TTN as a candidate gene for distal arthrogryposis type 10 pathogenesis.

BACKGROUND: Arthrogryposis is a medical term used to describe congenital contractures which often affect multiple limbs. Distal arthrogryposis (DA) is one of the major categories of arthrogryposis that primarily affects the distal parts of the body, i.e., the hands and the legs. Although ten different types and several subtypes of DAs have been described, the genes associated with each of these DAs are yet to be characterized. Distal arthrogryposis type 10 (DA10) is a rare genetic disease, which is distinguished from the other arthrogryposis types by plantar flexion contractures resulting in toe-walking during infancy as well as variability in contractures of the hip, hamstring, elbow, wrist and finger joints with no ocular or neurological abnormalities. Symptoms of DA10 indicate impairment specifically in the musculoskeletal system. DA10 is still poorly studied. AIM: The objective of this study was to identify the candidate gene for DA10 by scrutinizing the protein-protein interaction (PPI) networks using in silico tools. RESULTS: Among the genes that reside within the previously reported genomic coordinates (human chromosome assembly 38 or GRCh38 coordinates 2:179,700,000-188,500,000) of the causative agent of DA10, only TTN (the gene that codes for the protein Titin or TTN) follows the expression pattern similar to the other known DA associated genes and its expression is predominant in the skeletal and heart muscles. Titin also participates in biological pathways and processes relevant to arthrogryposes. TTN-related known skeletal muscle disorders follow the autosomal-dominant pattern of inheritance, which is a common characteristic of distal arthrogryposes as well. CONCLUSION: Based on the findings of the analyses and their correlation with previous reports, TTN appears to be the candidate gene for DA10. Our attempt to discover a potential candidate gene may eventually lead to an understanding of disease mechanism and possible treatment strategies, as well as demonstrate the suitability of PPI in the search for candidate genes.

Retraction: Severe Dengue With Multisystem Inflammatory Syndrome in Children Due to COVID-19: A Co-infection Case Series.

[This retracts the article DOI: 10.7759/cureus.19516.].

Severe Dengue With Multisystem Inflammatory Syndrome in Children Due to COVID-19: A Co-infection Case Series.

Severe dengue with the multisystem inflammatory syndrome in children (MIS-C) can be difficult to diagnose as both diseases have similar symptoms and laboratory findings. Bangladesh is currently facing a double burden of severe dengue and SARS-CoV-2 infection. Co-infection with these viruses can result in severe morbidity. Worldwide this co-infection is rare. However, we present five cases of severe dengue with possible MIS-C due to SARS-CoV-2 infection in children. All the children presented with shock with variable degrees of plasma leakage. Mucocutaneous and gastrointestinal involvement were common. All tested positive for dengue nonstructural protein 1 antigen on the second to the third day of fever and tested positive for anti-SARS-CoV-2 IgG by enzyme-linked immunosorbent assay. Echocardiographic evaluation in all patients showed coronary arterial abnormalities. Cardiac enzymes were abnormal, and there were raised inflammatory markers and abnormal coagulation profiles. One patient had neurological involvement and needed mechanical ventilatory support. All cases were successfully managed according to dengue shock syndrome guidelines and required intravenous immunoglobulin with prednisolone, aspirin, and in some cases, enoxaparin for the management of coronary arterial involvements, which is not a documented feature for severe dengue infection, but typically found in MIS-C due to SARS-CoV-2 infection or Kawasaki disease. This case series aims to describe the possibility of co-infection of severe dengue with MIS-C due to SARS-CoV-2 infection in a dengue-endemic region during the coronavirus disease 2019 (COVID-19) pandemic, and alternatively, dengue virus as an unusual etiology for Kawasaki disease was also entertained. Severe dengue in endemic regions can coexist with COVID-19 during an outbreak, making it hard to diagnose. It can be fatal without early, appropriate management.

Sequence of refusals for donor quality, organ utilization, and survival after lung transplantation.

