Inhibition of CD38 with the Thiazoloquin(az)olin(on)e 78c Protects the Heart against Postischemic Injury.

Inhibition of and genetic deletion of the NAD(P)+ hydrolase [NAD(P)ase] CD38 have been shown to protect against ischemia/reperfusion (I/R) injury in rat and mouse hearts. CD38 has been shown to enhance salvage of NADP(H), which in turn prevents impairment of endothelial nitric oxide synthase function, a hallmark of endothelial dysfunction. Despite growing evidence for a role of CD38 in postischemic injury, until recently there had been a lack of potent CD38 inhibitors. Recently, a new class of thiazoloquin(az)olin(on)e compounds were identified as highly potent and specific CD38 inhibitors. Herein, we investigate the ability of one of these compounds, 78c, to inhibit CD38 and protect the heart in an ex vivo model of myocardial I/R injury. The potency and mechanism of CD38 inhibition by 78c was assessed in vitro using recombinant CD38. The dose-dependent tissue uptake of 78c in isolated mouse hearts was determined, and high tissue permeability of 78c was observed when delivered in perfusate. Treatment of hearts with 78c was protective against both postischemic endothelial and cardiac myocyte injury, with preserved nitric oxide synthase-dependent vasodilatory and contractile function, respectively. Myocardial infarction was also significantly decreased in 78c-treated hearts, with preserved levels of high-energy phosphates. Protective effects peaked at 10 µM treatment, and similar protection without toxicity was seen at 5-fold higher doses. Overall, 78c was shown to be a potent and biologically active CD38 inhibitor with favorable tissue uptake and marked protective effects against I/R injury with enhanced preservation of contractile function, coronary flow, and decreased infarction.

A Case Report of Dermatofibrosarcoma Protuberans and Refractory Hypomagnesemia: Unveiling a Paraneoplastic Syndrome.

Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive soft tissue sarcoma of the skin. DFSP typically presents as an asymptomatic, firm plaque in its earliest stage, gradually enlarging over months to years. This case report delineates a singular instance involving a 66-year-old female patient previously diagnosed with and treated for DFSP. The individual presented with a recurrent history of hospital admissions, manifesting symptoms of loose stools, generalised weakness, and diminished appetite. Investigations revealed persistent hypomagnesemia. The patient was treated with magnesium correction. Eventually, all complaints were resolved, and the patient was discharged satisfactorily. This case report aims to elucidate an exceptional correlation between DFSP and hypomagnesemia, characterised as its paraneoplastic syndrome (PNS). This study intends to comprehensively outline the clinical manifestations, diagnostic approaches, and therapeutic interventions pertaining to this distinct association.

Utility of Platelet Indices as Prognostic Markers of Sepsis: A Medical Intensive Care Unit-Based Cross-Sectional Study at a Rural Setup.

Introduction Even after the breakthrough advancements in the management and prognostic scoring of sepsis, it remains an important cause of morbidity and mortality encountered in intensive care units (ICUs) throughout the globe. This study highlights the utility of platelet indices as prognostic markers of sepsis. Methods In the present prospective cross-sectional study, a total of 177 patients with sepsis were enrolled using the Sepsis-3 criteria. The platelet indices were then linked to severity using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. The correlation of platelet indices to morbidity in terms of the length of ICU stay, need for a mechanical ventilator, types of infection, and mortality was also assessed. Results The results showed that mean platelet volume (p = 0.004) and platelet distribution width (PDW; p = 0.009) were positively correlated with the severity of sepsis. Among all the parameters, plateletcrit (%) was the best predictor of the need for an invasive mechanical ventilator at a cutoff point of ≤0.22 with a 60.90% chance of correctly predicting the need for an invasive mechanical ventilator, as was mortality at a cutoff point of ≤0.22 with a 67.30% chance of correct prediction. Among the platelet indices, only PDW showed a significant association with growth in culture because patients with growth had significantly higher PDW as compared to those who did not have growth (22.4 ± 4.47 vs 20.81 ± 4.29, p = 0.011). Conclusion The difference between the survivors and non-survivor groups was statistically significant for platelet indices, making them easily available, cost-effective, and useful prognostic markers for patients in septic shock. This will help in easy understanding and preventing its morbid complications, even at the primary care physician level.

Electrocardiogram (EKG) knowledge and interpretation proficiency among healthcare professionals in Pakistan: a prospective cross-sectional study.

