Examination of Huntington\u27s disease with atypical clinical features in a Bangladeshi family tree

Atypical manifestation of Huntington\u27s disease (HD) could inform ongoing research into HD genetic modifiers not present in the primarily European populations studied to date. This work demonstrates that expanding HD genetic testing into under-resourced healthcare settings can benefit both local communities and ongoing research into HD etiology and new therapies

Mechanical Circulatory Support: a Comprehensive Review With a Focus on Women.

PURPOSE OF THE REVIEW: The purpose of this review is to analyze the evidence for use of mechanical circulatory support (MCS) with a focus on women, namely, intra-aortic balloon pump (IABP), Impella, ventricular assist devices (VAD), and extracorporeal membrane oxygenation (ECMO). RECENT FINDINGS: There is paucity of data examining management options for cardiogenic shock (CS) in women specifically. In published data, although only a minority of MCS recipients (33%) were women, there is a trend toward even lower use in women relative to men over time. Women presenting with CS tend to have a higher risk profile including older age, greater comorbidities, higher Society of Cardiothoracic Surgery (STS) mortality scores, more hypotension and index vasopressor requirements, and longer duration of CS. Overall, women receiving mechanical support suffer increased bleeding and vascular complications and have higher 30-day readmission rates. The incidence of cardiogenic shock (CS) has been rising at a higher rate in women compared to men. Women in CS tend to present with an overall higher risk profile including older age, greater burden of medical comorbidities, more hypotension and index vasopressor requirements, higher STS mortality scores, and more out-of-hospital cardiac arrest. After adjusting for comorbidities and traditional cardiovascular risk factors, mortality remained higher in younger women compared to men of similar age. In spite of these facts, evidence points to the underutilization of support devices in eligible female patients. Higher complication rates, such as vascular complications requiring surgery and bleeding requiring transfusion, may be deterring factors that limit the use of MCS and hinderoperator confidence and experience with devices in women. This suggests that future research should address the sex disparities in outcomes of contemporary MCS practices

Examination of Huntington's disease with atypical clinical features in a Bangladeshi family tree

Atypical manifestation of Huntington's disease (HD) could inform ongoing research into HD genetic modifiers not present in the primarily European populations studied to date. This work demonstrates that expanding HD genetic testing into under‐resourced healthcare settings can benefit both local communities and ongoing research into HD etiology and new therapies

A multicenter observational study on outcomes of moderate and severe pediatric traumatic brain injuries-time to reappraise thresholds for treatment

Purpose: Children with moderate traumatic brain injury (modTBI) (Glasgow Coma Scale (GCS) 9-13) may benefit from better stratification. We aimed to compare neurocritical care utilization and functional outcomes between children with high GCS modTBI (hmodTBI, GCS 11-13), low GCS modTBI (lmodTBI, GCS 9-10), and severe TBI (sTBI, GCS ≤ 8). We hypothesized that patients with lmodTBI have higher neurocritical care needs and worse outcomes than patients with hmodTBI and are similar to patients with sTBI. Methods: Prospective observational study from June 2018 to October 2022 in 28 pediatric intensive care units (PICU) in Asia, South America, and Europe. We included children (age \u3c 18 years) with modTBI and sTBI admitted to PICU and measured functional outcomes at 3 months using the Glasgow Outcome Scale-Extended Pediatric Revision (GOS-E Peds, scale 1-8, 1 = upper good recovery, 8 = death). Results: We analyzed 409 patients: 98 (24%) and 311 (76%) with modTBI and sTBI, respectively. Patients with lmodTBI (vs. hmodTBI) were more likely to have invasive ICP monitoring (32.3% vs. 4.5%, p \u3c 0.001), longer PICU stay (days, median [IQR]; 5.00 [4.00, 9.75] vs 4.00 [2.00, 5.00], p = 0.007), and longer hospital stay (days, median [IQR]: 13.00 [8.00, 17.00] vs. 8.00 [5.00, 12, 25], p = 0.015). Median GOS-E Peds scores were significantly different (hmodTBI (1.00 [1.00, 3.00]), lmodTBI (3.00 [IQR 2.00, 5.75]), and sTBI (5.00 [IQR 1.00, 6.00]) (p \u3c 0.001)). After adjusting for age, sex, presence of polytrauma and cerebral edema, lmodTBI, and sTBI remained significantly associated with higher GOS-E scores (adjusted coefficient (standard error): 1.24 (0.52), p = 0.018, and 1.27 (0.33), p \u3c 0.001, respectively) compared with hmodTBI. Conclusions: Children with lmodTBI have higher rates of neurocritical care utilization and worse functional outcomes than those with hmodTBI but better than those with sTBI. Children with lmodTBI may benefit from guideline-based management similar to what is implemented in children with sTBI. This work was performed in hospitals within the PACCMAN and LARed networks. No reprints will be ordere

