Managing Heart Failure in Patients on Dialysis: State-of-the-Art Review.

Heart failure (HF) and end-stage kidney disease (ESKD) frequently coexist; 1 comorbidity worsens the prognosis of the other. HF is responsible for almost half the deaths of patients on dialysis. Despite patients' with ESKD composing an extremely high-risk population, they have been largely excluded from landmark clinical trials of HF, and there is, thus, a paucity of data regarding the management of HF in patients on dialysis, and most of the available evidence is observational. Likewise, in clinical practice, guideline-directed medical therapy for HF is often down-titrated or discontinued in patients with ESKD who are undergoing dialysis; this is due to concerns about safety and tolerability. In this state-of-the-art review, we discuss the available evidence for each of the foundational HF therapies in ESKD, review current challenges and barriers to managing patients with HF on dialysis, and outline future directions to optimize the management of HF in these high-risk patients.

Meta-Analysis Evaluating Risk of Hyperkalemia Stratified by Baseline MRA Usage in Patients with Heart Failure Receiving SGLT2 Inhibitors.

BACKGROUND: Both mineralocorticoid receptor antagonists (MRAs) and sodium-glucose co-transporter type 2 inhibitors (SGLT2is) have demonstrated beneficial reductions in cardiovascular outcomes. However, the risk of precipitating hyperkalemia with their concomitant usage remains unclear. METHODS: MEDLINE and Cochrane were searched from inception through March 2022. Randomized controlled trials on patients with heart failure (HF) evaluating the effect of SGLT2is on clinical outcomes between MRA users and non-users were considered for inclusion. Outcomes of interest were mild and moderate/severe hyperkalemia, for which hazard ratios (HR) were pooled using a random effects model. RESULTS: From the 972 articles retrieved from the initial search, three RCTs (n = 14,462 patients) were included in our meta-analysis. Pooled analysis demonstrated no significant difference in the incidence of mild hyperkalemia between MRA users (HR 0.82 [0.70-0.97]) and non-users (HR 0.95 [0.77-1.17]) (P-interaction = 0.28). The risk of severe hyperkalemia was significantly decreased in MRA users (HR 0.59 [0.44-0.78]; p = 0.0002; I2 = 0%) but not in non-users (HR 0.76 [0.56-1.02]; p = 0.07; I2 = 0%) (P-interaction = 0.22). Sensitivity analysis including patients with HF with reduced ejection fraction (HFrEF) revealed similar results across all subgroups, but no significant reduction in the incidence of mild hyperkalemia (HR 0.89 [0.76-1.04] was noted in MRA users with HFrEF. CONCLUSION: MRAs reduced the risk of mild or moderate/severe hyperkalemia, when added to SGLT2is. Future clinical trials should target scrupulous assessment of the risk of mild and moderate/severe hyperkalemia when used concomitantly with MRAs.

Sex-based Disparities Among Surgical Faculty Positions Across Medical Colleges in Pakistan.

INTRODUCTION: Despite women being under-represented in academic surgery, there is no publicly accessible repository describing the distribution of surgeons by sex and specialty in Pakistan. This short report aims to fulfill this gap by describing female representation across surgical faculty positions in medical colleges across Pakistan. METHODS: This cross-sectional study was conducted in 2021 across medical universities in Pakistan. A dual mode of data collection was employed, whereby data regarding sex, academic designation, and subspecialty of surgical faculty was retrieved via emails to representative faculty from medical colleges, and from medical colleges' websites. RESULTS: A total of 97/114 (85.1%) medical colleges across Pakistan were included, providing us with data of 2070 surgical faculty. Overall, only 10.3% of surgical faculty were women, with women comprising 14.1% of assistant professors, 9.3% of associate professors, and only 5.7% of professors. Most women surgical faculty were assistant professors (63.1%), with only 17.8% being professors. Sindh (14.3%) and Punjab (9.7%) had the greatest percentage of women across surgical faculty overall, while Khyber Pakhtunkhwa had the lowest (6.5%). Apart from breast surgery (100%), pediatric surgery (29.4%), ophthalmology (15.0%) and general surgery (11.6%), women did not represent more than 10% of surgical faculty for any surgical subspecialty. CONCLUSION: In Pakistan, there is a blatant lack of female representation across all faculty positions and in most surgical specialties, with imbalances more pronounced in the relatively under-developed Khyber Pakhtunkhwa and Balochistan. These sex disparities may aggravate the surgical disease burden and adversely impact surgical prospects for women across the country.

