A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1-5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia-reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

Serum neurofilament light chain measurements following nerve trauma.

BACKGROUND: Optimal functional recovery following peripheral nerve injuries (PNIs) is dependent upon early recognition and prompt referral to specialist centres for appropriate surgical intervention. Technologies which facilitate the early detection of PNI would allow faster referral rates and encourage improvements in patient outcomes. Serum Neurofilament light chain (NfL) measurements are cheaper to perform, easier to access and interpret than many conventional methods used for nerve injury diagnosis, such as electromyography and/or magnetic resonance imaging assessments, but changes in serum NfL levels following traumatic PNI have not been investigated. This pre-clinical study aimed to determine whether serum NfL levels can: (1) detect the presence of a nerve trauma and (2) delineate between different severities of nerve trauma. METHODS: A rat sciatic nerve crush and common peroneal nerve crush were implemented as controlled animal models of nerve injury. At 1-, 3-, 7- and 21-days post-injury, serum samples were retrieved for analysis using the SIMOA® NfL analyser kit. Nerve samples were also retrieved for histological analysis. Static sciatic index (SSI) was measured at regular time intervals following injury. RESULTS: Significant 45-fold and 20-fold increases in NfL serum levels were seen 1-day post-injury following sciatic and common peroneal nerve injury, respectively. This corresponded with an eightfold higher volume of axons injured in the sciatic compared to the common peroneal nerve (p < .001). SSI measurements post-injury revealed greater reduction in function in the sciatic crush group compared with the common peroneal crush group. CONCLUSIONS: NfL serum measurements represent a promising method for detecting traumatic PNI and stratifying their severity. Clinical translation of these findings could provide a powerful tool to improve the surgical management of nerve-injured patients.

A retrofit to enable dynamic B1+ steering for transmit arrays without multiple amplifiers.

PURPOSE: B1+ shimming is an important method for mitigating B1 inhomogeneity in high-field MRI. Using independent power amplifiers for each transmit (Tx) element is the preferred method for B1 shimming but comes with a high cost. Conversely, the simplest approach to control a Tx array is by using coaxial cables of varying length in the Tx chain, but this approach is cumbersome and impractical for dynamic shimming. In this article, a system is described that enables dynamic, phase-only, eight-channel B1+ steering on a 7T MR scanner with only two power amplifiers. METHODS: Power dividers were utilized to first split the existing two-channel Tx signal into eight channels. Digitally controlled phase shifters on each channel were designed to provide independent phase shifts with a resolution of 22.5° (from 0°, 22.5° … 337.5°). To validate the system, an eight-channel body dipole array was simulated and constructed for bench and 7T imaging and evaluation. RESULTS: The phase conjugate B1+ steering method was employed at three different spatial positions in simulation, bench measurements, and scanner measurements-all with matching results. At the desired points, regions with homogenous B1+ were generated, indicating good Tx steering to the selected region. CONCLUSION: The described system can be used as a simple retrofit to existing hardware to provide phase control while avoiding the need to manually switch cables and without requiring independent power amplifiers for each channel, thus demonstrating the ability to perform dynamic B1+ shimming with increased degrees of freedom but without significantly increased hardware cost.

Atrial Fibrillation as a Predictor of Mortality in High Risk COVID-19 Patients: A Multicentre Study of 171 Patients.

PURPOSE: Certain patient demographics and biomarkers have been suggested to predict survival in patients infected with COVID-19. However, predictors of outcome in patients who are critically ill are unclear. MATERIALS AND METHODS: We performed a multicentre analysis of 171 consecutive patients with confirmed COVID-19 who were admitted to the intensive care unit (ICU) between 1 March 2020 and 30 April 2020 and were followed until 23 May 2020. Demographic data, past medical history, laboratory values, echocardiographic and telemetry data were analysed. Patient status was classified as either alive or deceased at hospital discharge or the end of follow-up period. RESULTS: Mean patient age was 66±13 and 57% were male. Mortality rate of this ICU cohort at the end of follow-up was 46.2%. A multivariable logistic regression analysis identified the presence or history of atrial fibrillation (Odds Ratio 4.8, p=0.004) as a significant cardiovascular attribute that contributed to increased mortality. CONCLUSION: Mortality of critically ill COVID-19 patients is high. This study suggests a relationship between atrial fibrillation and increased mortality from COVID-19. Early aggressive treatment patients with high risk characteristics, such as atrial fibrillation could improve clinical outcome.

Chemical Modifications of Porous Shape Memory Polymers for Enhanced X-ray and MRI Visibility.

