A potential approach toward the management of sepsis: The extracorporeal cytokine hemadsorption therapy.

Infectious diseases are among the most common cause of morbidity and mortality among hospitalized patients while systemic inflammatory response syndrome is primarily attributed to the imbalance between pro-inflammatory and anti-inflammatory cytokines. Despite the improvements in the antibiotherapy alternatives and diagnostic modalities, the morbidity and mortality rates of sepsis and septic shock are relatively high among patients admitted to the intensive care units. Extracorporeal cytokine hemadsorption therapies are therapeutic approaches for such patient group with promising early results that especially have grown during COVID-19 pandemic. In this narrative review, our aim is to evaluate the current pre-clinical and clinical knowledge regarding the use of cytokine filtration systems among patients with septic shock.

Effect of tirzepatide on blood pressure and lipids: A meta-analysis of randomized controlled trials.

AIM: To perform a meta-analysis to quantify the effect of tirzepatide on blood pressure and lipids. METHODS: PubMed, Ovid/Medline, Web of Science, Scopus, Cochrane Library and CINAHL databases were screened and the randomized controlled trials evaluating the effects of tirzepatide on either blood pressure or lipid profiles were included. RESULTS: Seven randomized controlled trials have investigated the effects of tirzepatide on blood pressure and lipid profiles. Regardless of the dose administered, tirzepatide resulted in significant decreases in systolic blood pressure of median -4.20 (95% confidence interval [CI] -5.17 to -3.23) mmHg for 5 mg, -5.34 (-6.31 to -4.37) mmHg for 10 mg, and -5.77 (-6.73 to -4.81) mmHg for 15 mg. At all three once-weekly doses, tirzepatide treatment resulted in significant decreases in total cholesterol levels: median -3.76% (95% CI -5.20% to -2.31%) for 5 mg; -4.63% (-6.07% to -3.19%) for 10 mg; and -5.93% (-7.36% to -4.49%) for 15 mg. Additionally, tirzepatide treatment led to increased high-density lipoprotein (HDL) cholesterol levels and decreased low-density lipoprotein (LDL) cholesterol and triglyceride levels. CONCLUSIONS: Tirzepatide induced clinically meaningful reductions in the levels of systolic and diastolic blood pressure, total cholesterol, LDL cholesterol and triglycerides, along with increases in the level of HDL cholesterol.

Discrepancy between IDSA and ESGBOR in Lyme disease: Individual participant meta-analysis in Türkiye.

BACKGROUND: The evidence on the prevalence of Lyme borreliosis (LB) is limited, but there is a suspicion of overdiagnosis of LB in recent years. We reviewed the LB diagnosis and treatment-related data in Türkiye, based on the Infectious Diseases Society of America (IDSA) 2020 and European Society of Clinical Microbiology and Infectious Diseases Study Group for Lyme Borreliosis (ESGBOR) 2018 guidelines. By detecting the disagreements between these two, we outlined the areas to be improved for future guidelines. METHODS: We performed a literature search according to the PRISMA guidelines in PubMed, Ovid-Medline, Web of Science, Turkish Medline, Scopus, CINAHL, ULAKBIM TR Index, Google Scholar and Cochrane Library databases. We included the published cases in a database and evaluated according to IDSA and ESGBOR guidelines. We outlined the reasons for misdiagnoses and inappropriate uses of antibiotics. RESULTS: We included 42 relevant studies with 84 LB cases reported from Türkiye between 1990 and December 2022. Among 84 cases, the most common clinical findings were nervous system findings (n = 37, 44.0%), erythema migrans (n = 29, 34.5%) and ophthalmologic findings (n = 15, 17.9%). The IDSA 2020 and ESGBOR 2018 guidelines agreed on the diagnosis of 71 (84.5%) cases; there was an agreement that 31 cases (36.9%) were misdiagnosed and 40 cases (47.6%) were correctly diagnosed, and there was disagreement for 13 cases (15.5%). Serum immunoglobulin M (IgM), IgG measurements by ELISA and western blot were widely performed, and they were effective in definitive diagnosis merely when used according to guidelines. Inappropriate use of antibiotics was detected in 42 (50.0%) of cases which were classified in the following categories: incorrect LB diagnosis, inappropriate choice of antibiotic, inappropriate route of drug administration and prolonged antibiotic treatment. CONCLUSION: Overdiagnosis and non-adherence to guidelines is a common problem. The discordance between seroprevalence and clinical studies necessitates a consensus over the best clinical approach.

