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Sickle cell disease (SCD), an inherited hemoglobinopathy that most commonly affects persons of African ancestry, is estimated to affect 1 in 365 Black persons in the United States (1). Persons [...]

During hemolysis, macrophages in the liver phagocytose damaged erythrocytes to prevent the toxic effects of cell-free hemoglobin and heme. It remains unclear how this homeostatic process modulates phagocyte functions in inflammatory diseases. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we found that erythrophagocytosis skewed liver macrophages into an antiinflammatory phenotype that we defined as [Marco.sup.hi][Hmox.sup.hi]MHC class [II.sup.lo] [degrees] erythrophagocytes. This phenotype transformation profoundly mitigated disease expression in a model of an anti-CD40-induced hyperinflammatory syndrome with necrotic hepatitis and in a nonalcoholic steatohepatitis model, representing 2 macrophage-driven sterile inflammatory diseases. We reproduced the antiinflammatory erythrophagocyte transformation in vitro by heme exposure of mouse and human macrophages, yielding a distinctive transcriptional signature that segregated heme-polarized from M1- and M2-polarized cells. Mapping transposase-accessible chromatin in single cells by sequencing defined the transcription factor NFE2L2/NRF2 as a critical driver of erythrophagocytes, and Nfe2l2/Nrf2 deficiency restored heme-suppressed inflammation. Our findings point to a pathway that regulates macrophage functions to link erythrocyte homeostasis with innate immunity., Introduction The archetypical functions of macrophages are their roles as sensors, effectors, and resolvers of inflammation and tissue damage (1). Historically defined as inflammatory M1-like and antiinflammatory M2-like, macrophage phenotypes [...]

BACKGROUND. Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains [beta]3-adrenergic receptors ([beta]3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the [beta]3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis. METHODS. Before and after [beta]3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle. RESULTS. The clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and [beta] cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in [beta] cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPAR[gamma] coactivator 1 [alpha] (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001). CONCLUSION. Mirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulinresistant humans. Since [beta] cells and skeletal muscle do not express [beta]3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves [beta] cell function. TRIAL REGISTRATION. Clinicaltrials.gov NCT02919176. FUNDING. NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998., Introduction The [beta]3-adrenergic receptor ([beta]3-AR) has long been a therapeutic target to combat obesity and metabolic disease. Since the [beta]3-AR is present in adipose tissue, but not in most other [...]

Cancer-related anemia is present in more than 60% of newly diagnosed cancer patients and is associated with substantial morbidity and high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates and improve quality of life. Clinical studies have observed an unexpected improvement in hemoglobin and RBC transfusionindependence in patients with acute myeloid leukemia (AML) treated with the isocitrate dehydrogenase 2 (IDH2) mutantspecific inhibitor enasidenib, leading to improved quality of life without a reduction in AML disease burden. Here, we demonstrate that enasidenib enhanced human erythroid differentiation of hematopoietic progenitors. The phenomenon was not observed with other IDH1/2 inhibitors and occurred in IDH2-deficient CRISPR-engineered progenitors independently of D-2-hydroxyglutarate. The effect of enasidenib on hematopoietic progenitors was mediated by protoporphyrin accumulation, driving heme production and erythroid differentiation in committed [CD71.sup.+] progenitors rather than hematopoietic stem cells. Our results position enasidenib as a promising therapeutic agent for improvement of anemia and provide the basis for a clinical trial using enasidenib to decrease transfusion dependence in a wide array of clinical contexts., Introduction Acute myeloid leukemia (AML) remains one of the most difficult cancers to treat, with a low cure rate (~25%) and a 5-year survival rate of 28% (1, 2). High-throughput [...]

Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding., Introduction Aneurysmal subarachnoid hemorrhage (aSAH) represents 5%-10% of all strokes and has an estimated global incidence of 6.67 per 100,000 people (1, 2). The loss of productive life years due [...]

