Cardiac monoamine oxidase-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control.

AIMS: A mechanistic link between depression and risk of arrhythmias could be attributed to altered catecholamine metabolism in the heart. Monoamine oxidase-A (MAO-A), a key enzyme involved in catecholamine metabolism and longstanding antidepressant target, is highly expressed in the myocardium. The present study aimed to elucidate the functional significance and underlying mechanisms of cardiac MAO-A in arrhythmogenesis. METHODS AND RESULTS: Analysis of the TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared with those treated with selective serotonin reuptake inhibitors. This effect was phenocopied in mice with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef), which showed a significant reduction in both incidence and duration of catecholamine stress-induced ventricular tachycardia compared with wild-type mice. Additionally, cMAO-Adef cardiomyocytes exhibited altered Ca2+ handling under catecholamine stimulation, with increased diastolic Ca2+ reuptake, reduced diastolic Ca2+ leak, and diminished systolic Ca2+ release. Mechanistically, cMAO-Adef hearts had reduced catecholamine levels under sympathetic stress, along with reduced levels of reactive oxygen species and protein carbonylation, leading to decreased oxidation of Type II PKA and CaMKII. These changes potentiated phospholamban (PLB) phosphorylation, thereby enhancing diastolic Ca2+ reuptake, while reducing ryanodine receptor 2 (RyR2) phosphorylation to decrease diastolic Ca2+ leak. Consequently, cMAO-Adef hearts exhibited lower diastolic Ca2+ levels and fewer arrhythmogenic Ca2+ waves during sympathetic overstimulation. CONCLUSION: Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress.

Renal Denervation in the Management of Resistant Hypertension: A Comprehensive Review of Literature.

Resistant hypertension is a condition in which blood pressure remains elevated despite using 3 or more antihypertensive medications. Though contemporary antihypertensive drug therapies have been essential in treating hypertension, in recent years different studies have explored renal denervation (RDN) as an adjunctive or a replacement modality. Here we summarize an open-label, Symplicity HTN 2 trial and 7 randomized, sham-controlled clinical trials: Spyral-HTN OFF MEDS (Spyral Pivotal), Spyral-HTN ON MEDS, RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, RADIANCE II, SYMPLICITY-HTN 1, and SYMPLICITY-HTN 3, which evaluated safety and efficacy of multiple renal denervation systems (RDN) at lowering blood pressure from baseline, and in comparison, to control group. Prior systematic reviews and meta-analyses evinced a modest reduction of ambulatory and office blood; however, these trials and analyses were limited by short-term follow-up. In our updated comprehensive literature review we summarize the short-term, and long-term effects of RDN, based on the latest randomized clinical trials. Our conclusions based on each summary are unanimous with previous literature findings.

Ultrasound Directed Reduction of Colles' type distal radial fractures in ED (UDiReCT): a feasibility randomised controlled trial.

BACKGROUND: There is a high rate of surgical fixation of displaced Colles' type distal radial wrist fractures despite fracture manipulation in the ED. Point-of-care ultrasound has been used to guide ED manipulations but its effect on the quality of fracture reduction or subsequent need for surgical fixation is unknown. This study aims to assess the feasibility of conducting a definitive randomised controlled trial to assess the use of ultrasound to guide these fracture manipulations. METHODS: We conducted a pragmatic randomised controlled feasibility trial in two EDs in England over a 6-month period (7 October 2019 to 6 April 2020). Adult patients with wrist fractures undergoing manipulation in the ED were randomised 1:1 to ultrasound-guided distal radial fracture manipulation or manipulation with sham ultrasound. The primary outcome for this study was trial recruitment rate. Other measures were recorded to assess potential future definitive trial outcomes and feasibility. RESULTS: Of 120 patients meeting inclusion criteria, 48 (40%) were recruited and randomised in the two centres, giving overall recruitment rates of 0.3 and 1.8 participants per week at each site, respectively, and 1 participant per week overall. The most common reason that patients were not included was research staff availability. After 6 weeks, six patients in each group (26% intervention, 24% control) had undergone surgical fixation, with 98% data completeness for this potential definitive trial primary outcome. Randomisation, blinding and data collection processes were effective but there were data limitations in the X-ray assessment of fracture positions. CONCLUSION: A definitive study of a similar design would be feasible within UK ED practice but organisational factors and research staff availability should be considered when estimating the predicted recruitment rate and required sites. 6-week surgical fixation rate was the most reliable outcome measure. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03868696).

Radiotherapy-associated sensorineural hearing loss in pediatric oncology patients.