A Pilot Study of Circulating Monocyte Subsets in Patients Treated with Stem Cell Transplantation for High-Risk Hematological Malignancies.

Background and Objectives: Autologous and allogeneic stem cell transplantation is used in the treatment of high-risk hematological malignancies, and monocytes are probably involved in hematological reconstitution as well as posttransplant immunoregulation. The aim of our study was to investigate the levels of circulating monocyte subsets in allotransplant recipients. Materials and Methods: The levels of the classical, intermediate, and nonclassical monocyte subsets were determined by flow cytometry. Sixteen patients and 18 healthy controls were included, and the levels were analyzed during pretransplant remission (n = 13), early posttransplant during cytopenia (n = 9), and early reconstitution (n = 9). Results: Most patients in remission showed a majority of classical monocytes. The patients showed severe early posttransplant monocytopenia, but the total peripheral blood monocyte counts normalized very early on, and before neutrophil and platelet counts. During the first 7-10 days posttransplant (i.e., during cytopenia) a majority of the circulating monocytes showed a nonclassical phenotype, but later (i.e., 12-28 days posttransplant) the majority showed a classical phenotype. However, the variation range of classical monocytes was wider for patients in remission and during regeneration than for healthy controls. Conclusions: The total peripheral blood monocyte levels normalize at the very early stages and before neutrophil reconstitution after stem cell transplantation, and a dominance of classical monocytes is reached within 2-4 weeks posttransplant.

Circulating monocyte subsets in multiple myeloma patients receiving autologous stem cell transplantation - a study of the preconditioning status and the course until posttransplant reconstitution for a consecutive group of patients.

BACKGROUND: Induction therapy of multiple myeloma patients prior to autologous stem cell transplantation has changed from conventional chemotherapy to treatment based on proteasome inhibitors or immunomodulatory drugs. We used flow cytometry to analyze total monocyte and monocyte subset (classical, intermediate and non-classical monocytes) peripheral blood levels before and following auto-transplantation for a consecutive group of myeloma patients who had received the presently used induction therapy. RESULTS: The patients showed normal total monocyte concentrations after induction/stem cell mobilization, but the concentrations of classical monocytes were increased compared with healthy controls. Melphalan conditioning reduced the levels of total CD14+ as well as classical and non-classical monocytes, whereas intermediate monocytes were not affected. Thus, melphalan has a non-random effect on monocyte subsets. Melphalan had a stronger effect on total and classical monocyte concentrations for those patients who had received induction therapy including immunomodulatory drugs. Total monocytes and monocyte subset concentrations decreased during the period of pancytopenia, but monocyte reconstitution occurred before hematopoietic reconstitution. However, the fractions of various monocyte subsets varied considerably between patients. CONCLUSIONS: The total level of circulating monocytes is normalized early after auto-transplantation for multiple myeloma, but pre- and post-transplant levels of various monocyte subsets show considerable variation between patients.

Translation of a standardized manufacturing protocol for mesenchymal stromal cells: A systematic comparison of validation and manufacturing data.

BACKGROUND: Many data are available on expansion protocols for mesenchymal stromal cells (MSCs) for both experimental settings and manufacturing for clinical trials. However, there is a lack of information on translation of established protocols for Good Manufacturing Practice (GMP) from validation to manufacturing for clinical application. We present the validation and translation of a standardized pre-clinical protocol for isolation and expansion of MSCs for a clinical trial for reconstitution of alveolar bone. METHODS: Key parameters of 22 large-scale expansions of MSCs from bone marrow (BM) for validation were compared with 11 expansions manufactured for the clinical trial "Jaw bone reconstruction using a combination of autologous mesenchymal stromal cells and biomaterial prior to dental implant placement (MAXILLO1)" aimed at reconstruction of alveolar bone. RESULTS: Despite variations of the starting material, the robust protocol led to stable performance characteristics of expanded MSCs. Manufacturing of the autologous advanced therapy medicinal product MAXILLO-1-MSC was possible, requiring 21 days for each product. Transport of BM aspirates and MSCs within 24 h was guaranteed. MSCs fulfilled quality criteria requested by the national competent authority. In one case, the delivered MSCs developed a mosaic in chromosomal finding, showing no abnormality in differentiation capacity, growth behavior or surface marker expression during long-term culture. The proportion of cells with the mosaic decreased in long-term culture and cells stopped growth after 38.4 population doublings. CONCLUSIONS: Clinical use of freshly prepared MSCs, manufactured according to a standardized and validated protocol, is feasible for bone regeneration, even if there was a long local distance between manufacturing center and clinical site. Several parameters, such as colony forming units fibroblasts (CFU-F), percentage of CD34+ cells, cell count of mononuclear cells (MNCs) and white blood cells (WBCs), of the BM may serve as a predictive tool for the yield of MSCs and may help to avoid unnecessary costs for MSC manufacturing due to insufficient cell expansion rates.