The goal of this work was to develop a shape memory polymer (SMP) foam with visibility under both X-ray and magnetic resonance imaging (MRI) modalities. A porous polymeric material with these properties is desirable in medical device development for applications requiring thermoresponsive tissue scaffolds with clinical imaging capabilities. Dual modality visibility was achieved by chemically incorporating monomers with X-ray visible iodine-motifs and MRI visible monomers with gadolinium content. Physical and thermomechanical characterization showed the effect of increased gadopentetic acid (GPA) on shape memory behavior. Multiple compositions showed brightening effects in pilot, T1-weighted MR imaging. There was a correlation between the polymeric density and X-ray visibility on expanded and compressed SMP foams. Additionally, extractions and indirect cytocompatibility studies were performed to address toxicity concerns of gadolinium-based contrast agents (GBCAs). This material platform has the potential to be used in a variety of medical devices.

Acceptability of alginate enriched bread and its effect on fat digestion in humans.

Lifestyle interventions and physical activity remain the cornerstone of obesity management, as pharmacological therapies (orlistat) are associated with gastrointestinal (GI) side effects. Combining orlistat with fibers can reduce side effects, improving compliance. Therefore, a fiber that inhibits lipase without side effects could help treat obesity. The aims of the present work were to assess whether alginate enriched bread could inhibit fat digestion, and assess the acceptability of alginate bread and its effect on GI wellbeing. A double-blind, randomised, controlled cross-over pilot study (NCT03350958) assessed the impact of an alginate bread meal on; lipid content in ileal effluent and circulating triacylglycerol levels. This was compared against the same meal with non-enriched (control) bread. GI wellbeing and acceptability of alginate bread was compared to control bread through daily wellbeing questionnaires and food diaries (NCT03477981). Control bread followed by alginate bread were consumed for two weeks respectively. Consumption of alginate bread reduced circulating triacylglycerol compared to control (2% reduction in AUC) and significantly increased lipid content in ileal effluent (3.8 g ±â€¯1.6 after 210 min). There were no significant changes to GI wellbeing when comparing alginate bread to control bread. A significant increase in the feeling of fullness occurred with alginate bread compared to baseline and the first week of control bread consumption. This study showed that sustained consumption of alginate enriched bread does not alter GI wellbeing and can decrease lipolysis, increasing lipid leaving the small intestine. Further studies are required to demonstrate that reduced fat digestion through the action of alginate can reduce fat mass or body weight.

Building new twenty-first century medical school libraries from the ground up: challenges, experiences, and lessons learned.

The twenty-first century library at a newly opened medical school often differs from those at traditional medical schools. One obvious difference is that the new medical school library tends to be a born-digital library, meaning that the library collection is almost exclusively digital. However, the unique issues related to building a library at a new medical school are not limited to online collections. A unique start-up culture is prevalent, of which newly appointed directors and other library and medical school leaders need to be aware. This special paper provides an overview of best practices experienced in building new medical school libraries from the ground up. The focus is on the key areas faced in a start-up environment, such as budgeting for online collections, space planning, staffing, medical informatics instruction, and library-specific accreditation issues for both allopathic and osteopathic institutions.

Biological activity of alginate and its effect on pancreatic lipase inhibition as a potential treatment for obesity.

Alginates are classed as a dietary fibre and have been shown to inhibit digestive enzymes in vitro, and therefore could be used as an obesity treatment. The current study aims to assess whether alginate in a bread vehicle maintains its inhibition properties despite cooking and digestion, and may therefore be used as a potential treatment for obesity. After 180 min in a model gut that replicates digestion in the mouth, stomach and small intestines alginate bread (AB), control bread (CB), CB with Manucol® DM alginate, free DM alginate and model gut solution were collected. DM, LFR 5/60 and SF200 were heated at 37 °C and 200 °C, with DM also heated at 50, 100 and 150 °C. Samples from the model gut and heated alginate were assessed for molecular size and inhibition properties using viscosity, gel filtration and a lipase turbidity assay. AB does not significantly increase viscosity in the model gut. Viscosity of alginate reduces beyond 100 °C, although alginate retains its inhibition properties up to 150 °C. Cooking into the bread does not reduce the molecular size of the alginate or affect its inhibition properties. These data demonstrate the robustness of alginates lipase inhibition despite the cooking process and digestion. Therefore adding alginate to a bread vehicle may have the potential in the treatment for obesity.

Cardiac Implications of Itraconazole Therapy in Histoplasmosis Patients.