During the radiotherapeutic treatment of pediatric oncology patients, they would be at a latent risk of developing ionizing radiation-induced ototoxicity when the cochlea or auditory nerve is located within the radiation field. Sensorineural hearing loss (SNHL) is an irreversible late complication of radiotherapy, and its incidence depends on various factors such as the patient's hearing sensitivity, total radiation dose to the cochlea, radiotherapy fractionation regimen, age and chemoradiation. Importantly, this complication exhibits serious challenges to adult survivors of childhood cancer, as it has been linked to impairments in academic achievement, psychosocial development, independent living skills, and employment in the survivor population. Therefore, early detection and proper management can alleviate academic, speech, language, social, and psychological morbidity arising from hearing deficits. In the present review, we have addressed issues such as underlying mechanisms of radiation-induced SNHL, audiometric findings of pediatric cancer patients treated with radiotherapy, and management and protection measures against radiation-induced ototoxicity.

Fulminant Hepatitis A and E Co-infection Leading to Acute Liver Failure: A Case Report.

Acute liver failure (ALF) is a severe clinical condition with a high mortality rate. Although several factors can cause ALF, viral hepatitis remains one of the leading causes. Hepatitis A virus (HAV) and hepatitis E virus (HEV), which typically cause self-limiting acute disease, are rare but emerging causes of ALF, especially when both viruses infect the same individual. Both of these hepatotropic viruses share an enteric route and are most commonly transmitted through the fecal-oral route. The impact of HAV/HEV co-infection on acute hepatitis prognosis is not entirely understood, but dual infection can further exacerbate liver damage, leading to fulminant hepatic failure (FHF) with a higher mortality rate than a single virus infection. Here, we present a case of a 32-year-old male with no prior liver disease who presented to the emergency department with a two-week history of jaundice, abdominal pain, and hepatomegaly. Upon admission, he was disoriented with grade 2 encephalopathy. After a thorough investigation, co-infection with hepatitis A and E was identified as the primary cause of his ALF. The patient underwent intensive medical treatment and interventions, including dialysis. Unfortunately, the patient's survival was not possible due to the absence of availability of a transplanted organ, which is currently the only definitive treatment option. This case report underscores the significance of prompt diagnosis, timely intervention, and the accessibility of transplantation in the survival of liver failure, as it remains the sole definitive treatment for acute liver failure. Moreover, it provides a concise overview of the current literature on fulminant co-infection of HAV and HEV, including epidemiology, clinical characteristics, pathogenesis, diagnosis, treatment, and risk factors associated with co-infection of hepatitis A and E and their role in causing ALF. It also highlights the significance of identifying high-risk populations and implementing appropriate prevention and control measures such as vaccination, practising good hygiene and sanitation, and avoiding the consumption of contaminated food and water.

Utility of artificial intelligence to identify antihyperglycemic agents poisoning in the USA: introducing a practical web application using National Poison Data System (NPDS).

Clinical effects of antihyperglycemic agents poisoning may overlap each other. So, distinguishing exposure to these pharmaceutical drugs may take work. This study examined the application of machine learning techniques in identifying antihyperglycemic agent exposure using the national poisoning database in the USA. In this study, the data of single exposure due to Biguanides and Sulfonylureas (n=6183) was requested from the National Poison Data System (NPDS) for 2014-2018. We have tried five machine learning models (random forest classifier, k-nearest neighbors, Xgboost classifier, logistic regression, neural network Keras). For the multiclass classification modeling, we have divided the dataset into two parts: train (75%) and test (25%). The performance metrics used were accuracy, specificity, precision, recall, and F1-score. The algorithms used to get the classification results of different models to diagnose antihyperglycemic agents were very accurate. The accuracy of our model in determining these two antihyperglycemic agents was 91-93%. The precision-recall curve showed average precision of 0.91, 0.97, 0.97, and 0.98 for k-nearest neighbors, logistic regression, random forest, and XGB, respectively. The logistic regression, random forest, and XGB had the highest AUC (AUC=0.97) among both biguanides and sulfonylureas groups. The negative predictive values (NPV) for all the models were between 89 and 93%. We introduced a practical web application to help physicians distinguish between these agents. Despite variations in accuracy among the different types of algorithms used, all of them could accurately determine the specific exposure to biguanides and sulfonylureas retrospectively. Machine learning can distinguish antihyperglycemic agents, which may be useful for physicians without any background in medical toxicology. Besides, Our suggested ML-based Web application might help physicians in their diagnosis.

Beneficial Impacts of Fenoldopam on Patients With or at Risk for Acute Renal Failure and Undergoing Surgery: A Meta-Analysis of Randomized Clinical Trials.