The healthy donor profile of immunoregulatory soluble mediators is altered by stem cell mobilization and apheresis.

BACKGROUND: Peripheral blood stem cells from healthy donors mobilized by granulocyte colony-stimulating factor (G-CSF) and thereafter harvested by leukapheresis are commonly used for allogeneic stem cell transplantation. METHODS: Plasma levels of 38 soluble mediators (cytokines, soluble adhesion molecules, proteases, protease inhibitors) were analyzed in samples derived from healthy stem cell donors before G-CSF treatment and after 4 days, both immediately before and after leukapheresis. RESULTS: Donors could be classified into two main subsets based on their plasma mediator profile before G-CSF treatment. Seventeen of 36 detectable mediators were significantly altered by G-CSF; generally an increase in mediator levels was seen, including pro-inflammatory cytokines, soluble adhesion molecules and proteases. Several leukocyte- and platelet-released mediators were increased during apheresis. Both plasma and graft mediator profiles were thus altered and showed correlations to graft concentrations of leukocytes and platelets; these concentrations were influenced by the apheresis device used. Finally, the mediator profile of the allotransplant recipients was altered by graft infusion, and based on their day +1 post-transplantation plasma profile our recipients could be divided into two major subsets that differed in overall survival. DISCUSSION: G-CSF alters the short-term plasma mediator profile of healthy stem cell donors. These effects together with the leukocyte and platelet levels in the graft determine the mediator profile of the stem cell grafts. Graft infusion also alters the systemic mediator profile of the recipients, but further studies are required to clarify whether such graft-induced alterations have a prognostic impact.

Immunological Heterogeneity of Healthy Peripheral Blood Stem Cell Donors-Effects of Granulocyte Colony-Stimulating Factor on Inflammatory Responses.

Interleukin-6 (IL-6) contributes to the development of immune-mediated complications after allogeneic stem cell transplantation. However, systemic IL-6 levels also increase during granulocyte colony-stimulating factor (G-CSF) mobilization of hematopoietic stem cells in healthy donors, but it is not known whether this mobilization alters systemic levels of other IL-6 family cytokines/receptors and whether such effects differ between donors. We examined how G-CSF administration influenced C-reactive protein (CRP) levels (85 donors) and serum levels of IL-6 family cytokines/receptors (20 donors). G-CSF increased CRP levels especially in elderly donors with high pretherapy levels, but these preharvesting levels did not influence clinical outcomes (nonrelapse mortality, graft versus host disease). The increased IL-6 levels during G-CSF therapy normalized within 24 h after treatment. G-CSF administration did not alter serum levels of other IL-6-familly mediators. Oncostatin M, but not IL-6, showed a significant correlation with CRP levels during G-CSF therapy. Clustering analysis of mediator levels during G-CSF administration identified two donor subsets mainly characterized by high oncostatin M and IL-6 levels, respectively. Finally, G-CSF could increase IL-6 release by in vitro cultured monocytes, fibroblasts, and mesenchymal stem cells. In summary, G-CSF seems to induce an acute phase reaction with increased systemic IL-6 levels in healthy stem cell donors.

Immunomodulation Induced by Stem Cell Mobilization and Harvesting in Healthy Donors: Increased Systemic Osteopontin Levels after Treatment with Granulocyte Colony-Stimulating Factor.