Molecular Analysis of Glucose-6-Phosphate Dehydrogenase Gene Mutations in Bangladeshi Individuals.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked human enzyme defect of red blood cells (RBCs). Individuals with this gene defect appear normal until exposed to oxidative stress which induces hemolysis. Consumption of certain foods such as fava beans, legumes; infection with bacteria or virus; and use of certain drugs such as primaquine, sulfa drugs etc. may result in lysis of RBCs in G6PD deficient individuals. The genetic defect that causes G6PD deficiency has been identified mostly as single base missense mutations. One hundred and sixty G6PD gene mutations, which lead to amino acid substitutions, have been described worldwide. The purpose of this study was to detect G6PD gene mutations in hospital-based settings in the local population of Dhaka city, Bangladesh. Qualitative fluorescent spot test and quantitative enzyme activity measurement using RANDOX G6PDH kit were performed for analysis of blood specimens and detection of G6PD-deficient participants. For G6PD-deficient samples, PCR was done with six sets of primers specific for G6PD gene. Automated Sanger sequencing of the PCR products was performed to identify the mutations in the gene. Based on fluorescence spot test and quantitative enzyme assay followed by G6PD gene sequencing, 12 specimens (11 males and one female) among 121 clinically suspected patient-specimens were found to be deficient, suggesting a frequency of 9.9% G6PD deficiency. Sequencing of the G6PD-deficient samples revealed c.C131G substitution (exon-3: Ala44Gly) in six samples, c.G487A substitution (exon-6:Gly163Ser) in five samples and c.G949A substitution (exon-9: Glu317Lys) of coding sequence in one sample. These mutations either affect NADP binding or disrupt protein structure. From the study it appears that Ala44Gly and Gly163Ser are the most common G6PD mutations in Dhaka, Bangladesh. This is the first study of G6PD mutations in Bangladesh

Impaired acylcarnitine profile in transfusion-dependent beta-thalassemia major patients in Bangladesh

Patients with beta-thalassemia major (BTM) suffer from fatigue, poor physical fitness, muscle weakness, lethargy, and cardiac complications which are related to an energy crisis. Carnitine and acylcarnitine derivatives play important roles in fatty acid oxidation, and deregulation of carnitine and acylcarnitine metabolism may lead to an energy crisis. The present study aimed to investigate carnitine and acylcarnitine metabolites to gain an insight into the pathophysiology of BTM. Dried blood spots of 45 patients with BTM and 96 age-matched healthy controls were analyzed for free carnitine and 24 acylcarnitines by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Although medium chain acylcarnitine levels were similar in the patients with BTM and healthy controls, free carnitine, short chain acylcarnitines, long chain acylcarnitines, and total acylcarnitine levels were significantly lower in patients with BTM than in the healthy controls (P < 0.05). Moreover, an impaired fatty acid oxidation rate was observed in the patients with BTM, as manifested by decreased fatty acid oxidation indicator ratios, namely C2/C0 and (C2 + C3)/C0. Furthermore, an increase in the C0/(C16 + C18) ratio indicated reduced carnitine palmitoyltransferase-1 (CPT-1) activity in the patients with BTM compared with that in the healthy controls. Thus, a low level of free carnitine and acylcarnitines together with impaired CPT-1 activity contribute to energy crisis-related complications in the patients with BTM. Keywords: Beta-thalassemia major, Carnitine-acylcarnitine levels, Impairment in fatty acid oxidation, Carnitine Palmitoyltransferase-1 activit