This meta-analysis aims to determine the beneficial impacts of fenoldopam on patients with or at high risk of acute kidney injury (AKI) and undergoing surgery. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed while performing the present meta-analysis. Two investigators searched electronic databases including PubMed, EMBASE, and the Cochrane library, from inception until January 10, 2023, for relevant studies. The key terms used to search for relevant articles included "fenoldopam", "acute kidney injury" and "surgery". The primary outcome was the incidence of new AKI. Secondary outcomes included change in serum creatine from baseline (mg/dl), length of stay in ICU (days), renal replacement therapy (RRT), and all-cause mortality that included mortality before or at 30 days. A total of 10 studies involving 1484 patients were included in the present meta-analysis. The risk of AKI was lower in the fenoldopam group compared to the control group [risk ratio (RR): 0.73, 95% CI: 0.57-0.95]. The length of ICU stay was also shorter in the fenoldopam group [mean difference (MD): -0.35 days, 95% confidence interval (CI): -0.68, -0.03]. No significant differences were reported in terms of all-cause mortality, change in serum creatinine, and RRT. In conclusion, our meta-analysis of studies on the use of fenoldopam in adult patients undergoing major surgery showed that fenoldopam significantly reduces the risk of AKI and shortens ICU stays. However, there was no significant impact on all-cause mortality or RRT.

Idiopathic Spontaneous Pneumomediastinum in an Adolescent.

Idiopathic spontaneous pneumomediastinum (ISPM) is a diagnosis of exclusion after a spontaneous pneumomediastinum (SPM) occurs without any identifiable predisposing factors or known aetiology. It is a rare diagnosis in adolescents, with a few cases reported in the literature. To increase awareness of this rare diagnosis, we present a case of a 17-year-old, fit and healthy male who presented with acute atraumatic chest pain. On examination, surgical emphysema in the supraclavicular fossa was identified. His chest X-ray and a subsequent computed tomography (CT) of the thorax showed extensive pneumomediastinum, with infiltration of air into the soft tissues of the neck and upper arms, but with no identifiable cause. On follow-up, he remained asymptomatic, and a repeat CT of the thorax four weeks after his initial presentation showed complete resolution of the pneumomediastinum. Once confirmed, ISPM is expected to resolve spontaneously without complications, with a very low rate of recurrence in nearly all cases.

Ultrasound-directed reduction of distal radius fractures in adults: a systematic review.

OBJECTIVE: To conduct a systematic review of the clinical literature to determine whether ultrasound can be used to improve the reduction of distal radius fractures in adults in the ED. METHODOLOGY: A study protocol was registered on PROSPERO. EMBASE, PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov of the US National Library of Medicine were searched for studies evaluating ultrasound-assisted distal radial fracture reductions in comparison with standard care. The primary outcome of interest was manipulation success rates, defined as the proportion of fracture manipulations resulting in acceptable anatomical alignment, with secondary outcome being subsequent surgical intervention rates in ultrasound and standard care group of patients. RESULTS: 248 were screened at title and abstract, and 10 studies were included for a narrative synthesis. The quality of this evidence is limited but suggests ultrasound is accurate in determining distal radius fracture reduction and may improve the quality of reduction compared with standard care. However, there is insufficient evidence to determine whether this affects the rate of subsequent surgical intervention or functional outcome. CONCLUSION: There is a lack of evidence that using ultrasound in the closed reduction of distal radius fractures benefits patients. Properly conducted randomised controlled trials with patient-orientated outcomes are crucial to investigate this technology.

Mesenteric Lipoma with Volvulus: A Rare Cause of Acute Abdomen in a Child.

Lipoma is benign tumor of mature fat cells and is reported to develop anywhere in the body, e.g. trunk and extremities; however, lipoma in the mesentery of gut is rare, particularly in children. Mesenteric lipomas may be asymptomatic or may present with acute abdomen by leading to volvulus of gut. We report a 6-year female with intestinal obstruction. Exploratory laparotomy revealed a large mesenteric lipoma in the mesentery of small bowel causing volvulus of ileum. Lipoma was excised and postoperative recovery remained uneventful both in the hospital and on subsequent follow up. We believe mesenteric lipoma should be considered as a cause of volvulus and in differential diagnosis of acute abdomen in children. Key Words:  Mesentery, Lipoma, Volvulus, Ileum, Intestinal obstruction.

Colles' type distal radial fractures undergoing manipulation in the ED: a multicentre observational cohort study.