* Context.--Urine myoglobin testing is primarily indicated for diagnosis and risk assessment of kidney injury in patients with rhabdomyolysis. However, its utility is limited by a lack of rapid and reliable results. Myoglobin reacts positively for blood by urine dipstick, which can serve as an indicator of myoglobinuria. Objective.--To evaluate the performance and value of blood and red cell measurements by urinalysis as a surrogate test for myoglobinuria in routine clinical practice. Design.--This study is a retrospective observational study involving analysis of hemoglobin and red blood cell results by urinalysis in patients tested for urine myoglobin. Results.--A total of 13 139 urine myoglobin results from 88 Veterans Affairs facilities during a 15-year period ending in October 2014 were evaluated. Among methods used by each laboratory, qualitative urine myoglobin tests declined from 25 of 53 (47.1%) in 2000 to 5 of 77 (6.4%) in 2013. Of 7311 tests (55.6%) performed by quantitative methods with concomitant urinalysis, 3915 (53.5%) showed negative to trace blood results, of which myoglobin was 1000 [micro]g/L or greater in 17 (0.4%). Among 1875 (25.5%) with 3+ (large) blood results, urine myoglobin was [greater than or equal to] 1000 [micro]g/L in 273 of 1533 (17.8%) with hematuria ([greater than or equal to] 5 red blood cells per microliter) and 109 of 342 (31.9%) without hematuria. Conclusions.--Urinalysis results reliably predicted the absence of myoglobinuria and could be used to avert overtesting for urine myoglobin while also providing useful diagnostic information when urine myoglobin test results are not immediately available. (Arch Pathol Lab Med. 2019;143:1378-1381; doi: 10.5858/arpa.2018-0475-0A), Rhabdomyolysis is a syndrome involving acute muscle injury caused by numerous conditions, such as trauma (eg, crush, burn, or electrical injuries), intense exercise, inflammatory or hereditary myopathies, snake toxins, seizures, [...]

Type 2 Diabetes Mellitus is a metabolic disorder characterized by hyperglycemia due to relative insulin secretion deficiency and insulin resistance. It is a global public health concern with increasing prevalence each year. Social demographic, lifestyle and metabolic characteristic, play a crucial role in development and progression of Type 2 diabetes mellitus. Poor glycemic control worsens the condition, leading to complications that are very costly to treat. This calls for a need to explore the relationship between patient characteristics and glycemic control (HbA1c). One hundred and fifty three (153) participants with Type 2 diabetes mellitus aged 20-79 years and attending the Thika Level Five Hospital were enrolled in the study. Socio-demographic, clinical and lifestyle data were obtained using questionnaires. The nutrition status was determined by anthropometry. Lipid profile that included total cholesterol, (TC); high density lipoprotein-cholesterol, (HDL-c); low density lipoprotein cholesterol, (LDL-c) and triglyceride, (TG,) were determined by enzymatic method while glycated hemoglobin (HbA1c) and fasting blood sugar (FBS) were determined using high-performance liquid chromatography (HPLC) and glucose oxidase methods, respectively. Blood pressure of the patients was also determined. Overall sample size was 153 (40.5% men and 59.5% women). The overall mean age of patients was 56.07 years, and the mean age of patients with poor glycemic control (HbA1c>7%) was 56.79 years. The prevalence of the poor glycemic control (HbA1c>7%) was 77.8%. Participants with HbA1c > 7% showed statistically significant higher means for FBG, TC, and LDL-c than their counterparts with good glycemic control [11.71[+ or -]3.11mmol/l vs. 8.54[+ or -]3.19; 5.11[+ or -]1.21mmol/l vs. 4.48[+ or -]1.16 and 2.66[+ or -]1.07 mmol/l vs. 2.22[+ or -]1.04, respectively, (P Key words: Type 2 Diabetes Mellitus, glycemic control, cardiovascular risk, Patient characteristics, INTRODUCTION Type 2 diabetes mellitus is a heterogeneous disorder characterized by hyperglycemia due to relative insulin insufficiency and impaired effectiveness of insulin action [1]. It is a global public health [...]

