Targeting PKCa alleviates iron overload in diabetes and hemochromatosis through the inhibition of ferroportin.

Ferroportin (Fpn) is the only iron exporter, playing a crucial role in systemic iron homeostasis. Fpn is negatively regulated by its ligand hepcidin, but other potential regulators in physiological and disease conditions remain poorly understood. Diabetes is a metabolic disorder that develops body iron loading with unknown mechanisms. By utilizing diabetic mouse models and human duodenal specimens, we demonstrated that intestinal Fpn expression was increased in diabetes in a hepcidin-independent manner. Protein kinase C (PKC) is hyperactivated in diabetes. We showed that PKC was required to sustain baseline Fpn expression and diabetes induced Fpn upregulation in the enterocytes and macrophages. Knockout of PKC abolished diabetes associated iron overload. Mechanistically, activation of PKC increased the exocytotic while decreased the endocytic trafficking of Fpn in the resting state. Hyperactive PKC also suppressed hepcidin-induced ubiquitination, internalization, and degradation of Fpn. We further observed that iron loading in the enterocytes and macrophages activated PKC, acting as a novel mechanism to enhance Fpn-dependent iron efflux. Finally, we demonstrated that the loss-of-function of PKC and pharmacological inhibition of PKC significantly alleviated hereditary hemochromatosis associated iron overload. Our study has highlighted, for the first time, that PKC is an important positive regulator of Fpn and a new target in the control of iron homeostasis.

The Role of High-Resolution Manometry Prior to and Following Antireflux Surgery: The Padova Consensus.

BACKGROUND: In the last two decades the development of high-resolution manometry (HRM) has changed and revolutionized the diagnostic assessment of patients complain foregut symptoms. The role of HRM before and after antireflux procedure remains unclear, especially in surgical practice, where a clear understanding of esophageal physiology and hiatus anatomy is essential for optimal outcome of antireflux surgery (ARS). Surgeons and gastroenterologists (GIs) agree that assessing patients following antireflux procedures can be challenging. Although endoscopy and barium-swallow can reveal anatomic abnormalities, physiologic information on HRM allowing insight into the cause of eventually recurrent symptoms could be key to clinical decision making. METHOD: A multi-disciplinary international working group (14 surgeons and 15 GIs) collaborated to develop consensus on the role of HRM pre- and post- ARS, and to develop a postoperative classification to interpret HRM findings. The method utilized was detailed literature review to develop statements, and the RAND/University of California, Los Angeles Appropriateness Methodology (RAM) to assess agreement with the statements. Only statements with an approval rate >80% or a final ranking with a median score of 7 were accepted in the consensus. The working groups evaluated the role of HRM prior to ARS and the role of HRM following ARS. CONCLUSION: This international initiative developed by surgeons and GIs together, summarizes the state of our knowledge of the use of HRM pre- and post-ARS. The Padova Classification was developed to facilitate the interpretation of HRM studies of patients underwent ARS.

Insights and Opinions of Critical Care Healthcare Professionals in the Management of Carbapenem-resistant Enterobacteriaceae Cases and Antibiotic-Resistant Infections in the Intensive Care Unit Setting: A Survey-Based Approach.

INTRODUCTION: A survey-based approach to managing antibiotic-resistant infections in the intensive care unit (ICU) setting, with a focus on carbapenem-resistant Enterobacteriaceae (CRE) cases, was conducted. Among CRE, New Delhi metallo-ß-lactamase 1 (NDM-1) is a carbapenemase that is resistant to ß-lactam antibiotics and has a broader spectrum of antimicrobial resistance than other carbapenemase types. The article explains that healthcare-associated infections (HAIs) are a significant problem, particularly in low- and middle-income countries, and that carbapenem in combination with other antibiotics are the most potent class of antimicrobial agents effective in treating life-threatening bacterial infections, including those caused by resistant strains. AIM: The survey aimed to gather critical care healthcare professionals (HCPs') opinions on their current practices in managing infections acquired in the hospital and ICU settings, with a focus on CRE cases, specifically NDM-1 and other antibiotic-resistant infections. METHODS: Responses from critical care healthcare professionals, including online surveys and in-person interviews, to gain insights into the management of infections caused by multidrug-resistant bacteria. The findings related to the insights on the prevalence of bacterial flora, clinical experiences on efficacy and safety of meropenem sulbactam ethylenediaminetetraacetic acid (EDTA) (MSE) in CRE cases, and various combination therapies of antibiotics used to treat antibiotic-resistant infections in ICU setting were evaluated. RESULTS: Klebsiella pneumoniae bacteria were the most common bacteria in cultures, followed by Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. NDM-1 was the type of carbapenemase found in around 50% of CRE patients. MSE is among the most preferred antibiotics besides colistin, polymyxin B, and ceftazidime avibactum for CRE cases and specifically for NDM-1 cases due to its high rate of efficacy and safety. CONCLUSION: The article concludes with a discussion on the antibiotics used in response to CRE cases, reporting that critical care HCP considers MSE with high efficacy and safe antibiotic combination and was used as both monotherapy and in combination with other antibiotics. The survey highlights the need for exploring and better understanding the role of MSE in the management of CRE infections, especially in NDM-1.