A male patient in his 60s, with a history of tobacco use, presented with fever, weight loss, and cough, and was ultimately diagnosed with histoplasmosis. Initial treatment with itraconazole (ITZ) led to symptom improvement. However, two months later, he returned with lower extremity swelling and dyspnea. Imaging showed pleural effusions and reduced ejection fraction, suggesting itraconazole-induced cardiac toxicity. Transition to voriconazole and initiation of guideline-directed medical therapy improved symptoms. This case report delves into the cardiac side effects of itraconazole, notably heart failure, and elucidates the potential underlying mechanisms. Our goal is to emphasize the importance of monitoring patients on itraconazole for potential cardiac complications, necessitating timely intervention to mitigate adverse outcomes.

An assessment of co-contraction in reinnervated muscle.

Aim: To investigate co-contraction in reinnervated elbow flexor muscles following a nerve transfer. Materials & methods: 12 brachial plexus injury patients who received a nerve transfer to reanimate elbow flexion were included in this study. Surface electromyography (EMG) recordings were used to quantify co-contraction during sustained and repeated isometric contractions of reinnervated and contralateral uninjured elbow flexor muscles. Reuslts: For the first time, this study reveals reinnervated muscles demonstrated a trend toward higher co-contraction ratios when compared with uninjured muscle and this is correlated with an earlier onset of muscle fatigability. Conclusion: Measurements of co-contraction should be considered within muscular function assessments to help drive improvements in motor recovery therapies.

Beyond the Benefits: A Case Study on the Complications of Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors (Euglycemic Diabetic Ketoacidosis (DKA) and Takotsubo Cardiomyopathy).

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, integral in type 2 diabetes mellitus (T2DM) management, are not without risks, with reported adverse effects including euglycemic diabetic ketoacidosis (EDKA). We present a case of a 75-year-old female with T2DM on canagliflozin, who developed altered mental status (AMS), nausea, vomiting, and hypotension. The laboratory results revealed ketoacidosis, elevated troponins, and Takotsubo cardiomyopathy (TC), prompting the cessation of canagliflozin. This paradoxical EDKA case underscores the necessity for cautious prescribing. Additionally, our discussion delves into the risk factors, mechanisms, and epidemiology of EDKA associated with SGLT2 inhibitors (SGLT2i), emphasizing the importance of individualized medicine and shared decision-making in their use, despite their proven cardiovascular benefits.

Navigating Asymptomatic Mitral Regurgitation: Diagnostic Dilemmas and Treatment Strategies.

This case report explores the complexities involved in the diagnosis and management of asymptomatic mitral regurgitation (MR) in a 64-year-old male presenting with an incidental systolic murmur. Torrential MR with flail mitral valve (MV) segments was identified through comprehensive imaging and clinical evaluation, including echocardiography and catheterization. The discussion highlights the nuances of surgical timing, emphasizing the importance of tailored approaches based on left ventricular (LV) function and dilation. This report sheds light on the evolving landscape of managing asymptomatic MR, underscoring the need for balancing surveillance with proactive intervention to optimize patient outcomes.

Right Coronary Artery-to-Right Atrial Fistula Accompanied by Multiple Right Coronary Artery Aneurysms: A Case Report.

A coronary artery aneurysm (CAA) denotes a localized dilation of the coronary artery, while a coronary artery fistula signifies an aberrant connection between a coronary artery and a cardiac chamber or adjacent vessel. Here, we present a case study of a 68-year-old female with a previously diagnosed right coronary artery-to-right atrial fistula concomitant with multiple right coronary artery aneurysms. Initially asymptomatic, the patient subsequently manifested atrial fibrillation. Management involved augmenting the patient's home regimen with metoprolol tartrate, followed by successful cardioversion and restoration of sinus rhythm. Given the stability of the fistula and the absence of symptomatic exacerbation, no further interventional measures were undertaken. The patient was discharged with an adjusted metoprolol regimen and scheduled follow-up with her cardiologist. Subsequent imaging assessments unveiled progressive fistula expansion alongside the development of concurrent CAA, inciting deliberations concerning optimal treatment modalities.

The MUC2 Gene Product: Polymerisation and Post-Secretory Organisation-Current Models.