Background: More than half the diabetes-related health care costs in Canada relate to drug costs. We aimed to determine the effect of Roux-en-Y gastric bypass (RYGB) on the use of insulin and orally administered hypoglycemic medications in patients with diabetes. We also looked to determine overall cost savings with the procedure. Methods: We reviewed the bariatric clinic records of all patients with a confirmed diagnosis of type 2 diabetes mellitus who underwent RYGB between 2010/11 and 2014/15. Percentage estimated weight loss was recorded at 1 year, along with reductions in glycated hemoglobin ([HbA.sub.1c]) level and use of oral hypoglycemic therapy and insulin. We estimated medication costs using Manitoba-specific pricing data. Results: Fifty-two patients with at least 12 months of complete follow-up data were identified. The mean percentage estimated weight loss was 50.2%. The mean [HbA.sub.1c] level decreased from 7.6% to 6.0%, the mean number of orally administered hypoglycemics declined from 1.6 to 0.2, and the number of patients receiving insulin decreased from 18 (35%) to 3 (6%) (all p < 0.001). The rate of resolution of type 2 diabetes was 71%. Estimated mean annual per-patient medication costs decreased from S508.56 to S79.17 (p < 0.001). Potential overall health care savings could total $3769 per patient in the first year, decreasing to $1734 at 10 years. Conclusion: Roux-en-Y gastric bypass resulted in significant improvement in diabetic control, with a reduction in hypoglycemic medication use and associated costs in the early postoperative period. Potentially, large indirect and direct cost savings can be realized in the longer term. Contexte : Plus de la moitié des coûts des soins de santé liés au diabète au Canada sont générés par les médicaments. Nous avons voulu déterminer l'effet de la dérivation gastrique de Roux-en-Y sur l'utilisation des agents hypoglycémiants oraux et de l'insuline chez les patients diabétiques. Nous avons aussi cherché à déterminer l'ensemble des économies associées à cette intervention. Méthodes : Nous avons passé en revue les dossiers cliniques bariatriques de tous les patients ayant un diagnostic confirmé de diabète de type 2 qui ont subi une dérivation gastrique de Roux-en-Y entre 2010-2011 et 2014-2015. La perte de poids--estimée en pourcentage--a été notée après un an, ainsi que les réductions des taux d'hémoglobine glyquée ([HbA.sub.1c]) et du recours aux hypoglycémiants oraux et à l'insuline. Nous avons estimé les coûts des médicaments à partir des données de tarification du Manitoba. Résultats : Cinquante-deux patients pour lesquels on disposait d'au moins 12 mois de données de suivi complètes ont été retenus. La perte de poids moyenne estimée en pourcentage était de 50,2%. Le taux moyen [d'HbA.sub.1c] a diminué de 7,6% à 6,0%, le nombre moyen de comprimés d'hypoglycémiants oraux est passé de 1,6 à 0,2, et le nombre de patients sous insuline a diminué de 18 (35%) à 3 (6%) (tous p < 0,001). Le taux de résolution du diabète de type 2 était de 71%. Le coût annuel moyen estimé des médicaments par patient est passé de 508,56$ à 79,17$ (p < 0,001). Les économies potentielles globales pour le système de santé pourraient totaliser 3769$ par patient au cours de la première année, puis passer graduellement à 1734$ au cours des 10 années suivantes. Conclusion : La dérivation gastrique de Roux-en-Y a permis d'améliorer significativement le contrôle du diabète, ainsi que de réduire le recours aux hypoglycémiants et les coûts associés au début de la période postopératoire. A plus long terme, d'importantes économies sur le plan des coûts indirects et directs pourraient potentiellement être réalisées., Obesity-related type 2 diabetes mellitus is a growing pandemic. In 2015, just over 3 million Canadians had a diagnosis of type 2 diabetes. (1) The majority of these patients are [...]

BACKGROUND. The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. [beta]-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce. METHODS. MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD3[4.sup.+] HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models. RESULTS. We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche-associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models. CONCLUSION. Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation. FUNDING. This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente., Introduction [beta]-Thalassemia (BT) is one of the most common inherited monogenic disorders in the world, with an overall carrier rate of 1.5% of the world population, and 60,000 BT symptomatic [...]