Peripheral blood stem cells from healthy donors mobilized by granulocyte colony-stimulating factor (G-CSF) and harvested by leukapheresis are commonly used for allogeneic stem cell transplantation. The frequency of severe graft versus host disease is similar for patients receiving peripheral blood and bone marrow allografts, even though the blood grafts contain more T cells, indicating mobilization-related immunoregulatory effects. The regulatory phosphoprotein osteopontin was quantified in plasma samples from healthy donors before G-CSF treatment, after four days of treatment immediately before and after leukapheresis, and 18-24 h after apheresis. Myeloma patients received chemotherapy, combined with G-CSF, for stem cell mobilization and plasma samples were prepared immediately before, immediately after, and 18-24 h after leukapheresis. G-CSF treatment of healthy stem cell donors increased plasma osteopontin levels, and a further increase was seen immediately after leukapheresis. The pre-apheresis levels were also increased in myeloma patients compared to healthy individuals. Finally, in vivo G-CSF exposure did not alter T cell expression of osteopontin ligand CD44, and in vitro osteopontin exposure induced only small increases in anti-CD3- and anti-CD28-stimulated T cell proliferation. G-CSF treatment, followed by leukapheresis, can increase systemic osteopontin levels, and this effect may contribute to the immunomodulatory effects of G-CSF treatment.

Pretransplant Levels of CRP and Interleukin-6 Family Cytokines; Effects on Outcome after Allogeneic Stem Cell Transplantation.

Several pretransplant factors, including CRP (C-reactive protein) levels, reflect the risk of complications after allogeneic stem cell transplantation. IL-6 induces CRP increase, and we therefore investigated the effects of pretransplant IL-6, soluble IL-6 receptors, IL-6 family cytokines and CRP serum levels on outcome for 100 consecutive allotransplant recipients. All patients had related donors, none had active infections and 99 patients were in complete remission before conditioning. The incidence of acute graft versus host disease (aGVHD) requiring treatment was 40%, survival at Day +100 82%, and overall survival 48%. Despite a significant correlation between pretransplant CRP and IL-6 levels, only CRP levels significantly influenced transplant-related mortality (TRM). However, CRP did not influence overall survival (OS). Pretransplant IL-31 influenced late TRM. Finally, there was a significant association between pretransplant IL-6 and early postconditioning weight gain (i.e., fluid retention), and this fluid retention was a risk factor for aGVHD, TRM and OS. To conclude, pretransplant CRP, IL-31 and early posttransplant fluid retention were independent risk factors for TRM and survival after allotransplantation.

Extracorporeal photopheresis (photochemotherapy) in the treatment of acute and chronic graft versus host disease: immunological mechanisms and the results from clinical studies.

Extracorporeal photopheresis (ECP) is an immunomodulatory alternative for treatment of graft versus host disease (GVHD). The blood is then separated into its various components through apheresis; buffy coat cells are thereafter treated with 8-methoxypsoralen before exposure to ultraviolet light and finally reinfused into the patient. There is a general agreement that this treatment has an anti-GVHD effect, but the mechanisms of action behind this effect are only partly understood. However, altered maturation of dendritic cells (DC) and thereby indirect modulation of T-cell reactivity seems to be one important mechanism together with DC-presentation of antigens derived from apoptotic donor T cells and induction of regulatory T cells. The treatment has been best studied in patients with chronic GVHD (both pediatric and adult patients), but most studies are not randomized and it is difficult to know whether the treatment is more effective than the alternatives. The clinical studies of ECP in adults with acute GVHD are few and not randomized; it is not possible to judge whether this treatment should be a preferred second- or third-line treatment. There is no evidence for increased risk of leukemia relapse or suppression of specific graft versus leukemia reactivity by this treatment, so specific antileukemic immunotherapy may still be possible. Thus, even though the treatment seems effective in patients with GVHD, further clinical (especially randomized) as well as biological studies with careful standardization of the treatment are needed before it is possible to conclude how ECP should be used in acute and chronic GVHD.

Immune checkpoint inhibitor-induced cardiotoxicity in patients with lung cancer: a systematic review and meta-analysis.