MUC2 mucin, the primary gel-forming component of intestinal mucus, is well researched and a model of polymerisation and post-secretory organisation has been published previously. Recently, several significant developments have been made which either introduce new ideas or challenge previous theories. New ideas include an overhaul of the MUC2 C-terminal globular structure which is proposed to harbour several previously unobserved domains, and include a site for an extra intermolecular disulphide bridge dimer between the cysteine 4379 of adjacent MUC2 C-termini. MUC2 polymers are also now thought to be secreted attached to the epithelial surface of goblet cells in the small intestine and removed following secretion via a metalloprotease meprin ß-mediated cleavage of the von Willebrand D2 domain of the N-terminus. It remains unclear whether MUC2 forms intermolecular dimers, trimers, or both, at the N-termini during polymerisation, with several articles supporting either trimer or dimer formation. The presence of a firm inner mucus layer in the small intestine is similarly unclear. Considering this recent research, this review proposes an update to the previous model of MUC2 polymerisation and secretion, considers conflicting theories and data, and highlights the importance of this research to the understanding of MUC2 mucus layers in health and disease.

Transdermal bisoprolol for prevention of postoperative atrial fibrillation: A systematic review and meta-analysis.

Background: The transdermal patch of bisoprolol available in Japan has been reported to demonstrate superior efficacy in preventing postoperative atrial fibrillation, possibly surpassing its oral counterpart. However, there has been no systematic review and meta-analysis assessing the efficacy of transdermal bisoprolol. Methods: A comprehensive systematic literature search was conducted on PubMed, Embase, and Cochrane to identify all relevant studies assessing the efficacy of transdermal bisoprolol in preventing postoperative atrial fibrillation. The search covered studies from inception up to December 4, 2023. For data analysis, Review Manager (RevMan) 5.4 software was employed, using a random-effects model to calculate risk ratios (RR) and 95% confidence intervals (CI). Results: Three studies, comprising a total of 551 patients (transdermal bisoprolol 228 and control 323), were included. There was a decreased risk of postoperative atrial fibrillation or atrial tachyarrhythmias in patients treated with transdermal bisoprolol (RR 0.43, 95% CI 0.27-0.67, p = .0002, I 2 = 0%). Conclusion: Transdermal administration of bisoprolol has consistently shown efficacy, and this pooled analysis supports its effectiveness. The heterogeneity of the included studies limits certain interpretations. Future randomized clinical trials may elucidate the superiority of transdermal administration over oral administration.

Cardiac Challenges in Immune Checkpoint Therapy: Complete Heart Block With Pembrolizumab.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet they come with a spectrum of immune-related adverse events, including cardiac complications. We present the case of a 72-year-old male with metastatic renal cell carcinoma who developed complete heart block and ventricular arrhythmias following pembrolizumab therapy. Despite no evidence of myocarditis, the patient's condition rapidly deteriorated, ultimately resulting in his demise. This case underscores the critical need for vigilance in recognizing and managing potential cardiotoxicity associated with ICIs. Additionally, it highlights the importance of multidisciplinary collaboration in optimizing diagnostic and therapeutic strategies for patients undergoing immune checkpoint inhibitor therapy.

Pulmonary Artery Denervation as a New Therapeutic Option for Pulmonary Hypertension: A Systematic Review and Meta-Analysis.

Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality. The treatment is based on the type of PH. Prognosis still remains poor despite the use of different medications. Pulmonary artery denervation (PADN) has been studied as a novel therapeutic option in these patients. PUBMED, EMBASE and COCHRANE databases were searched by 2 investigators until January 2023. Information was analyzed for the following outcomes: 6-minute walk distance (6MWD), mean pulmonary artery pressure, pulmonary vascular resistance and cardiac output. Subgroup analysis comparing pre and post PADN in different PH groups was done. Statistical analysis was performed with the Review Manager version 5.4. This meta- analysis included 6 controlled trials and 6 single-arm prospective studies with a total of 616 patients. Our pooled analysis showed a significant reduction in mean pulmonary artery pressure [WMD -6.51, 95% CI (-9.87, -3.15), p = 0.0001], pulmonary vascular resistance [WMD -3.69, 95% CI (-6.74, -0.64), p = 0.02] and increased cardiac output [WMD -0.37, 95% CI (0.08, 0.65), p = 0.01]. Subgroup analysis pre and post PADN demonstrated a significant improvement in 6MWD in the WHO group 1 [WMD 99.53, 95% CI (19.60, 179.47), p = 0.01], group 2 [WMD: 69.96, 95% CI (36.40, 103.51), p = < 0.0001] and group 4 [WMD: 99.54, 95% CI (21.80, 177.28), p = 0.01]. This meta-analysis supports PADN as a therapeutic option for patients with PH, regardless of group class. Further randomized trials are still needed to evaluate safety and efficacy.

Return to work following brachial plexus injury: A cross-sectional study.