Background: Electrocardiogram (EKG) is a commonly used diagnostic tool for the evaluation of the electrical activity of the heart. The purpose of this study was to assess the knowledge and interpretation proficiency of EKG among healthcare professionals (HCPs) in Pakistan. Methods: This prospective cross-sectional study was conducted among HCPs working in different healthcare settings. A structured questionnaire was used to assess the participants' theoretical knowledge and ability to interpret EKG findings. The data were analyzed using descriptive statistics and χ2 tests. The study indicates that EKG knowledge and interpretation proficiency among HCPs in Pakistan is unsatisfactory. The inadequacy of training periods of EKG training sessions and insufficient participation of HCPs in offered training opportunities put forward the need for the formation and introduction of better structured and efficient EKG training programmes. Results: A total of 511 HCPs participated in the study, 28% of whom reportedly had received formal training for EKG interpretation. About 80% of the participants correctly identified theoretical questions pertaining to EKG, while 58% of the participants were able to accurately interpret EKG findings, and most HCPs (69.9%) read fewer than ten EKGs per week. Conclusion: This study demonstrates a lack of expertise and a poor understanding of EKG in HCPs of Pakistan. The low level of EKG knowledge and interpretation proficiency among HCPs may lead to diagnostic errors and poor patient outcomes. Therefore, efforts should be made to improve EKG education and training among HCPs in Pakistan.

"Pre-Histologic" Antibody-Mediated Rejection Detected by Donor-Derived Cell-Free DNA and a Novel Tissue Gene Expression Assay: A Case Report.

BACKGROUND: Despite its well-characterized association with poor long-term graft outcomes, subclinical antibody-mediated rejection (ABMR) in recipients of kidney transplants continues to pose a significant diagnostic and therapeutic challenge. Specifically, its detection currently relies on invasive histologic surveillance, a relatively uncommon practice among US transplant centers. We describe a subclinical, "pre-histologic" antibody-mediated rejection identified and characterized by a combination of novel molecular tools, donor-derived cell-free DNA (dd-cfDNA), and molecular histology. CASE REPORT: A 67-year-old kidney transplant recipient was found to have a marked elevation of dd-cfDNA on routine testing at 3 months post-transplant; other laboratory parameters were stable. A biopsy was performed, demonstrating the absence of rejection by traditional histology, but evidence of rejection was seen when tissue was evaluated using a research use molecular histology assay. Four months later, in the setting of persistently elevated dd-cfDNA, the patient developed graft dysfunction and was found to have C4d-negative ABMR, which was treated with improvement in both graft function and dd-cfDNA. CONCLUSION: This case highlighted the complementary use of dd-cfDNA and molecular histology to aid in the early detection and characterization of graft injury. Hybrid approaches combining these tools may allow more expeditious therapeutic intervention, leading to improved graft and patient outcomes.

Outcomes of Transplantation of Single Kidneys From Pediatric Donors Into Adult Recipients.

Background Organs from extreme ages have been sought after to help increase the donor pool and alleviate transplantation wait times. There has been a growing evolution of the use of pediatric donor kidneys, including the use of en bloc kidneys (EBK), to now separating them into single kidneys (SKT), allowing for transplantation of two recipients. This study reports our outcomes utilizing SKT. Methods A retrospective review of all SKT performed from 2014 to 2022 at our center was conducted. Donors >8 years of age or >25 kg in weight were excluded. Donor and recipient characteristics and outcomes were analyzed, comparing <18 kg and ≥18 kg donor cohorts. Results Between 2014 and 2022, 81 adults received SKT. Recipients' mean age, weight, and body mass index were 49 years (22-74), 74 kg (39-136), and 26.4 mg/m2 (19.6- 39.8), respectively. Donors' mean age, weight, and kidney size were 35.7 months (8-96), 17.8 kg (8-25), and 7.2 cm (4.5-8.5), respectively. At one year post-transplant, patient survival was 100%, graft survival was 98.7%, mean serum creatinine was 1.25 mg/dL, and mean glomerular filtration rate (GFR) was 68.3 ml/min. Hyperfiltration injury was seen in 43.75% of recipients. None of the outcomes correlated with any of the donor or recipient characteristics. Conclusion Our study shows excellent short-term outcomes of single pediatric kidney transplantation in adult recipients. Exploring a lower donor weight cut-off for SKT, compared to the current Organ Procurement and Transplantation Network's (OPTN's) ≥18 kg, could expand the organ pool and lead to an increased number of transplants.

The Art and Science of Kidney Transplant Offer Evaluation.