BACKGROUND: Lung donor utilization rates remain low, with many organs refused for donor quality. However, some centers have successfully transplanted these organs despite multiple refusals for donor quality (RDQs) by other centers. We hypothesized that the number of refusals due to donor quality does not impact post-transplant outcomes. METHODS: Lung transplants (LTxs) from 2006 to 2015, identified using the United Network for Organ Sharing (UNOS) database, were matched against the potential transplant recipient (PTR) data set by donor identification. Transplants were categorized into 2 groups: low RDQ (0 to 3 RDQs) and high RDQ (>3 RDQs). Post-transplant survival and predictors for high RDQ were observed using Kaplan‒Meier and logistic regression analyses, respectively. RESULTS: Of 10,126 adult (>18 years) LTxs, 77% had at least 1 RDQ, with a median of 4 RDQs. Post-transplant 1-year survival was similar for both the low and high RDQ groups (p = 0.49). Furthermore, groups of recipients who received donors with an increasing number of RDQs (>3, >6, or >10) also had similar post-transplant 1-year survival (p = 0.77). Treatment for rejection within 1 year and intubation at 72 hours post-transplant were higher in the high RDQ group (p < 0.01). An inverse relationship was identified between the number of RDQs and likelihood of utilization. After 10 RDQs, the likelihood of utilization varied significantly by donor characteristics. CONCLUSIONS: Lung transplant survival is not associated with number of refusals due to donor quality. When determining whether an organ is suitable for transplant, the number of refusals due to donor quality should not influence one's decision, especially in this era of limited donor supply.

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

RATIONALE : Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. AIMS : The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. STUDY DESIGN : This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. OUTCOMES : The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Missed opportunities for diagnosis and treatment of diabetes, hypertension, and hypercholesterolemia in a Mexican American population, Cameron County Hispanic Cohort, 2003-2008.

INTRODUCTION: Diabetes, hypertension, and hypercholesterolemia are common chronic diseases among Hispanics, a group projected to comprise 30% of the US population by 2050. Mexican Americans are the largest ethnically distinct subgroup among Hispanics. We assessed the prevalence of and risk factors for undiagnosed and untreated diabetes, hypertension, and hypercholesterolemia among Mexican Americans in Cameron County, Texas. METHODS: We analyzed cross-sectional baseline data collected from 2003 to 2008 in the Cameron County Hispanic Cohort, a randomly selected, community-recruited cohort of 2,000 Mexican American adults aged 18 or older, to assess prevalence of diabetes, hypertension, and hypercholesterolemia; to assess the extent to which these diseases had been previously diagnosed based on self-report; and to determine whether participants who self-reported having these diseases were receiving treatment. We also assessed social and economic factors associated with prevalence, diagnosis, and treatment. RESULTS: Approximately 70% of participants had 1 or more of the 3 chronic diseases studied. Of these, at least half had had 1 of these 3 diagnosed, and at least half of those who had had a disease diagnosed were not being treated. Having insurance coverage was positively associated with having the 3 diseases diagnosed and treated, as were higher income and education level. CONCLUSIONS: Although having insurance coverage is associated with receiving treatment, important social and cultural barriers remain. Failure to provide widespread preventive medicine at the primary care level will have costly consequences.

Socioeconomic status and prevalence of obesity and diabetes in a Mexican American community, Cameron County, Texas, 2004-2007.

INTRODUCTION: Mexican Americans are at increased risk for obesity and diabetes. We established a cohort on the United States-Mexico border to determine the prevalence of obesity and diabetes in this Mexican American population and to see whether minor economic advantages had any effect on health. METHODS: We randomly selected and extensively documented 810 people aged 35 to 64 years. Weighted data were analyzed to establish prevalence of obesity and diabetes and other markers of poor health such as elevated glycated hemoglobin levels. RESULTS: Rates of obesity (body mass index > or = 30 kg/m(2)) were 57% in the first (lower) of 4 socioeconomic strata by income and were 55.5% in the third (higher). People in the higher socioeconomic stratum were significantly less likely to have undiagnosed diabetes (2% vs 9%). Among people aged 55 to 64 years, rates of diabetes were significantly higher among those in the lower socioeconomic stratum than among those in the higher stratum. Rates of undiagnosed diabetes had similar differences. Approximately three-fourths of the respondents reported having no health insurance, and we found no difference between people in different socioeconomic strata. CONCLUSION: Rates of obesity and diabetes in this border community are among the highest in the United States. Belonging to the lower socioeconomic stratum significantly increased the likelihood of having undiagnosed diabetes and, in patients too young to be eligible for Medicare, the overall risk of developing diabetes. Modest improvement in income has a beneficial effect on health in this racial/ethnic minority community.

Simplified dosing of gentamicin for treatment of sepsis in Bangladeshi neonates.