Anaemia, vitamin-A deficiency and under nutrition are prevalent among children at levels of public health significance in developing countries of which Ghana is no exception. The objective of this study was to assess the anaemia, low vitamin-A level and anthropometric nutritional status of 162 randomly selected young Ghanaian school children 4 - 8 years in Kodzobi, a peri-urban community and establish associated factors. Questionnaires were used to collect background data from parents of study participants. Vitamin-A and haemoglobin concentrations were determined using High Performance Liquid Chromatography and Haemocue hemoglobinometer, respectively. Malaria parasitaemia was examined by the Giemsa staining technique. Weight and height measurements were taken according to WHO's standard procedures to assess participants' nutritional status. The mean haemoglobin and serum retinol concentrations were 11.6 [+ or -] 1.1 g/dl and 22.8 [+ or -] 6.5 [micro]g/dl, respectively. Prevalence of anaemia and vitamin-A deficiency among study participants were 38.3 % and 24.0 %, respectively. The prevalence of underweight, stunting, thinness and overweight were 9.3 %, 9.9 %, 4.3 % and 3.7 %, respectively. Haemoglobin correlated positively and significantly with weight, weight-for-age and body mass index-for-age z scores. Child's sex, vitamin-A status and parental monthly income associated with anaemia status. Females had a higher risk of being anaemic compared to males (OR = 2.519; 95 % CI: 0.965 - 6.580; p = 0.049). Participants with normal vitamin-A concentration were at lower risk of being anaemic (OR = 0.302; 95 % CI: 0.109 - 0.840; p = 0.022) than those with low vitamin-A concentration. Anaemia and young child age negatively associated with vitamin-A status, at p = 0.039 and p = 0.037, respectively. Anaemia and vitamin-A deficiency are issues of public health importance among school-aged children in Ghana. There is, therefore, the need to invest in actions that prevent their occurrence and management especially among children of school going age. Key words: Anaemia, vitamin-A deficiency, nutritional status, retinol, haemoglobin, school children, peri-urban, INTRODUCTION Anaemia, Vitamin-A deficiency (VAD) and under nutrition are prevalent among children and are issues of public health interest in developing countries. Approximately 25.4 % of school-aged children in the [...]

Ferrous fumarate, an excellent pharmaceutical drug, was investigated theoretically, which was found to be in accordance with experimental results. FT-Raman and FT-IR spectra were recorded and effectively correlated with computed vibrational studies. DFT/B3PW91 method using 6-311G basis set was employed to determine the optimized structure of ferrous fumarate. Consecutive vibrational modes have been assigned and the calculated structural parameters were compatible with the experimental results. Ionization energy was found to be very low (0.263 eV), thereby the hardness analysis confirms the ferrous fumarate is soft (13.872 eV). Frontier molecular orbital theory confirms the low stability of the molecule. Molecular electrostatic potential map (MEP) shows the nucleophilic and electrophilic sites, which favour the possible reactive sites for future ligand attachments. Molecular docking studies of ferrous fumarate against harmful fungal pathogens and hemoglobin variants aids in the detection of effective binding modes of receptor-ligand complex, which lead towards novel drug discovery. Key words: DFT, Raman and IR spectroscopy, vibrational modes, MEP, stability, molecular docking. Nous presentons une etude theorique du fumarate ferreux, par ailleurs un excellent medicament, qui s'avere etre en accord avec les valeurs experimentales. Les spectres Raman-FT et IR-FT sont enregistres et effectivement correles avec les etudes vibrationnelles calculees en utilisant la methode de la theorie de la fonctionnelle de densite TFD/B3PW91, avec l'ensemble de base base 6-311G, pour determiner la structure optimisee du fumarate ferreux. Nous identifions les modes vibrationnels issus des calculs et evaluons les parametres structuraux, qui s'averent etre compatibles avec les valeurs experimentales. Nous trouvons que l'energie d'ionisation est tres basse a 0,263 eV, alors que l'analyse de durete confirme que le compose en titre est mou (13,872 eV). La theorie des orbitales moleculaires frontieres confirme la faible stabilite de la molecule. La carte du potentiel electrostatique moleculaire (PEM) montre les sites nucleophiles et electrophiles qui favorisent les sites reactifs possibles pour de futurs liens ligands. Les etudes d'amarrage moleculaire du fumarate ferreux contre des pathogenes fongiques et des variantes d'hemoglobine aident la detection des modes effectifs de liens de complexes recepteurs-ligands, ce qui peut mener a la decouverte de nouveaux medicaments. [Traduit par la Redaction] Mots-cles : TFD, theorie de la fonctionnelle de densite, PEM, potentiel electrostatique moleculaire, stabilite, amarrage moleculaire., 1. Introduction Iron and its moieties maintain specific functions in oxidative mechanisms for regulating the metabolism in biological organisms. Iron deficiency is a chronic ailment that causes anemia, thalassemia, chronic [...]