High resolution melting curve analysis enables rapid and reliable detection of G6PD variants in heterozygous females

Abstract Background Like glucose-6-phosphate dehydrogenase (G6PD) deficient hemizygous males and homozygous females, heterozygous females could also manifest hemolytic crisis, neonatal hyperbilirubinemia or kernicterus upon exposure to oxidative stress induced by certain foods such as fava beans, drugs or infections. Although hemizygous males and homozygous females are easily detected by conventional G6PD enzyme assay method, the heterozygous state could be missed by the conventional methods as the mosaic population of both normal and deficient RBCs circulates in the blood. Thus the present study aimed to apply high resolution melting (HRM) curve analysis approach to see whether HRM could be used as a supplemental approach to increase the chance of detection of G6PD heterozygosity. Results Sixty-three clinically suspected females were evaluated for G6PD status using both enzyme assay and HRM analysis. Four out of sixty-three participants came out as G6PD deficient by the enzyme assay method, whereas HRM approach could identify nine participants with G6PD variants, one homozygous and eight heterozygous. Although only three out of eight heterozygous samples had G6PD enzyme deficiency, the HRM-based heterozygous G6PD variants detection for the rest of the samples with normal G6PD enzyme activities could have significance because their newborns might fall victim to serious consequences under certain oxidative stress. Conclusions In addition to the G6PD enzyme assay, HRM curve analysis could be useful as a supplemental approach for detection of G6PD heterozygosity

High resolution melting curve analysis targeting the HBB gene mutational hot-spot offers a reliable screening approach for all common as well as most of the rare beta-globin gene mutations in Bangladesh

Abstract Background Bangladesh lies in the global thalassemia belt, which has a defined mutational hot-spot in the beta-globin gene. The high carrier frequencies of beta-thalassemia trait and hemoglobin E-trait in Bangladesh necessitate a reliable DNA-based carrier screening approach that could supplement the use of hematological and electrophoretic indices to overcome the barriers of carrier screening. With this view in mind, the study aimed to establish a high resolution melting (HRM) curve-based rapid and reliable mutation screening method targeting the mutational hot-spot of South Asian and Southeast Asian countries that encompasses exon-1 (c.1 - c.92), intron-1 (c.92 + 1 - c.92 + 130) and a portion of exon-2 (c.93 - c.217) of the HBB gene which harbors more than 95% of mutant alleles responsible for beta-thalassemia in Bangladesh. Results Our HRM approach could successfully differentiate ten beta-globin gene mutations, namely c.79G > A, c.92 + 5G > C, c.126_129delCTTT, c.27_28insG, c.46delT, c.47G > A, c.92G > C, c.92 + 130G > C, c.126delC and c.135delC in heterozygous states from the wild type alleles, implying the significance of the approach for carrier screening as the first three of these mutations account for ~85% of total mutant alleles in Bangladesh. Moreover, different combinations of compound heterozygous mutations were found to generate melt curves that were distinct from the wild type alleles and from one another. Based on the findings, sixteen reference samples were run in parallel to 41 unknown specimens to perform direct genotyping of the beta-thalassemia specimens using HRM. The HRM-based genotyping of the unknown specimens showed 100% consistency with the sequencing result. Conclusions Targeting the mutational hot-spot, the HRM approach could be successfully applied for screening of beta-thalassemia carriers in Bangladesh as well as in other countries of South Asia and Southeast Asia. The approach could be a useful supplement of hematological and electrophortic indices in order to avoid false positive and false negative results

Bacterial and viral pathogen spectra of acute respiratory infections in under-5 children in hospital settings in Dhaka city.