BACKGROUND: The use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer may precipitate cardiotoxic events. We aimed to perform a meta-analysis to evaluate the cardiotoxicity associated with ICIs in patients with lung cancer. METHODS: A literature search was conducted across four electronic databases (Cochrane CENTRAL, MEDLINE, OVID EMBASE and Google Scholar) from inception through 31st May 2023. Randomized controlled trials (RCTs) assessing the impact of ICIs on cardiac outcomes in lung cancer patients were considered for inclusion. Risk ratios (RR) with 95% confidence intervals (CIs) were pooled and analysis was performed using a random-effects model. The Grading of Recommendations Assessment, Development and Evaluation approach was followed to assess confidence in the estimates of effect (i.e., the quality of evidence). RESULTS: A total of 30 studies including 16,331 patients, were included in the analysis. Pooled results showed that single ICI (RR: 2.15; 95% CI: 1.13-4.12; p = 0.02; I2 = 0%) or a combination of single ICI plus chemotherapy (RR: 1.38 [1.05-1.82]; p = 0.02) significantly increased the risk of cardiac adverse events when compared with chemotherapy alone. No significant difference was noted when a dual ICI (RR: 0.48 [0.13-1.80]; p = 0.27) was compared with single ICI. In addition, there was no significant association between the use of ICIs and incidence of cardiac failure (RR: 1.11 [0.48-2.58]; p = 0.80), or arrhythmia (RR: 1.87; [0.69-5.08]; p = 0.22). CONCLUSION: Compared with chemotherapy alone, use of a single ICI or a combination of single ICI plus chemotherapy significantly increased the risk of cardiotoxicity. However, employing dual immunotherapy did not result in a significant increase in the risk of cardiotoxicity when compared to the use of a single ICI.

Cardiovascular and Cerebrovascular Outcomes With Vitamin D Supplementation: A Systematic Review and Meta-Analysis.

Vitamin D supplementation has seen a sharp increase in the primary healthcare setting but its efficacy in decreasing the risk of cardiovascular and cerebrovascular events is yet to be reliably established. We aim to determine whether vitamin D supplementation can significantly impact the risk of cardiovascular and cerebrovascular events. An extensive literature search of PubMed, Embase, and Cochrane CENTRAL was conducted from inception till August 2023 to include all the articles comparing vitamin D and placebo. Cardiovascular and cerebrovascular outcomes were presented as risk ratios (RR) with 95% confidence intervals (CIs) and pooled using a random effects model. Thirty-six trials consisting of 493,389 participants were included in our analysis. Our pooled analysis demonstrated no significant difference between vitamin D supplementation and placebo for the risk of cardiovascular mortality (RR 1.01, 95% CI 0.94-1.08; P = 0.80), stroke or cerebrovascular events (RR 1.03, 95% CI 0.95-1.11; P = 0.48), myocardial infarction (MI) (RR 0.98, 95% CI 0.91-1.06; P = 0.65), cerebrovascular mortality (RR 1.00, 95% CI 0.68-1.46; P = 0.99), arrhythmias (RR 0.98, 95% CI 0.66-1.44; P = 0.90) and hemorrhagic or ischemic stroke. There was no significant heterogeneity between the studies in any analysis. There was no significant difference in the risk of cardiovascular and cerebrovascular outcomes with vitamin D supplementation or placebo. Additional large high-powered studies focused on high-risk and vitamin D-deficient populations are required to resolve the current discrepancy in the literature and provide a definitive conclusion to this end.

Angiotensin-Neprilysin inhibition in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials.

BACKGROUND: The effect of sacubitril/valsartan on patients with heart failure (HF) with preserved ejection fraction (HFpEF) is a topic of ongoing debate. METHODS: Medline was queried from inception through the last week of May 2023 for randomized studies assessing the effects of sacubitril/valsartan in patients with HFpEF. For continuous outcomes, we pooled either the geometric mean ratios (gMR) or weighted mean difference (WMD) with 95% confidence intervals (CI). For dichotomous outcomes, we pooled Risk ratios (RR) with 95% CI. RESULTS: Four trials were included (N=8,129). Compared to the control, sacubitril/valsartan was associated with a reduction in NT-proBNP levels (gMR: 0.84, 95% CI 0.80, 0.88) and improvement in KCCQ score (WMD: 0.85, 95% CI: 0.02, 1.67). We observed no differences for HF hospitalization (RR: 0.90, 95% CI: 0.79, 1.01), cardiovascular mortality (RR: 0.83, 95% CI: 0.52, 1.32), all-cause mortality (RR: 0.99, 95% CI: 0.86-1.13) and improvement (RR: 1.15, 95% CI: 0.93, 1.42) or worsening (RR: 0.92, 95% CI: 0.78, 1.09) of NYHA class between the sacubitril/valsartan and comparator group. Sacubitril/valsartan was generally safe, and patients were less likely to have a ≥50% decline in eGFR compared to control (RR: 0.60, 95% CI: 0.39, 0.92). CONCLUSION: Pooled analysis suggests that sacubitril/valsartan reduces natriuretic peptide levels and improves the quality of life in patients with HFpEF, which may translate into better clinical outcomes as observed by a numerical trend towards improvement in major HF outcomes with sacubitril/valsartan therapy.