The optimal oxygenation target needed to prevent the extremes of hypoxia and oxygen toxicity in premature and sick newborns has been the subject of much research and debate. The advent of the pulse oximeter has allowed the continuous monitoring of oxyhemoglobin saturation and the delivery of oxygen with greater precision. Well-run, large clinical trials to determine the safest oxygen concentration have led to several revisions in guidelines for neonatal care. However, monitoring of oxyhemoglobin saturation has its limitations and does not provide a comprehensive assessment of tissue oxygenation. To identify optimal oxygen therapy, various other factors (partial pressure of arterial carbon dioxide, hemoglobin concentration, blood pH, and tissue metabolic demand) that influence perfusion and tissue oxygenation need to be considered. Key words: oxygen saturation, newborn, oxygen target. L'oxygenation cible optimale necessaire en vue de prevenir les situations extremes comme l'hypoxie et la toxicite a l'oxygene chez les nouveau-nes prematures et malades a fait l'objet de beaucoup de recherches et de debats. L'avenement de l'oxymetrie de pouls a donne le moyen de surveiller la saturation en oxyhemoglobine en continu et d'administrer de l'oxygene avec une plus grande precision. De vastes essais cliniques bien realises en vue d'etablir la concentration d'oxygene la plus securitaire ont mene a plusieurs revisions des lignes directrices pour les soins en neonatalogie. Cependant, la surveillance de la saturation en oxyhemoglobine en continu ses propres limites, et ne permet pas d'obtenir une evaluation integrale de l'oxygenation tissulaire. En vue d'etablir le traitement par l'oxygene optimal, il convient de prendre en compte divers autres facteurs qui influencent la perfusion et l'oxygenation tissulaire (pression partielle du sang arteriel en dioxyde de carbone, concentration d'hemoglobine, pH sanguin et demande metabolique tissulaire). [Traduit par la Redaction] Mots-cles : saturation en oxygene, nouveau-ne, oxygenation cible., Introduction Oxygen therapy is a life-sustaining intervention and remains the most commonly used drug in the care of sick newborns (Vento and Saugstad 2010). In the 1940s and 1950s, flooding [...]