The study aimed to examine for the first time the spectra of viral and bacterial pathogens along with the antibiotic susceptibility of the isolated bacteria in under-5 children with acute respiratory infections (ARIs) in hospital settings of Dhaka, Bangladesh. Nasal swabs were collected from 200 under-five children hospitalized with clinical signs of ARIs. Nasal swabs from 30 asymptomatic children were also collected. Screening of viral pathogens targeted ten respiratory viruses using RT-qPCR. Bacterial pathogens were identified by bacteriological culture methods and antimicrobial susceptibility of the isolates was determined following CLSI guidelines. About 82.5% (n = 165) of specimens were positive for pathogens. Of 165 infected cases, 3% (n = 6) had only single bacterial pathogens, whereas 43.5% (n = 87) cases had only single viral pathogens. The remaining 36% (n = 72) cases had coinfections. In symptomatic cases, human rhinovirus was detected as the predominant virus (31.5%), followed by RSV (31%), HMPV (13%), HBoV (11%), HPIV-3 (10.5%), and adenovirus (7%). Streptococcus pneumoniae was the most frequently isolated bacterial pathogen (9%), whereas Klebsiella pneumaniae, Streptococcus spp., Enterobacter agglomerans, and Haemophilus influenzae were 5.5%, 5%, 2%, and 1.5%, respectively. Of 15 multidrug-resistant bacteria, a Klebsiella pneumoniae isolate and an Enterobacter agglomerans isolate exhibited resistance against more than 10 different antibiotics. Both ARI incidence and predominant pathogen detection rates were higher during post-monsoon and winter, peaking in September. Pathogen detection rates and coinfection incidence in less than 1-year group were significantly higher (P = 0.0034 and 0.049, respectively) than in 1-5 years age group. Pathogen detection rate (43%) in asymptomatic cases was significantly lower compared to symptomatic group (P<0.0001). Human rhinovirus, HPIV-3, adenovirus, Streptococcus pneumonia, and Klebsiella pneumaniae had significant involvement in coinfections with P values of 0.0001, 0.009 and 0.0001, 0.0001 and 0.001 respectively. Further investigations are required to better understand the clinical roles of the isolated pathogens and their seasonality

Age-Specific Cut-off Values of Amino Acids and Acylcarnitines for Diagnosis of Inborn Errors of Metabolism Using Liquid Chromatography Tandem Mass Spectrometry

Liquid Chromatography tandem mass spectrometry (LC-MS/MS) is used for the diagnosis of more than 30 inborn errors of metabolisms (IEMs). Accurate and reliable diagnosis of IEMs by quantifying amino acids (AAs) and acylcarnitines (ACs) using LC-MS/MS systems depend on the establishment of age-specific cut-offs of the analytes. This study aimed to (1) determine the age-specific cut-off values of AAs and ACs in Bangladesh and (2) validate the LC-MS/MS method for diagnosis of the patients with IEMs. A total of 570 enrolled healthy participants were divided into 3 age groups, namely, (1) newborns (1-7 days), (2) 8 days–7 years, and (3) 8–17 years, to establish the age-specific cut-offs for AAs and ACs. Also, 273 suspected patients with IEMs were enrolled to evaluate the reliability of the established cut-off values. Quantitation of AAs and ACs was performed on an automated LC-MS/MS system using dried blood spot (DBS) cards. Then the specimens of the enrolled clinically suspected patients were analyzed by the established method. Nine patients came out as screening positive for different IEMs, including two borderline positive cases of medium-chain acyl-CoA dehydrogenase deficiency (MCAD). A second-tier test for confirmation of the screening positive cases was conducted by urinary metabolic profiling using gas chromatography- mass spectrometry (GC-MS). Out of 9 cases that came out as screening positive by LC-MS/MS, seven cases were confirmed by urinary GC-MS analysis including 3 cases with phenylketonuria, 1 with citrullinemia type II, 1 with methylmalonic acidemia, 1 with isovaleric acidemia and 1 with carnitine uptake defect. Two borderline positive cases with MCAD were found negative by urinary GC-MS analysis. In conclusion, along with establishment of a validated LC-MS/MS method for quantitation of AAs and ACs from the DBS cards, the study also demonstrates the presence of predominantly available IEMs in Bangladesh