Currently, there are more than 100,000 patients on the transplant waitlist in the United States. There exists a significant gap between the supply and demand for kidney transplants. Despite this, about a quarter of kidneys recovered from deceased donors are not being utilized. There is a significant variation in kidney acceptance criteria by transplant centers. The current kidney allocation system allows transplant centers to place kidneys into appropriate recipients who may not be at the top of the list to increase organ utilization. A recent study questioned this practice of "list diving." In this editorial, we seek to support "list diving" through a discussion of the various factors a transplant center could take into consideration while evaluating organ offers.

Effect of Oral Zinc Supplementation on Serum Bilirubin Levels in Term Neonates With Hyperbilirubinemia Undergoing Phototherapy: A Double-blind Randomized Controlled Trial.

BACKGROUND: Background: Enterohepatic bilirubin circulation is one of the determinants of neonatal jaundice. OBJECTIVE: To evaluate the role of oral zinc in reducing serum bilirubin in term neonates with hyperbilirubinemia. STUDY DESIGN: Double-blind, randomized, placebo-controlled trial. PARTICIPANTS: 106 term neonates with jaundice within the phototherapy range admitted to a level III neonatal intensive care unit. INTERVENTION: Neonates were randomized and allocated to receive either oral zinc sulfate (5 mg/day) or matching placebo for 5 days. Both groups received conventional phototherapy as per American Academy of Pediatrics (AAP) guidelines. OUTCOMES: Primary: Reduction in total serum bilirubin levels at 24, 48, 72, and 96 hr after intervention. Secondary: Duration of phototherapy, and hospital stay. RESULTS: The mean (SD) total serum bilirubin levels in zinc and placebo groups were 15.3 (2.85) vs 17.1 (2.21) mg/dL (MD 1.74; P<0.001) at 24 h; 11.7 (4.46) vs. 14.62 (3.83) mg/dL (MD 2.89; P<0.001) at 48 h; 6.7 (4.77) vs 9.5 (3.70) mg/dL (MD 2.79; P <0.001) at 72 h; and 5.1 (3.95) vs 6.5 (3.70) mg/dL (MD 1,49; P=0.045) after 72 hr, respectively. The mean (SD) duration of phototherapy was significantly lower in zinc group than placebo group [ 53.42 (19.62) vs 71.4 (19.43) h; P<0.001]. There was no significant difference in hospital stay between the two groups [mean (SD) 81.05 (19.43) vs 86.25 (20.02) h; P= 0.227]. CONCLUSION: Oral zinc sulfate supplementation at a dose of 5 mg once a day along with phototherapy significantly reduced total and indirect serum bilirubin levels and also reduced the total duration of phototherapy required in the term neonatal hyperbilirubinemia, with minimal or no adverse effects.

Peroral Endoscopic Myotomy; Novice Surgeon Learning Curve.

INTRODUCTION: Peroral endoscopic myotomy (POEM) is a novel endoscopic procedure used to treat achalasia and other spastic esophageal disorders that is an alternative to Heller myotomy. We seek to define the learning curve of POEM for a foregut surgeon with no formal endoscopic or POEM training by analyzing different intraoperative factors in a single series. METHODS AND PROCEDURES: The first 38 consecutive patients undergoing POEM by a single foregut surgeon were included in this retrospective study. Inverse curve regression models were used to analyze total operative time (TOT) and total operative time per centimeter of myotomy (TOT-CM), in addition to other intraoperative variables. Clinical outcomes were reported as pre- and post-operative Eckardt Scores. RESULTS: All patients had type II achalasia with no post-operative complications observed. Eckardt scores improved postoperatively (median (range): 1 (0-4)) compared with the preoperative scores (10 (8-12)) (P < .001). The total operative time (median 76 minutes, range 51-129) decreased significantly over the course of the series (R2 = .38, P < .001), with a learning plateau at 70 minutes and a learning rate of 12 cases. Total operative time per centimeter of myotomy (median 7.08 min/cm, range 4.25 to 15.38) decreased over time (R2 = .45, P < .001), with a learning plateau at 7 minutes/cm and a learning rate of 12 cases. CONCLUSION: The number of cases for a foregut surgeon to become proficient in a POEM procedure was found to be 12-14 cases. The learning curve for a POEM in a formally trained foregut surgeon may be comparable to an endoscopically trained interventionist.

Context-aware electromagnetic design for continuously wearable biosymbiotic devices.

Imperceptible wireless wearable devices are critical to advance digital medicine with the goal to capture clinical-grade biosignals continuously. Design of these systems is complex because of unique interdependent electromagnetic, mechanic and system level considerations that directly influence performance. Typically, approaches consider body location, related mechanical loads, and desired sensing capabilities, however, design for real world application context is not formulated. Wireless power casting eliminates user interaction and the need to recharge batteries, however, implementation is challenging because the use case influences performance. To facilitate a data-driven approach to design, we demonstrate a method for personalized, context-aware antenna, rectifier and wireless electronics design that considers human behavioral patterns and physiology to optimize electromagnetic and mechanical features for best performance across an average day of the target user group. Implementation of these methods result in devices that enable continuous recording of high-fidelity biosignals over weeks without the need for human interaction.