Objective To evaluate the performance of diagnostic tools for diabetes mellitus, Including laboratory methods and clinical risk scores, In newly-diagnosed pulmonary tuberculosis patients from four middle-income countries.Methods In a multicentre, prospective study, we recruited 2185 patients with pulmonary tuberculosis from sites in Indonesia, Peru, Romania ' and South Africa from January 2014 to September 2016. Using laboratory-measured glycated haemoglobin (HbA1c) as the gold standard, we measured the diagnostic accuracy of random plasma glucose, point-of-care HbA1c, fasting blood glucose, urine dipstick, published and newly derived diabetes mellitus risk scores and anthropometric measurements. We also analysed combinations of tests, including a two-step test using point-of-care HbA1cwhen Initial random plasma glucose was [greater than or equal to] 6.1 mmol/L.Findings The overall crude prevalence of diabetes mellitus among newly diagnosed tuberculosis patients was 283/2185 (13.0%; 95% confidence interval, CI: 11.6-14.4). The marker with the best diagnostic accuracy was point-of-care HbA1c (area under receiver operating characteristic curve: 0.81; 95% CI: 0.75-0.86). A risk score derived using age, point-of-care HbA1c and random plasma glucose had the best overall diagnostic accuracy (area under curve: 0.85; 95% CI: 0.81-0.90). There was substantial heterogeneity between sites for all markers, but the two-step combination test performed well in Indonesia and Peru.Conclusion Random plasma glucose followed by point-of-care HbA1c testing can accurately diagnose diabetes in tuberculosis patients, particularly those with substantial hyperglycaemla, while reducing the need for more expensive point-of-care HbA1c testing. Risk scores with or without biochemical data may be useful but require validation.Objectif Evaluer la performance des outils de diagnostic du diabete sucre, et notamment les methodes de laboratoire et les cotes de risque clinique, chez les patients souffrant d'une tuberculose pulmonaire recemment diagnostiquee dans quatre pays a revenu intermediaire.Methodes Dans le cadre d'une etude multicentrique et prospective, nous avons recrute 2185 patients atteints de tuberculose pulmonaire dans differents endroits en Afrique du Sud, en Indonesie, au Perou et en Roumanie entre janvier 2014 et septembre 2016. En utilisant comme referencel'hemoglobineglyquee (HbA1c) mesuree en laboratoire, nous avons evalue la precision diagnostique de la glycemie aleatoire, de l'HbAI c sur le lieu d'intervention, de la glycemie a jeun, de la bandelette urinaire, des cotes de risque deja publiees et recemment obtenues pour le diabete sucre et des mesures anthropometriques. Nous avons egalement analyse des combinaisons de tests, et notamment un test en deux etapes qui utilise l'HbA1c sur le lieu d'intervention lorsque la glycemie aleatoire initiale est [greater than or equal to] 6,1 mmol/LResultats La prevalence brute generale du diabete sucre chez les patients souffrant d'une tuberculose recemment diagnostiquee etait de 283/2185 (13,0%; intervalle de confiance, IC, a 95%: 11,6-14,4). Le marqueur fournissant la meilleure precision diagnostique etait l'HbA1c sur le lieu d'intervention (aire sous la courbe ROC: 0,81; IC a 95%: 0,75-0,86). La meilleure precision diagnostique generale a ete obtenue a l'aide d'une cote de risque calculee au moyen de l'age, de l'HbA1c sur le lieu d'intervention et de la glycemie aleatoire (aire sous la courbe ROC: 0,85; IC a 95%: 0,81-0,90). Une forte heterogeneite entre les differents endrolts a ete constatee pourtous les marqueurs, mais le test en deux etapes a donne de bons resultats en Indonesie et au Perou.Conclusion L'utilisation de la glycemie aleatoire suivie de l'HbA1c sur le lieu d'intervention permet de diagnostiquer avec precision le diabete chez les patients atteints de tuberculose, en particulier lorsqu'ils souffrent d'une importante hyperglycemie, tout en diminuant le besoin de tests HbA1c sur le lieu d'intervention, plus couteux. Les cotes de risque associees ou non a des donnees biochimiques peuvent etre utiles, mais doivent etre validees.Objetivo Evaluar el rendimiento de las herramientas de diagnostico para la diabetes mellitus, incluidos los metodos de laboratorio y los indices de riesgo clinico, en pacientes recien diagnosticados con tuberculosis pulmonar de cuatro paises de ingresos medios.Metodos En un estudio prospectivo multicentrico, se seleccionaron 2185 pacientes con tuberculosis pulmonar de algunas regiones de Indonesia, Peru, Rumania y Sudafrica entre enero de 2014 y septiembre de 2016. Usando hemoglobina glicosilada medida en laboratorio (HbA1 c) como el patron de excelencia, se midio la precision diagnostica de glucosa plasmatica al azar, estando HbA1 c en el punto de atencion, glucemia en sangre en ayunas, tira reactiva de orina, indices de riesgo de diabetes mellitus publicados recientemente y medidas antropometricas. Tambien se analizaron combinaciones de pruebas, incluida una prueba de dos pasos con HbA1c en el punto de atencion cuando la glucosa plasmatica aleatoria inicial fue [greater than or equal to] 6,1 mmol/L.Resultados La prevalencia general cruda de diabetes mellitus entre los pacientes con tuberculosis recien diagnosticados fue de 283/2185 (13,0 %, intervalo de confianza del 95 %, IC: 11,6-14,4). El marcador con la mejor precision diagnostica fue la HbA1c en el punto de atencion (area bajo la curva caracteristica operativa del receptor: 0,81; IC del 95 %: 0,75-0,86). Un indice de riesgo derivado de la edad, la HbA1c en el punto de atencion y la glucosa plasmatica al azar obtuvieron la mejor precision diagnostica general (area bajo la curva: 0,85; IC del 95 %: 0,81 -0,90). Hubo una heterogeneidad sustancial entre las regiones para todos los marcadores, pero la prueba combinada de dos pasos funciono de manera correcta en Indonesia y Peru.Conclusion La glucosa plasmatica al azar seguida de la prueba de HbA1c en el punto de atencion puede diagnosticar con precision la diabetes en pacientes con tuberculosis, particularmente en aquellos con hiperglucemia sustancial, mientras se reduce la necesidad de pruebas mas costosas de HbA1 c en el punto de atencion. Los indices de riesgo con o sin datos bioquimicos pueden ser utiles, pero requieren validacion., [phrase omitted]IntroductionTuberculosis is a major global public health concern. In 2016, the World Health Organization (WHO) estimated that there were 10.4 million new tuberculosis patients worldwide and 1.8 million tuberculosis-related [...]