Extended-interval dosing of gentamicin has several advantages over conventional multiple-daily dosing for the treatment of sepsis. The study was conducted to evaluate the pharmacokinetics of gentamicin for the treatment of neonatal sepsis in predetermined doses at 24- or 48-hour intervals, according to weight category, and to develop a simplified protocol for use in peripheral healthcare settings in developing countries. This prospective observational study was conducted among 59 neonates admitted to the Special Care Nursery at Dhaka Shishu Hospital, Bangladesh, with suspected sepsis and treated with antibiotics, including gentamicin. Intravenous dosing of gentamicin according to weight category was: 10 mg every 48 hours if the infant weighed < 2,000 g (n = 23), 10 mg every 24 hours if the infant weighed 2,000-2,249 g (n = 12), or 13.5 mg every 24 hours if the infant weighed 2,500-3,000 g (n = 24). Peak and trough concentrations of gentamicin and the presence of signs of nephrotoxicity and ototoxicity were determined. The mean +/- standard deviation peak concentration of gentamicin was 12.3 +/- 3.7 microg/mL in infants weighing < 2,000 g, 9.6 +/- 3.1 microg/mL in infants 2,000-2,249 g, and 10.0 +/- 3.4 microg/mL in infants 2,500-3,000 g. Initial peak concentration of gentamicin was > 12 microg/mL in 28.8% and initial trough concentration was > 2 microg/mL in 6.8% of the subjects. No signs of nephrotoxicity or ototoxicity were detected. Favourable pharmacokinetic parameters found with the simplified dosing regimen suggest that it is safe for the treatment of neonatal sepsis.

Safety and effect of chlorhexidine skin cleansing on skin flora of neonates in Bangladesh.

BACKGROUND: Chlorhexidine cleansing of newborn skin is a highly promising intervention for reducing neonatal mortality in developing countries, yet little is known of the mechanism of action. This study examined the impact of a single skin cleansing of hospitalized newborn infants in Bangladesh with baby wipes containing 0.25% chlorhexidine on both qualitative and quantitative skin flora. METHODS: Within 72 hours of birth, the skin of newborns admitted to Dhaka Shishu Hospital was wiped with baby wipes containing 0.25% chlorhexidine (n = 67) or placebo (n = 66) solution. Skin condition was assessed and skin swabs were taken from 3 sites (axillary, peri-umbilical, inguinal) at baseline and 2 hours, 24 hours, 3 days and 7 days after treatment. Skin flora was quantified and colonizing species were identified. FINDINGS: Skin cleansing with chlorhexidine had no adverse effects on skin condition, and resulted in minimal reduction (mean 0.5 degrees C) in body temperature. Positive skin culture rates 2 hours after skin cleansing were approximately 35%-55% lower than the baseline rates for placebo and chlorhexidine groups at all 3 sites. For the chlorhexidine group, positive skin culture rates remained significantly lower than the baseline rates for 24 hours to 3 days, whereas for the placebo group, beyond the first 2-hour follow-up, these values were not lower than baseline in any of the 3 sites. INTERPRETATION: Chlorhexidine skin treatment produced more extended skin cleansing effects than the placebo treatment. It is possible that the quantitative and qualitative reductions observed in the skin flora might contribute to reducing neonatal infections.

Determination of extended-interval gentamicin dosing for neonatal patients in developing countries.

BACKGROUND: Infectious diseases account for an estimated 36% of neonatal deaths globally. The purpose of this study was to determine safe, effective, simplified dosing regimens of gentamicin for treatment of neonatal sepsis in developing countries. METHODS: Neonates with suspected sepsis in the neonatal intensive care unit (NICU) at Christian Medical College and Hospital (CMC), Vellore, India (n = 49), and Dhaka Shishu Hospital (DSH), Bangladesh (n = 59), were administered gentamicin intravenously according to the following regimens: (1) 10 mg every 48 hours for neonates <2000 g; (2) 10 mg every 24 hours for neonates 2000-2249 g; and (3) 13.5 mg every 24 hours for neonates > or =2500 g. Serum gentamicin concentration (SGC) at steady state and pharmacokinetic indices were determined. Renal function was followed while under treatment and hearing was examined 6 weeks to 3 months after discharge. RESULTS: All neonates, except 1 weighing 2000-2249 g at DSH, had a peak SGC >4 microg/mL. Overall, 5 (10%) and 17 (29%) infants had a peak SGC level > or =12 microg/mL from CMC and DSH, respectively, and 10 (20%) and 4 (7%) cases from CMC and DSH, respectively, had a trough SGC level > or =2 microg/mL. However, no infant <2000 g had a trough SGC level > or =2 microg/mL. We found no evidence of gentamicin nephrotoxicity or ototoxicity. CONCLUSION: Safe, therapeutic gentamicin dosing regimens were identified for treatment of neonatal sepsis in developing country settings. Administration of these doses could be simplified through use of Uniject, a prefilled, single injection device designed to make injections safe and easy to deliver in developing country settings.