Background: Qualitative studies following Brachial Plexus Injury (BPI) suggest that return to employment has a major influence on life satisfaction and psychological well-being. However, few studies have focused on return to work following BPI. The physical strain and intensity of an occupation may influence the ability of an individual to return to employment. This study aimed to provide information about the impact of workload intensity on employment status following BPI. Methods: This is an observational, retrospective study of 74 participants who responded to a postal questionnaire, sharing information regarding their employment status pre- and post-BPI. The reported occupations were assessed for workload intensity and assigned a Reichsausschuss für Arbeitszeitermittlung (REFA) classification by two assessors. Results: Forty-one out of 74 participants (57%) had to change their employment following their BPI. Changes in occupation were more likely if the pre-injury REFA score was 3 or 4 (n = 22). In the Complete plexus injury group (n = 8), 100% changed occupation. In the Partial plexus injury group (n = 66) 50% changed occupation. Hand dominance had no significant influence on change of employment (p = 0.37). Conclusion: This study is the first to focus on the impact of BPI on employment status and workload intensity. Just over half the participants did not maintain the same employment following their BPI and one in five became unemployed. Future research should review the factors that contribute to the inability to return to work. This may direct enhancements in rehabilitation provision and enable healthcare services to focus on facilitating individuals back to the workplace.

Intensive Cardiac Rehabilitation Attenuates the Gender Gap in Cardiac Rehabilitation Participation.

Traditional cardiac rehabilitation (CR) programs historically have had considerable gender gaps in CR outcomes. Intensive-Cardiac-Rehabilitation (ICR) has nonexercise components such as stress management, peer support and diet modification, in addition to exercise, which may reduce barriers to CR completion. However, there is a paucity of data in ICR outcomes based on gender. We conducted a nationwide retrospective cohort study of 15,613 patients enrolled in 46 Ornish-ICR programs across the United States from January 2016 to December 2020 and compared ICR physical and psychological outcomes in women vs men. Primary endpoints were depression scores (CESD), health status (SF-36 physical and mental composite-scores) and exercise minutes per week. Of 15,613 ICR participants who participated in the program, 6788 (44%) were women. ICR completion rates were 64.7% overall and nearly equal between men and women (63.3% women vs 65.9% men). There were a few small differences in outcomes after ICR completion: women had slightly more improvement in depression scores (women: -6.10 ± 8.79, 49.6% reduction vs men: -4.92 ± 7.80, 46.4% reduction; P < 0.01) and SF-36 physical (women: 5.95 ± 6.86 vs men: 5.28 ± 6.71, P < 0.01) and SF-36 mental (women: 5.76 ± 8.11 vs men: 4.60 ± 7.33, P < 0.01) composite scores than men. There was no significant difference in exercise-minutes per week between the 2 groups. ICR attenuates the gender gap in CR completion. Further, of the completers, women achieved slightly higher depression and quality-of-life improvements compared to men. As such, ICR can be a good option to reduce gender-based differences in CR participation.

Intensive Cardiac Rehabilitation Outcomes in Patients with Heart Failure.

INTRODUCTION: Cardiac rehabilitation (CR) has proven to be beneficial for patients with heart failure (HF), potentially reducing morbidity and mortality while improving fitness and psychological outcomes. Intensive cardiac rehabilitation (ICR) represents an emerging form of CR that has demonstrated advantages for patients with various cardiovascular diseases. Nevertheless, the specific outcomes of ICR in patients with HF remain unknown. OBJECTIVES: The purpose of this study is to assess the effectiveness of ICR in patients with HF. METHODS: This retrospective study involved 12,950 patients who participated in ICR at 46 centers from January 2016 to December 2020. Patients were categorized into two groups: the HF group, comprising 1400 patients (11%), and the non-HF group, consisting of 11,550 patients (89%). The primary endpoints included the ICR completion rate, changes in body mass index (BMI), exercise minutes per week (EMW), and depression scores (CESD). A t-test was employed to compare variables between the two groups. RESULTS: The HF group comprises older patients, with 37% being females (compared to 44% in the non-HF group). The ICR completion rate was higher in the non-HF group. After ICR completion, adjusted analyses revealed that patients without HF demonstrated a greater improvement in BMI. There were no differences in fitness, as measured via EMW, or in depression scores, as measured via CESD, between the two groups. CONCLUSIONS: Despite the lower baseline functional status and psychosocial scores of HF patients compared to non-HF patients, patients with HF were able to attain similar or even better functional and psychosocial outcomes after ICR.