Anti-obesity Medication Use for Adolescent Metabolic and Bariatric Surgery Patients: A Systematic Literature Review.

Bariatric surgery, in combination with pharmacotherapy, has been proven to be successful in combatting weight regain in adults; however, the use of anti-obesity medications to augment weight loss in adolescents before and after bariatric surgery is not well studied. In adolescent obese patients, the efficacy of anti-obesity pharmacotherapy before and after bariatric surgery on weight loss compared to no interventions in various studies was investigated. A PubMed literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed to identify studies related to the pharmacologic treatment of obesity in adolescents with a history of bariatric surgery. Inclusion criteria consisted of clinical trials, case reports, case series, chart reviews, systematic reviews, and meta-analyses written in English and published between 2005 and 2022 using our search criteria. Exclusion criteria were studies that investigated adults, did not include pharmacotherapy, and were not relevant to the outcome of interest. The initial search yielded 1275 results, which was reduced to 879 after removal of duplicates. After applying exclusion criteria, the number of articles was reduced to 63. Full articles were examined and 44 were excluded due to relevance. Nineteen articles were included in the qualitative analysis. A total of 2471 adolescents were treated with various types of pharmacotherapy, 65 of whom had a history of bariatric surgery. The results showed varied effects of pharmacotherapy with the different medications studied. However, the 65 patients were included in cohorts of patients with no history of bariatric surgery. These studies did not include data specific to adolescent bariatric surgery patients.  There is a wealth of evidence highlighting the efficacy of pharmacotherapy in assisting with weight loss in adolescents with obesity; however, our literature search showed a lack of studies focusing on the use of pharmacotherapy in the adolescent bariatric surgery population. Potential limitations include missing studies in our literature search, the variability in methods between studies, and the lack of standardized quality assessment. Additionally, studies involving our objective of choice regarding bariatric surgery with anti-obesity medication were limited. Clinical trials to determine the efficacy of medications as an adjunct to bariatric surgery in preventing weight regain and leading to optimal weight loss in this population are of utmost importance.

Macro-Aspartate Aminotransferase: A Benign Cause of Abnormal Laboratory Findings.

Isolated, persistent elevations of aspartate aminotransferase (AST) without plausible explanation may lead to diagnostic confusion. Macro-enzyme aspartate aminotransferase (macro-AST) is an uncommon and benign cause of persistently elevated AST levels in the absence of other diseases. We present a case of macro-AST in an otherwise healthy adult male which was confirmed by polyethylene glycol (PEG) precipitation.

Acute Massive Gastric Dilatation and Gastric Perforation as a Result of Closed-Loop Obstruction of the Stomach.

Acute massive gastric dilatation is a rare event that is usually underdiagnosed. It can occur due to multiple etiologies, including medical and surgical, or as a postoperative complication. Acute massive gastric dilatation can lead to life-threatening fatal complications, including perforation, bleeding, or shock. We report a rare case of acute massive gastric dilatation with perforation of the stomach due to closed-loop obstruction of the stomach, which occurred in a patient with cricopharyngeal carcinoma due to a kink at the feeding jejunostomy site. Early diagnosis and treatment are essential, as acute massive gastric dilatation with perforation carries high morbidity and mortality.

Feasibility of Laparoscopic Closed Cystectomy for Hepatic Hydatid Cyst in Segments VI, VII, and VIII.

Background Laparoscopic closed cystectomy of the hepatic hydatid cyst (HHC) is increasingly being performed as it has improved postoperative recovery and reduced morbidity. However, laparoscopic closed cystectomy of HHC is difficult when located in segments VI, VII, and VIII. This study aimed to assess the laparoscopic closed cystectomy feasibility of the HHC when cysts are located at the difficult access site. Methodology Seven patients out of 13 patients of HHC treated laparoscopically in the surgery department from 2014 to 2018 were included. These patients had cysts located in segments VI, VII, and VIII of the liver. All patients received perioperative albendazole, underwent ultrasonography (USG) and contrast-enhanced computed tomography for diagnosis. We noted the demographic character of all the patients, cyst's location, cyst size, type of the cyst, mean operative time, intraoperative and postoperative complications, duration of the hospital stay, and recurrence of the cyst.  Results All patients underwent laparoscopic closed cystectomy of HHC. One patient had a conversion to open procedure, and one patient had an additional thoracoscopic approach added. The mean operative time was 191.86 minutes. There were no intraoperative complications. One patient had developed a surgical site infection, and three had a minor bile leak postoperatively. The hospital stay's mean duration was four days, and there was no recurrence in the 21 months follow-up. Conclusion The laparoscopic closed cystectomy of HHC located at segments VI, VII, and VIII is feasible, safe, and cost-effective. A thorough preoperative evaluation, preparation, and radiological planning of the procedure should be done.