Esophagogastric Junction Outflow Obstruction: A Diagnosis in Evolution.

Esophagogastric junction outflow obstruction (EGJOO) is a rapidly evolving diagnosis that can represent early or variant achalasia. Since the publication of the Chicago Classification version 4.0, the criteria for this diagnosis have been more stringent. Currently, the criteria include an elevated median integrated relaxation pressure (IRP) in both the supine and upright positions, elevated intrabolus pressure in at least 20% of supine swallows, dysphagia and/or chest pain, as well as an abnormal timed barium esophagram and/or impedance planimetry testing. Additionally, other secondary causes may result in an elevated IRP and must be excluded. The management of conclusive EGJOO is targeted therapy to the lower esophageal sphincter (LES), although treatment is not straightforward. Overall, adjuvant testing and data should be scrutinized for appropriateness of LES disruption. The spectrum of treatment options includes simple monitoring as well as more invasive therapies such as endoscopic dilation and myotomy. This article explores the newest criteria and management options for clinically relevant EGJOO.

SBMLToolkit.jl: a Julia package for importing SBML into the SciML ecosystem.

Julia is a general purpose programming language that was designed for simplifying and accelerating numerical analysis and computational science. In particular the Scientific Machine Learning (SciML) ecosystem of Julia packages includes frameworks for high-performance symbolic-numeric computations. It allows users to automatically enhance high-level descriptions of their models with symbolic preprocessing and automatic sparsification and parallelization of computations. This enables performant solution of differential equations, efficient parameter estimation and methodologies for automated model discovery with neural differential equations and sparse identification of nonlinear dynamics. To give the systems biology community easy access to SciML, we developed SBMLToolkit.jl. SBMLToolkit.jl imports dynamic SBML models into the SciML ecosystem to accelerate model simulation and fitting of kinetic parameters. By providing computational systems biologists with easy access to the open-source Julia ecosystevnm, we hope to catalyze the development of further Julia tools in this domain and the growth of the Julia bioscience community. SBMLToolkit.jl is freely available under the MIT license. The source code is available at https://github.com/SciML/SBMLToolkit.jl.

The functional lumen imaging probe contractile response pattern is the best predictor of botulinum toxin response in esophagogastric junction outflow obstruction.

BACKGROUND: Esophagogastric junction outflow obstruction (EGJOO) is a heterogenous disorder in which the correct management strategy is unclear. We assessed whether functional lumen imaging probe (FLIP) topography data could select EGJOO, which would benefit from lower esophageal sphincter Botulinum toxin (Botox) injection. METHODS: This was a single-center prospective study of adult patients meeting Chicago Classification (CC) v3.0 criteria for EGJOO. We assessed differences in pretreatment physiologic measurements on high-resolution manometry (HRM) and FLIP and other relevant clinical variables in predicting Botox response (>50% in BEDQ at 2 months). KEY RESULTS: Sixty-nine patients were included (ages 33-90, 73.9% female). Of these, 42 (61%) were Botox responders. Majority of physiologic measures on HRM and FLIP and esophageal emptying were not different based on Botox response. However, a spastic-reactive (SR) FLIP contractile response (CR) pattern predicted a Botox response with OR 25.6 (CI 2.9-229.6) when compared to antegrade FLIP CR; and OR for impaired-disordered/absent CR was 22.5 (CI 2.5-206.7). Logistic regression model using backward elimination (p value = 0.0001, AUC 0.79) showed that a SRCR or IDCR/absent response and the upright IRP predicted Botox response. Response rates in tiered diagnostic groups were: (i) CCv3.0 EGJOO (60.9%), (ii) CCv4.0 EGJOO (73.1%), (iii) CCv4.0 + FLIP REO (80%), (iv) CCv4.0, FLIP REO, and abnormal FLIP CR (84.2%), and (v) CCv4.0, FLIP REO, and SR FLIP CR (90%). CONCLUSIONS AND INFERENCES: FLIP helps identify patients with EGJOO who are likely to response to LES Botox therapy. An abnormal FLIP contractile response pattern is the single-most important predictor of a Botox response.

Perioperative care in acute liver failure: An anaesthesiologist perspective in the operating theatre.