Sickle cell disease (SCD) is a heritable disorder of hemoglobin that affects 1 of every 400 black newborns and approximately 100,000 persons in the United States (1). This disease burden [...]

Anemia is defined by low levels of circulating hemoglobin, resulting in insufficient tissue oxygenation. This condition results from both genetic and nutritional factors and affects more than a billion people worldwide. For the inherited anemias, progress made over the last 40 years has increased our understanding of the structural basis for normal red cell membrane function and allowed definition of the genetic and pathophysiological bases of many human RBC membrane disorders. Despite these advances, there are continued uncertainties in the genotype-phenotype relationship in cases of severe, membrane-linked anemia. In this issue of the JCI, Gallagher and colleagues have identified a severe form of inherited anemia that results from aberrant splicing of [alpha]-spectrin, which in turn leads to abnormal erythrocyte membrane structure and function. The identification and characterization of this splicing-associated genetic disease will facilitate diagnosis and treatment of severe anemia in affected patients. These findings not only improve understanding of red cell disorders, they are likely to impact many disciplines, as the disease-associated alternate branch point utilization defined in the report may be the underlying etiology for many other inherited or acquired disorders., Structure and function of normal red cell membrane Structural organization of the membrane enables the normal red cell to undergo large-scale rapid and reversible deformations while also maintaining mechanical integrity [...]

A 73-year-old male patient sought care from the otorhinolaryngology department at University Hospital, Marseille, France. He had a 5-month history of malignant otitis externa (MOE), which was worsening despite 4 [...]

Byline: Thashi. Chang, Praveen. Weeratunga, Thamal. Vithanage, Piumi. Wijewickrama, Sithara. Kularathne, Sachie. Fernando, Carukshi. Arambepola Background: Reduced hemoglobin concentration has an adverse impact on the ischemic penumbra in patients with [...]

Byline: Satadru. Biswas, Santanu. Acharyya, Pritha. Roy, Debdeep. Samaddar, Chandan. Dasgupta, Debarshi. Jana Context: Aside abdominal discomfort and pain, upper gastrointestinal bleeding (UGIB) significantly disgraces the quality of life (QoL), [...]

Introduction The cardiorespiratory system is responsible for oxygen delivery to the body. Abnormalities in either system can lead to hypoxaemia and its detrimental effects on every organ system. Oxygenation begins [...]

Byline: Aditya. Sharma, Mukesh. Gupta, Gopal. Sharma, Ravimohan. Mavuduru Renal arteriovenous malformation can be rarely associated with a renal mass. A vigilant approach and careful planning is required to tackle [...]

Byline: Madhusudhanan. Jegadeesan, A. Robert, Thodana. Sekar Blunt adrenal gland trauma is an uncommon injury owing to the location of the adrenal gland in the retroperitoneum surrounded by major viscera [...]

Background Although patients with type 2 diabetes mellitus (T2DM) may fail to achieve adequate hemoglobin A1c (HbA1c) control despite metformin-sulfonylurea (Met-SU) dual therapy, a third-line glucose-lowering medication-including dipeptidyl peptidase-4 inhibitor (DPP4i), insulin, or thiazolidinedione (TZD)-can be added to achieve this. However, treatment effects of intensification with the medications on the risk of severe hypoglycemia (SH), cardiovascular disease (CVD), and all-cause mortality are uncertain. Study aim was to compare the risks of all-cause mortality, CVD, and SH among patients with T2DM on Met-SU dual therapy intensified with DPP4i, insulin, or TZD. Methods and findings We analyzed a retrospective cohort data of 17,293 patients with T2DM who were free from CVD and on Met-SU dual therapy and who were intensified with DPP4i (n = 8,248), insulin (n = 6,395), or TZD (n = 2,650) from 2006 to 2017. Propensity-score weighting was used to balance out baseline covariates across groups. Hazard ratios (HRs) for all-cause mortality, CVD, and SH were assessed using Cox proportional hazard models. Mean age of all patients was 58.56 ± 11.41 years. All baseline covariates achieved a balance across the 3 groups. Over a mean follow-up period of 34 months with 49,299 person-years, cumulative incidences of all-cause mortality, SH, and CVD were 0.061, 0.119, and 0.074, respectively. Patients intensified with insulin had higher risk of all-cause mortality (HR = 2.648, 95% confidence interval [CI] 2.367-2.963, p < 0.001; 2.352, 95% CI 2.123-2.605, p < 0.001) than those intensified with TZD and DPP4i, respectively. Insulin users had the greatest risk of SH (HR = 1.198, 95% CI 1.071-1.340, p = 0.002; 1.496, 95% CI 1.342-1.668, p < 0.001) compared with TZD and DPP4i users, respectively. Comparing between TZDs and DPP4i, TZDs were associated with a higher risk of SH (HR = 1.249, 95% CI 1.099-1.419, p < 0.001) but not all-cause mortality (HR = 0.888, 95% CI 0.776-1.016, p = 0.084) or CVD (HR = 1.005, 95% CI 0.915-1.104, p = 0.925). Limitations of this study included the lack of data regarding lifestyle, drug adherence, time-varying factors, patients' motivation, and cost considerations. A limited duration of patients intensifying with TZD might also weaken the strength of study results. Conclusions Our results indicated that, for patients with T2DM who are on Met-SU dual therapy, the addition of DPP4i was a preferred third-line medication among 3 options, with the lowest risks of mortality and SH and posing no increased risk for CVD events when compared to insulin and TZD. Intensification with insulin had the greatest risk of mortality and SH events., Author(s): Carlos K. H. Wong 1,*, Kenneth K. C. Man 2,3, Margaret Shi 1, Esther W. Chan 2, Chu Wa Ho 1, Emily T. Y. Tse 1, Ian C. K. [...]