Amnioinfusion vs. standard management for the second trimester PPROM: a systematic review and meta-analysis of observational studies and RCTs.

OBJECTIVE: This meta-analysis aims to review the effect of serial transabdominal amnioinfusion (TAI) on short-term and long-term perinatal outcomes in mid-trimester preterm premature rupture of membranes (PPROM). METHODS: Literature searches of PubMed, Web of Sciences, Scopus, and Cochrane Library were performed from their inception to April 2022. Studies comparing conventional treatment with serial TAI in women with proven PPROM at less than 26 + 0 weeks of gestation with oligohydramnios were included. Studies that included oligohydramnios due to other reasons such as fetal growth retardation or renal anomalies were excluded. Risk of bias in observational studies was assessed using the tool of the Cochrane Review group identified as risk of bias in non-randomized studies - of interventions. The risk of bias assessments for RCTs were performed according to the Cochrane risk-of-bias tool for randomized trials. An I2 score was used to assess the heterogeneity of included studies. The analyses were performed by using random-effect model, and the results were expressed as relative risk (RR) or mean difference with 95% confidence intervals (CIs). RESULTS: Overall, eight relevant studies including five observational studies (n = 252; 130 women allocated to the intervention) and three RCTs (n = 183; 93 women allocated to the intervention) were eligible. The pooled latency period was 21.9 days (95% CI, 13.1-30.8) and 5.8 days (95% CI, -11.6-23.2) longer in the TAI group in the observational studies and RCTs, respectively. The perinatal mortality rate reduced in the intervention group when tested in observational studies (RR 0.68; 95% CI, 0.51-0.92), but not in RCTs (RR 0.79; 95% CI, 0.56-1.13). The rate of long-term healthy survival was higher in the children whose mothers were treated with the TAI (35.7%) than those were treated with the standard management (28.6%) (RR 1.30, 95% CI 0.47-3.60, "best case scenario"). CONCLUSIONS: The efficacy of serial TA on early PPROM associated morbidity and mortality is not attested. Additional randomized control trials with adequate power are needed.

Immune checkpoints inhibitors and its link to acute kidney injury and renal prognosis.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors (ICPi) may cause acute kidney injury (AKI) and their use is increasing. MATERIALS AND METHODS: This is a single-center retrospective cohort study of patients receiving ICPi drugs for solid organ malignancies. ICPi-related AKI, the need for renal replacement therapy during or following ICPi treatment, and the associated mortality was studied. RESULTS: Two hundred thirty five patients were included in the final analysis. Patients with (N = 40) and without (n = 195) AKI had similar age, sex, type of ICPi, baseline serum creatinine levels, comorbidities and mortality; while patients with AKI were more likely to be receiving a nephrotoxic agent or be treated for genitourinary malignancy. 18 patients had ICPi-related AKI; 7 of these patients underwent kidney biopsy, which showed acute interstitial nephritis while the remaining 11 were diagnosed on clinical parameters. 18 (45%) patients recovered kidney function after AKI. No differences were observed between patients with and without kidney function recovery, although patients without recovery had a numerical, but not statistically significant, higher mortality. Patients with biopsy-confirmed ICPi-induced AKI had an increased risk of mortality, as compared with the rest of the population-HR 1.83, 95% CI 1.22-2.74, p = 0.003. CONCLUSION: Use of nephrotoxic drugs and the location of malignancy appear to be common drivers of AKI in patients receiving ICPis for solid organ malignancy. Whether nephrotoxic agents or urinary tract obstruction may favor ICPi-related autoimmunity should be further studied.