Effectiveness of exercise modalities on breast cancer patient outcomes: a systematic review and meta-analysis.

BACKGROUND: The effects of exercise in patients with breast cancer (BC), has shown some profit, but consistency and magnitude of benefit remains unclear. We aimed to conduct a meta-analysis to assess the benefits of varying types of exercises in patients with BC. METHODS: Literature search was conducted across five electronic databases (MEDLINE, Web of Science, Scopus, Google Scholar and Cochrane) from 1st January 2000 through 19th January 2024. Randomized controlled trials (RCTs) assessing the impact of different types of exercise on outcomes related to fitness and quality of life (QOL) in patients with BC were considered for inclusion. Outcomes of interest included cardiorespiratory fitness (CRF), health-related quality of life (HRQOL), muscle strength, fatigue and physical function. Evaluations were reported as mean differences (MDs) with 95% confidence intervals (CIs) and pooled using random effects model. A p value < 0.05 was considered significant. RESULTS: Thirty-one relevant articles were included in the final analysis. Exercise intervention did not significantly improved the CRF in patients with BC when compared with control according to treadmill ergometer scale (MD: 4.96; 95%Cl [-2.79, 12.70]; P = 0.21), however exercise significantly improved CRF according to cycle ergometer scales (MD 2.07; 95% Cl [1.03, 3.11]; P = 0.0001). Physical function was significantly improved as well in exercise group reported by 6-MWT scale (MD 80.72; 95% Cl [55.67, 105.77]; P < 0.00001). However, exercise did not significantly improve muscle strength assessed using the hand grip dynamometer (MD 0.55; 95% CI [-1.61, 2.71]; P = 0.62), and fatigue assessed using the MFI-20 (MD -0.09; 95% CI [-5.92, 5.74]; P = 0.98) and Revised Piper scales (MD -0.26; 95% CI [-1.06, 0.55] P = 0.53). Interestingly, exercise was found to improve HRQOL when assessed using the FACT-B scale (MD 8.57; 95% CI [4.53, 12.61]; P < 0.0001) but no significant improvements were noted with the EORTIC QLQ-C30 scale (MD 1.98; 95% CI [-1.43, 5.40]; P = 0.25). CONCLUSION: Overall exercise significantly improves the HRQOL, CRF and physical function in patients with BC. HRQOL was improved with all exercise types but the effects on CRF vary with cycle versus treadmill ergometer. Exercise failed to improve fatigue-related symptoms and muscle strength. Large RCTs are required to evaluate the effects of exercise in patients with BC in more detail.

Treatment and Response Evaluation Challenges in a Pregnant Woman With B-Cell Lymphoblastic Leukemia and Li-Fraumeni Syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposing syndrome caused by pathogenic germline TP53 gene mutations with important therapeutic and prognostic implications for many types of cancer. A small proportion of LFS patients develop B-cell lymphoblastic leukemia (B-ALL) in adult years. Standard treatment often proves inadequate, but immunotherapy has provided new treatment options. The current case report presents a pregnant woman with LFS and newly diagnosed B-ALL with hypodiploidy developed after treatment for early-onset breast cancer. We describe the treatment course, treatment-related complications and provide laboratory data crucial for evaluating and modifying treatment for this difficult clinical case. Our findings support the need for close collaboration between clinicians and experts on immunophenotyping. Through our report, we show that immunotherapy is feasible in patients with LFS and B-ALL, despite a poor initial response to induction therapy.

Clinical Outcomes in Hypertensive Emergency: A Systematic Review and Meta-Analysis.