A Comprehensive Review of Neuronal Changes in Diabetics.

There has been an exponential rise in diabetes mellitus (DM) cases on a global scale. Diabetes affects almost every system of the body, and the nervous system is no exception. Although the brain is dependent on glucose, providing it with the energy required for optimal functionality, glucose also plays a key role in the regulation of oxidative stress, cell death, among others, which furthermore contribute to the pathophysiology of neurological disorders. The variety of biochemical processes engaged in this process is only matched by the multitude of clinical consequences resulting from it. The wide-ranging effects on the central and peripheral nervous system include, but are not limited to axonopathies, neurodegenerative diseases, neurovascular diseases, and general cognitive impairment. All language search was conducted on MEDLINE, COCHRANE, EMBASE, and GOOGLE SCHOLAR till September 2021. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "CNS," "Diabetic Neuropathy," and "Insulin." We explored the literature on diabetic neuropathy, covering its epidemiology, pathophysiology with the respective molecular pathways, clinical consequences with a special focus on the central nervous system and finally, measures to prevent and treat neuronal changes. Diabetes is slowly becoming an epidemic, rapidly increasing the clinical burden on account of its wide-ranging complications. This review focuses on the neuronal changes occurring in diabetes such as the impact of hyperglycemia on brain function and structure, its association with various neurological disorders, and a few diabetes-induced peripheral neuropathic changes. It is an attempt to summarize the relevant literature about neuronal consequences of DM as treatment options available today are mostly focused on achieving better glycemic control; further research on novel treatment options to prevent or delay the progression of neuronal changes is still needed.

Acute massive gastric dilatation as a result of closed-loop obstruction of stomach: an unusual and rare phenomenon.

Acute massive gastric dilatation (AMGD) is a rare event which is usually underdiagnosed. It can occur due to multiple etiologies, including medical and surgical, or as a postoperative complication. We report a rare case of AMGD as a result of closed-loop obstruction of the stomach following feeding jejunostomy in a patient with carcinoma oesophagus. A high index of suspicion, early diagnosis and prompt management is the key to the successful treatment. To the best of our knowledge, this is the second case report of a closed-loop obstruction of the stomach leading to AMGD in published literature.

Differential MicroRNA Signatures in the Pathogenesis of Barrett's Esophagus.

OBJECTIVES: Barrett's esophagus (BE) is the precursor lesion and a major risk factor for esophageal adenocarcinoma (EAC). Although patients with BE undergo routine endoscopic surveillance, current screening methodologies have proven ineffective at identifying individuals at risk of EAC. Since microRNAs (miRNAs) have potential diagnostic and prognostic value as disease biomarkers, we sought to identify an miRNA signature of BE and EAC. METHODS: High-throughput sequencing of miRNAs was performed on serum and tissue biopsies from 31 patients identified either as normal, gastroesophageal reflux disease (GERD), BE, BE with low-grade dysplasia (LGD), or EAC. Logistic regression modeling of miRNA profiles with Lasso regularization was used to identify discriminating miRNA. Quantitative reverse transcription polymerase chain reaction was used to validate changes in miRNA expression using 46 formalin-fixed, paraffin-embedded specimens obtained from normal, GERD, BE, BE with LGD or HGD, and EAC subjects. RESULTS: A 3-class predictive model was able to classify tissue samples into normal, GERD/BE, or LGD/EAC classes with an accuracy of 80%. Sixteen miRNAs were identified that predicted 1 of the 3 classes. Our analysis confirmed previous reports indicating that miR-29c-3p and miR-193b-5p expressions are altered in BE and EAC and identified miR-4485-5p as a novel biomarker of esophageal dysplasia. Quantitative reverse transcription polymerase chain reaction validated 11 of 16 discriminating miRNAs. DISCUSSION: Our data provide an miRNA signature of normal, precancerous, and cancerous tissue that may stratify patients at risk of progressing to EAC. We found that serum miRNAs have a limited ability to distinguish between disease states, thus limiting their potential utility in early disease detection.