Background To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994). Methods and findings Articles published on PubMed between 1 January 2011 and 27 September 2019 were screened. Articles reporting performance of the standard CSG from venous or capillary blood samples collected prospectively and considering spectrophotometry as gold standard (using kits from Trinity Biotech PLC, Wicklow, Ireland) were included. Authors of articles fulfilling the inclusion criteria were contacted to contribute anonymized individual data. Minimal data requested were sex of the participant, CSG result, spectrophotometry result in U/gHb, and haemoglobin (Hb) reading. The adjusted male median (AMM) was calculated per site and defined as 100% G6PD activity. G6PDd was defined as an enzyme activity of less than 30%. Pooled estimates for sensitivity and specificity, unconditional negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated comparing CSG results to spectrophotometry using a random-effects bivariate model. Of 11 eligible published articles, individual data were available from 8 studies, 6 from Southeast Asia, 1 from Africa, and 1 from the Americas. A total of 5,815 individual participant data (IPD) were available, of which 5,777 results (99.3%) were considered for analysis, including data from 3,095 (53.6%) females. Overall, the CSG had a pooled sensitivity of 0.96 (95% CI 0.90-0.99) and a specificity of 0.95 (95% CI 0.92-0.96). When the prevalence of G6PDd was varied from 5% to 30%, the unconditional NPV was 0.99 (95% CI 0.94-1.00), with an LR+ and an LR- of 18.23 (95% CI 13.04-25.48) and 0.05 (95% CI 0.02-0.12), respectively. Performance was significantly better in males compared to females (p = 0.027) but did not differ significantly between samples collected from capillary or venous blood (p = 0.547). Limitations of the study include the lack of wide geographical representation of the included data and that the CSG results were generated under research conditions, and therefore may not reflect performance in routine settings. Conclusions The CSG performed well at the 30% threshold. Its high NPV suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR- render the test suitable to confirm and exclude G6PDd. Further operational studies are needed to confirm the utility of the test in remote endemic settings., Author(s): Benedikt Ley 1,*, Ari Winasti Satyagraha 2, Hisni Rahmat 2, Michael E. von Fricken 3, Nicholas M. Douglas 1, Daniel A. Pfeffer 1, Fe Espino 4, Lorenz von Seidlein [...]

Byline: Mita. Sarkar, C. Sathyavani, Zachariah. Varghese A 34-year-old female, G2P1L1, presented at 40 weeks' gestation in active labour and requested for epidural analgesia. She had a previous normal vaginal [...]

Background Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. Methods and findings Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. Conclusions In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis., Author(s): Robert J. Commons 1,2,*, Julie A. Simpson 3, Kamala Thriemer 1, Tesfay Abreha 4, Ishag Adam 5, Nicholas M. Anstey 1, Ashenafi Assefa 6, Ghulam R. Awab 7,8, J. [...]