Background To study the prevalence and types of hypertension-mediated organ damage and the prognosis of patients presenting to the emergency department (ED) with hypertensive emergencies. Methods and Results PubMed was queried from inception through November 30, 2021. Studies were included if they reported the prevalence or prognosis of hypertensive emergencies in patients presenting to the ED. Studies reporting data on hypertensive emergencies in other departments were excluded. The extracted data were arcsine transformed and pooled using a random-effects model. Fifteen studies (n=4370 patients) were included. Pooled analysis demonstrates that the prevalence of hypertensive emergencies was 0.5% (95% CI, 0.40%-0.70%) in all patients presenting to ED and 35.9% (95% CI, 26.7%-45.5%) among patients presenting in ED with hypertensive crisis. Ischemic stroke (28.1% [95% CI, 18.7%-38.6%]) was the most prevalent hypertension-mediated organ damage, followed by pulmonary edema/acute heart failure (24.1% [95% CI, 19.0%-29.7%]), hemorrhagic stroke (14.6% [95% CI, 9.9%-20.0%]), acute coronary syndrome (10.8% [95% CI, 7.3%-14.8%]), renal failure (8.0% [95% CI, 2.9%-15.5%]), subarachnoid hemorrhage (6.9% [95% CI, 3.9%-10.7%]), encephalopathy (6.1% [95% CI, 1.9%-12.4%]), and the least prevalent was aortic dissection (1.8% [95% CI, 1.1%-2.8%]). Prevalence of in-hospital mortality among patients with hypertensive emergency was 9.9% (95% CI, 1.4%-24.6%). Conclusions Our findings demonstrate a pattern of hypertension-mediated organ damage primarily affecting the brain and heart, substantial cardiovascular renal morbidity and mortality, as well as subsequent hospitalization in patients with hypertensive emergencies presenting to the ED.

The association of antibiotic exposure with new-onset inflammatory bowel disease: A systematic review and meta-analysis.

INTRODUCTION: The role of antibiotics in the development of inflammatory bowel disease (IBD) remains controversial, primarily due to conflicting data from individual studies. We conduct a systematic review and meta-analysis to study the effect of antibiotic exposure on IBD development. METHODOLOGY: The MEDLINE and Cochrane CENTRAL databases were queried from their inception to April 2021 for published articles studying the association between antibiotic exposure and new-onset IBD. Our analysis was stratified by timing of antibiotic exposure - exposure in childhood and any lifetime exposure. Adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) from each study were pooled using a random-effects model. RESULTS: 10 case-control studies and 2 cohort studies (N = 29,880 IBD patients and N = 715,548 controls) were included. Patients with Crohn's Disease (CD), compared with controls, were associated significantly with antibiotic exposure in childhood and any lifetime exposure to antibiotics (OR 1.52 [1.23-1.87]; p<0.00001). Patients with Ulcerative Colitis (UC), compared with controls, reported non-significant association with antibiotic exposure in childhood and any lifetime exposure. (OR 1.11 [0.93-1.33]; p = 0.25) CONCLUSION: This meta-analysis suggests that exposure to antibiotics significantly increases the odds of developing CD and IBD. These findings re-emphasize the importance of cautious and judicious use of antibiotics.

IL-6 Responsiveness of CD4+ and CD8+ T Cells after Allogeneic Stem Cell Transplantation Differs between Patients and Is Associated with Previous Acute Graft versus Host Disease and Pretransplant Antithymocyte Globulin Therapy.