BACKGROUND: Colles' type fractures of the distal radius are one of the most commonly manipulated fractures in the ED. Local audit data suggest that a high proportion of these injuries undergo subsequent surgical fixation. If widespread, this could represent a potential burden on patients and the NHS worthy of further research. The aims of this study were to estimate the rate of surgical fixation of Colles' type distal radial fractures after ED fracture manipulation and explore variations in their management in UK EDs. METHODS: We conducted a multicentre observational study in 16 EDs in the UK from 4 February 2019 to 31 March 2019. All adult patients with a Colles' fracture who underwent fracture manipulation in the ED were included. Patients who could not be followed up and those with volar displaced fractures were excluded. We measured the rate of wrist fracture surgery at 6 weeks, patient demographics and variations in anaesthetic technique used. RESULTS: During the study period, 328 adult patients attended the participating EDs with a distal radial fracture. Of these, 83 patients underwent fracture manipulation in the ED and were eligible for the study. Their mean age (SD) was 65.3 (17.0) years, 84.3% were female and the most common method of anaesthesia used was haematoma block (38.6%). 34 (41.0%, 95 % CI 30.3 to 52.3) patients had subsequent surgical fixation of their fracture. Younger age was associated with higher rates of surgical fixation but ED anaesthetic technique did not affect the subsequent need for surgery in this sample. CONCLUSION: Subsequent surgical fixation was carried out in 41% of patients who underwent manipulation of Colles' type wrist fractures in this cohort. This merits further research and represents a potential target to rationalise repeat procedures.

Prediction of Postprostatectomy Biochemical Recurrence Using Quantitative Ultrasound Shear Wave Elastography Imaging.

Objectives: To determine the prognostic significance of tissue stiffness measurement using transrectal ultrasound shear wave elastography in predicting biochemical recurrence following radical prostatectomy for clinically localized prostate cancer. Patients and Methods: Eligible male patients with clinically localized prostate cancer and extraperitoneal laparoscopic radical prostatectomy between November 2013 and August 2017 were retrospectively selected. Information of potential biochemical recurrence predictors, including imaging (ultrasound shear wave elastography and magnetic resonance imaging), clinicopathological characteristics, and preoperative prostate specific antigen (PSA) levels were obtained. Recurrence-free survival (Kaplan-Meier curve) and a multivariate model were constructed using Cox regression analysis to evaluate the impact of shear wave elastography as a prognostic marker for biochemical recurrence. Results: Patients experienced biochemical recurrence in an average of 26.3 ± 16.3 months during their follow-up. A cutoff of 144.85 kPa for tissue stiffness measurement was estimated for recurrence status at follow-up with a sensitivity of 74.4% and a specificity of 61.7%, respectively (p < 0.05). In univariate analysis, shear wave elastography performed well in all preoperative factors compared to biopsy Gleason Score, PSA and magnetic resonance imaging; in multivariate analysis with postoperative pathological factors, shear wave elastography was statistically significant in predicting postoperative biochemical recurrence, which improved the C-index of predictive nomogram significantly (0.74 vs. 0.70, p < 0.05). Conclusions: The study revealed that quantitative ultrasound shear wave elastography-measured tissue stiffness was a significant imaging marker that enhanced the predictive ability with other clinical and histopathological factors in prognosticating postoperative biochemical recurrence following radical prostatectomy for clinically localized prostate cancer.

Prevalence and Associated Factors of Smoking Among Final Year Medical Students: A Multicentric Survey From Pakistan.

Introduction Smoking is the leading cause of lung cancer around the world. In a developing country like Pakistan with low levels of literacy and general awareness about adverse effects of smoking, doctors play a pivotal role in educating the masses about its harmful consequences and providing support for smoking cessation. However, their efficacy is affected if they smoke themselves, and oftentimes the habits cultivated during educational recourse are carried into the professional careers. The aim of this study was to document the prevalence of smoking among final year medical students of Lahore, Pakistan, and the factors associated with it. Methodology Study approval was obtained from Combined Military Hospital (CMH) Lahore Medical College, Ethics Review Committee. A cross-sectional survey was carried out in four medical colleges and hospitals of Lahore, Pakistan. A questionnaire consisting of 14 questions related to basic demographics and smoking was used after being pilot tested on 20 students of CMH. The overall response rate was 74.89%. Data was collected from 337 respondents, of which 38 forms were discarded and 299 forms were analyzed by SPSS V21. Results Among the 299 respondents, there were 128 males (42.81%) and 171 females (57.19%) with 32 (10.70%) smokers. Male students reported smoking (n = 27, 21.09%) more than their female counterparts (n = 5, 0.02%). The mean age of participants was 23.01 years. Students having an active smoker at home had statistically significant positive correlations with current smoking status and the number of cigarettes smoked per day. Students with household smoking contacts were also more likely to smoke if they belonged to the male gender. Conclusion Prevalence of smoking in medical students is lower than in the general population but still considerable in the male students. There is a need to target this particular population with interactive counseling sessions, education campaigns, and anti-smoking rules to decrease smoking among them and through them in the society.

