndrome in JFMS are often difficult to compare, because many of the symptoms are “medically unexplained” and often overlap frequently with other medical conditions. However, a valid diagnosis of JFMS often decreases parents’ anxiety, reduces unnecessary further investigations, and provides a rational framework for a management plan. The diagnostic criteria proposed by Yunus and Masi in 1985 to define JFMS were never validated or critically analyzed. In most cases, the clinical diagnosis is based on the history, the physical examination that demonstrates general tenderness (muscle, joints, tendons), the absence of other pathological conditions that could explain pain and fatigue, and the normal basic laboratory tests. Research and clinical observations defined that JFMS may have a chronic course that impacts the functional status and the psychosocial development of children and adolescents. This paper briefly reviews the existing knowledge on JFMS focusing on the diagnosis, clinical and the epidemiological characteristics in children and adolescents for better understanding of this disorder. (www.actabiomedica.it). © Mattioli 1885

Current treatment of hypoparathyroidism: Theory versus reality waiting guidelines for children and adolescents

The diagnosis of hypoparathyroidism(HPT)is readily made in the presence of hypocalcemia with markedly reduced or absent parathormone (PTH) levels. Currently available treatments for HPT include high dose vitamin D (ergocalciferol, D2 and cholecalciferol, D3) or, the active metabolite dihydroxy vitamin D (calcitriol), in addition to calcium supplements.This regimen, if not well monitored, can lead to hypercalciuria, as PTH deficiency impairs renal calcium reabsorption. Thus the goal of treatment, is to maintain serum calcium at the low end of the normal range. Undertreatment can cause symptomatic hypocalcemia, while overtreatment hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and renal insufficiency. At present, there is no consensus on the management of HPT in children and adolescents and only few studies are available on the long term outcome of patients with recombinant HPT treatment. The purpose of this article is to review, in a comprehensive manner, the major aspects of HPT management in children and adolescents waiting for authoritative guidelines for the treatment of HPT in this group of patients. Further research, addressing specific questions for this population are urgently needed to improve long-term safety of patients. Educational interventions are also needed for professionals, parents and patients to enable them to improve knowledge, quality of life and effective management care at home. (www.actabiomedica.it). © Mattioli 1885