Graft-versus-host disease (GVHD), one of the most common and serious complications after allogeneic stem cell transplantation, is mediated by allocative T cells. IL-6 mediates both pro- and anti-inflammatory effects and modulates T cell response through classical signaling and trans-signaling. We investigated the effects on the mTOR and JAK/STAT pathways after various types of IL-6 signaling for circulating T cells were derived from 31 allotransplant recipients 90 days post-transplant. Cells were stimulated with IL-6 alone, hyper-IL-6 (trans-signaling), IL-6+IL-6 receptor (IL-6R; classical + trans-signaling) and IL-6+IL-6R+soluble gp130-Fc (classical signaling), and flow cytometry was used to investigate the effects on phosphorylation of AKT (Thr308), mTOR (Ser2442), STAT3 (Ser727) and STAT3 (Tyr705). CD3+CD4+ and CD3+C8+ T cells responded to classical and trans IL-6 stimulation with increased STAT3 (Tyr705) phosphorylation; these responses were generally stronger for CD3+CD4+ cells. STAT3 (Tyr705) responses were stronger for patients with previous acute GVHD; CD3+CD4+ cells from GVHD patients showed an additional STAT3 (Ser727) response, whereas patients without acute GVHD showed additional mTOR (Ser2448) responses. Furthermore, treatment with antithymocyte globulin as a part of GVHD prophylaxis was associated with generally weaker STAT3 (Tyr705) responses and altered STAT3 (Ser727) responsiveness of CD3+CD4+ cells together with increased mTOR (Ser2448) responses for the CD3+CD8+ cells. Thus, early post-transplant CD3+CD4+ and CD3+ CD8+ T cell subsets differ in their IL-6 responsiveness; this responsiveness is modulated by antithymocyte globulin and differs between patients with and without previous acute GVHD. These observations suggest that allotransplant recipients will be heterogeneous with regard to the effects of post-transplant IL-6 targeting.

Effect of novel glucose lowering agents on non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND: The efficacy of novel glucose-lowering drugs in treating non-alcoholic fatty liver disease (NAFLD) in patients with and without type-2 diabetic patients (T2DM) remains unclear. AIM: To conduct a meta-analysis to evaluate the efficacy of 3 novel glucose-lowering drug classes, namely glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 (SGLT2) inhibitors, and dipeptidyl-peptidase-4 (DPP4) inhibitors on hepatic parameters: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Gamma-Glutamyl Transferase (GGT), Bilirubin, and FIB-4 (Fibrosis). METHODS: MEDLINE was searched from inception through October 2021 for randomized placebo or active glucose-lowering drug-controlled trials. A random-effects model was used to pool the results. A p-value of less than or equal to 0.05 was considered significant. Results were presented as weighted mean differences (WMD) and corresponding 95% confidence intervals (CIs). RESULTS: Our pooled analysis consisted of 40 studies. A significant reduction was seen in AST with SGLT2 inhibitors (WMD = -2.31 IU/L, 95%CI: -3.16 to -1.47 IU/L, P < 0.00001) and GLP-1RA (WMD = -3.29 IU/L, 95%CI: -5.98 to -0.61 IU/L, P = 0.02). Similarly, significant reduction was seen in ALT with SGLT2 inhibitors (WMD = -5.93 IU/L, 95%CI: -7.70 to -4.16 IU/L, P < 0.00001) and GLP-1RAs (WMD = -9.92 IU/L, 95%CI: -19.89 to 0.05 IU/L, P = 0.05). In contrast, DPP-4 inhibitors showed no significant reduction in AST (WMD = -3.20 IU/L, 95%CI: -11.13 to 4.73 IU/L, P = 0.43) or ALT (WMD = -4.81 IU/L, 95%CI: -15.83 to 6.21 IU/L, P = 0.39). A significant reduction in GGT was seen with SGLT2 inhibitors (WMD = -6.49 IU/L, 95%CI: -11.09 to -1.89 IU/L, P = 0.006) and GLP-1RAs (WMD = -12.38 IU/L, 95%CI: -15.69 to -9.07 IU/L, P < 0.00001). However, significant results were not observed with DPP-4 inhibitors (WMD = -0.92 IU/L, 95%CI: -5.80 to 3.96 IU/L, P = 0.71). There was a statistically significant reduction in FIB-4 index with SGLT2 inhibitors (WMD = -0.21, 95%CI: -0.40 to -0.03, P = 0.02) and GLP-1 RA (WMD = -0.15, 95%CI: -0.29 to 0.00, P = 0.05). Lastly, SGLT2 inhibitors led to a significant change in bilirubin levels (WMD = 2.03, 95%CI: 0.76 to 3.30, P = 0.002) while the change in bilirubin was not significant with GLP-1 agonists (WMD = -0.21, 95%CI: -1.09 to 0.66, P = 0.63) and DPP-4 inhibitors (WMD = 0.14, 95%CI: -1.55 to 1.83, P = 0.87). CONCLUSION: SGLT2 inhibitors and GLP-1 agonists have a beneficial effect on hepatic parameters in patients with NAFLD. However, further research is needed to evaluate the effect of DPP-4 inhibitors on hepatic function properly.