ONION PEEL APPEARANCE IN BALOS CONCENTRIC SCLEROSIS--A VARIANT OF MULTIPLE SCLEROSIS.

Balo's concentric sclerosis (BCS) is a variant of multiple sclerosis (MS). It may present as a lesior clinically and radiologically indistinguishable from brain tumour particularly on computerized tomography (CT) scans. Diagnosis only gets clear when magnetic resonance imaging and spectroscopy (MRI & MRS) and brain biopsy is done. We report a case of 30 year old male with progressive headache and left hemi paresis for 3 weeks. There was upper motor neuron (UMN) facial palsy on the left with bilateral papilledema. CT scan of brain showed large hypo-dense area in right frontoparietal lobe consistent with brain tumour. On MRI the diagnosis of BCS was made on basis of concentric lesions of myelinated and demyelinated rings. Demyelination wa confirmed on brain biopsy.

CRYPTOCOCCAL MENINGITIS IN IMMUNOCOMPETENT PATIENT.

Cryptococcal meningitis (CM) is life threatening fungal infection of central nervous system (CNS). Although it is commonly associated with immunosuppression but rarely it can occur in immune competent patient. We report a case of 21 year old non HIV infected girl. Based on initial diagnoses of tuberculosis Bacillus meningitis (TBM), she was started on anti-tuberculosis treatment (ATT). However failure to respond to treatment prompted a quest for alternative diagnosis. A final Diagnosis of CM was confirmed on latex agglutination antigen detection on cerebrospinal fluid (CSF) analysis. The patient responded well to antifungal treatment. Initially diagnosis was missed due to common occurrence of tuberculosis infection in Pakistan and resemblance of its symptomatology and magnetic resonance imaging (MRI) findings with CNS cryptoccocal infection.

Childhood primary angiitis of the central nervous system.

OBJECTIVE: To analyze the clinical course and magnetic resonance angiographic (MRA) abnormalities in children with primary angiitis of the central nervous system (cPACNS). STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: Neurosciences and Neuroradiology Department of the Children's Hospital, Lahore, from January 2009 to December 2010. METHODOLOGY: The cohort comprised consecutive patients diagnosed as having cPACNS based on clinical findings and identification of arterial stenosis on magnetic resonance angiography (MRA) in the absence of an underlying condition that could cause these findings. The treatment protocol for ischaemic infarcts consisted of induction therapy with intravenous steroids pulses and intravenous immunoglobulin followed by maintenance therapy with azathioprine and low dose aspirin. When indicated, they were treated with anticoagulants at least for 4 weeks along with induction therapy. Patients were followed at a single centre and systemically assessed for clinical presentation, classification of disease as progressive or non-progressive, adverse effects of anticoagulants, aspirin, azathioprine and their hospital course. RESULTS: Sixty-eight children with medium-large vessel cPACNS (62% boys, 38% girls) with mean age of 8.5 ± 3.5 years were enrolled in this study. Motor deficit (70%); headache (64%) and fever (20%) were the commonest symptoms; whereas hemiparesis (60%); seizures 55% (focal 35%, generalized 20%) and decreased conscious level (30%), were the commonest neurological findings. Neuroradiological findings were ischaemic strokes in 50 (73.5%), haemorrhagic strokes in 10 (14.7%) and ischaemic haemorrhagic lesions in 8 cases (11.8%). Angiographically 51 (51/68, 75%) of the cohort had non-progressive (obliterative) and 17 (17/68, 25%) had evidence of progressive arteriopathy at the time of admission. No secondary haemorrhagic lesions were documented among infarcts strokes, which were treated with heparin and oral anticoagulants. Outcome was survival in 56 cases (81.5%) and death in 12 cases (18.5%). All survivors were discharged on long-term oral aspirin; 15 of them were also commenced on azathioprine. Neurological findings among the 56 survivors were; normal 20%, minor disabilities in 25%, moderate disabilities in 20% and severe disabilities in 35%. CONCLUSION: The spectrum of cPACNS includes both progressive and non-progressive forms with significant morbidity and mortality. This treatment protocol of immunosuppressive therapy may improve long-term neurological outcome in children with medium-large vessel childhood primary angiitis of the CNS.