Acute liver failure (ALF) is a life-threatening condition characterized by rapid liver function deterioration, necessitating a multidisciplinary approach for optimal perioperative care. This comprehensive review focuses on the critical role of the anaesthesiologist throughout the preoperative, intraoperative, and postoperative phases, addressing the unique challenges posed by ALF. The article begins with an exploration of ALF, underlining the urgency of timely referral to specialized hepatology centres. Liver transplantation emerges as a life-saving intervention, and the complex decision-making process is discussed, emphasizing the need for a multidisciplinary team to assess transplantation candidacy based on established prognostic criteria. In the preoperative phase, the review stresses the importance of early engagement with tertiary liver centres for timely referrals and identifies patients suitable for transplantation. Safe transport protocols are detailed, highlighting the meticulous planning required for the secure transfer of ALF patients between healthcare facilities. The intraoperative management section delves into the anaesthesiologist's key concerns, including neurological status, sepsis, acute kidney injury, body mass index, and preoperative fasting. Hemodynamic stability, fluid management, and coagulation balance during surgery are emphasized, with insights into anaesthesia techniques, vascular access, monitoring, and hemodynamic management tailored to the challenges posed by ALF patients. The postoperative care is thoroughly examined covering neurological, hemodynamic, metabolic, renal, and nutritional aspects. Management of ALF involves multidisciplinary team, including nephrology for continuous renal replacement therapy, transfusion medicine for plasma exchange, critical care for overall patient care, nutritionists for ensuring adequate nutrition, and hepatologists as the primary guides. In conclusion, the review recognizes the anaesthesiologist as a linchpin in the perioperative care of ALF patients. The integration of safe transport protocols and multidisciplinary approach is deemed crucial for navigating complexities of ALF, contributing to improved patient outcomes. This article serves as an invaluable resource for gastroenterologist and intensivists, enhancing their understanding of the anaesthesiologist's indispensable role in the holistic care of ALF patients in an ever-evolving healthcare landscape.

Guillain Barre syndrome mimicking brain death.

A 49-year-old female patient presented at the hospital with a history of herpetic blisters, frequent episodes of vomiting and loose stools, bilateral upper and lower limb weakness, and diminishing sensorium. She was diagnosed with hyponatraemia and respiratory failure and later became unconscious with absent brainstem reflexes. The patient was initially treated for herpetic encephalitis, a chronic obstructive pulmonary disease with acute exacerbation, hyponatraemia and neuroparalytic snake bite. Further evaluation, however, identified the uncommon Guillain Barre syndrome presentation with overlap of Bickerstaff brainstem encephalitis. This is an uncommon disorder characterised by the involvement of higher mental functions, fixed dilated pupils, absent brainstem reflexes and quadriplegia that resembles a neuroparalytic snake bite and brain death. After receiving intravenous immunoglobulins for treatment, the patient completely recovered.

Correlation of oxygenation indices in invasive mechanical ventilated adult patients.

BACKGROUND: Mechanical ventilation is essential for managing acute respiratory failure, but traditional methods of assessing oxygenation, like the PaO2/FiO2 ratio, pose challenges due to invasiveness and cost. OBJECTIVE: This single-centre prospective observational study aimed to assess the potential of the non-invasive Oxygen Saturation Index (OSI), utilising SpO2 measurements, to diagnose hypoxemia in mechanically ventilated adults. The study sought to establish correlations between OSI, oxygenation index (OI), PaO2/FiO2 ratio and SpO2/FiO2 ratio. METHODS: From August 2022 to July 2023, data was collected from 1055 mechanically ventilated intensive care unit patients. Statistical analysis included correlation tests, receiver operating curve (ROC) analysis and cut-off value determination for hypoxemia diagnosis. RESULTS: We found that the P/F ratio had a statistically significant negative correlation with OI (correlation coefficient -0.832, P value: 0.000 in hypoxemic group and correlation coefficient -0.888, P value: 0.000 in the non-hypoxemic group), and OSI (correlation coefficient -0.746, P value: 0.000 in hypoxemic group and correlation coefficient -0.629, P value: 0.000 in non-hypoxemic group) and has a positive correlation with P/F ratio (correlation coefficient 0.92, P value: 0.000 in hypoxemic group and correlation coefficient -0.67, P value: 0.000 in non-hypoxemic group). OI and OSI had a statistically significant correlation (correlation coefficient 0.955, P value: 0.000 in hypoxemic group and correlation coefficient 0.815, P value: 0.000 in non-hypoxemic group). on ROC analysis P/F ratio was the most accurate in predicting hypoxia followed by OI and OSI. with a cut-off value, of OI being 7.07, and that for OSI being 3.90, at an 80% sensitivity level to diagnose hypoxemia. CONCLUSION: OSI can serve as a dependable surrogate for OI, simplifying ARDS severity assessment. The P/F ratio is the most accurate predictor of hypoxia. Further research, especially in larger multicentre studies, is needed to validate these findings and explore the long-term clinical implications of using OSI for oxygenation monitoring in mechanically ventilated patients.