The association between acute kidney injury and outcomes in cancer patients receiving immune checkpoint inhibitor therapy: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICPIs) are a novel therapeutic approach to cancer treatment that have changed the landscape of cancer therapy but also have some considerable drawbacks. Acute kidney injury (AKI) is one of these potential complications that may have effects on patient outcomes. In this review, we assessed the effect of AKI on mortality outcomes in cancer patients receiving this immunotherapy. Methods: We performed a systematic review and meta-analysis of prospective, retrospective, randomized and non-randomized studies, which examined the effects of AKI in cancer patients receiving immune checkpoint inhibitors. We searched through PubMed, Medline, Web of Science, Scopus and Cochrane Library databases. Results: Seven studies were included in the final analysis, with a total number of patients of 761. Overall, the risk of death was higher in patients that developed AKI during ICPI treatment [hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.05-1.92, P = 0.02; heterogeneity χ2 = 11.68, I2 = 66%, P = 0.02] compared with patients that did not develop AKI. In addition, there was a trend to a better survival in those with less severe AKI patients compared with those with more severe AKI (HR 1.35, 95% CI 0.99-1.83, P = 0.05). Lastly, it was seen that patients with persistent kidney dysfunction (non-recovery) had an increased risk for all-cause mortality (HR 2.93, 95% CI 1.41-6.08, P = 0.004; heterogeneity χ2 = 0.53, I2 = 0%, P = 0.47). Conclusions: Development of AKI in patients with cancer receiving immune checkpoint inhibitors is associated with increased risk of mortality.

Assessment of hypertension in obstructive sleep apnea by ambulatory blood pressure monitoring: a systematic review and meta-analysis.

Among obstructive sleep apnea (OSA) patients, there exists a high prevalence of hypertension. Determining the optimal blood pressure (BP) monitoring modality in this population will lead to a better understanding of hypertension profiles and a more accurate diagnosis of hypertension. PubMed, Ovid/Medline, Web of Science, Scopus, Cochrane Library, and CINAHL databases were screened, and the relevant articles regarding BP monitoring in OSA patient population were selected. Studies evaluating both ambulatory (ABPM) and office BP measurements were selected to be analyzed for the hypertension diagnosis specificity of ABPM measurement in OSA patients compared with office measurements. If reported, additional information regarding white-coat, masked hypertension, and circadian BP pattern prevalence was included. A cumulative analysis of five studies revealed a prevalence of hypertension based on BP to be 44%, whereas a cumulative analysis of four studies revealed a prevalence of hypertension based on ABPM to be 66%. Excluding a study with the nighttime assessment of hypertension reduced the cumulative prevalence of hypertension in OSA patients to 59%. The cumulative prevalence of Studies demonstrated the prevalence of masked and white-coat hypertension to be 34 and 9%, respectively. As a higher prevalence of hypertension was detected by ABPM and nighttime measurement, it can be deduced that ABPM is more sensitive in determining OSA patients with hypertension, and that nighttime ABPM further increases this sensitivity. The presence of masked and white-coat hypertension in OSA patients underlines the importance of correct hypertension diagnosis as it affects further management in this population with increased cardiovascular risk.

Perspectives on current models of Friedreich's ataxia.

Friedreich's ataxia (FRDA, OMIM#229300) is the most common hereditary ataxia, resulting from the reduction of frataxin protein levels due to the expansion of GAA repeats in the first intron of the FXN gene. Why the triplet repeat expansion causes a decrease in Frataxin protein levels is not entirely known. Generation of effective FRDA disease models is crucial for answering questions regarding the pathophysiology of this disease. There have been considerable efforts to generate in vitro and in vivo models of FRDA. In this perspective article, we highlight studies conducted using FRDA animal models, patient-derived materials, and particularly induced pluripotent stem cell (iPSC)-derived models. We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.

Capsaicin suppresses ciliary function, while inducing permeability in bronchial epithelial cell cultures of COPD patients.

Take Home Message: Capsaicin modified inflammatory response and caused toxicity in bronchial epithelial cultures from patients with COPD. More importantly, capsaicin decreased ciliary beat frequency and induced epithelial permeability and these effects were partially prevented by formoterol and roflumilast. Tear gas is widely used to halt mass demonstrations. Studies have reported its adverse effects on multiple organ systems; however, its effect on individuals with chronic respiratory diseases and the underlying mechanisms of these effects are unclear. For the first time in the literature, we investigated the effects of capsaicin, the active ingredient of tear gas, on bronchial epithelial cell (BEC) cultures obtained from well-characterized groups of nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). BEC cultures were incubated with 50-500 µM capsaicin in the absence and presence of formoterol (1µM) and roflumilast (0.1 µM) for 24 h. Ciliary beat frequency (CBF) and transepithelial electrical resistance (TEER) were assessed at T1/4, T1/2, T1, T2, T4, T6, and T24 h, whereas the release of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, and lactate dehydrogenase (LDH) was measured at T24 h. Capsaicin (250 µM) significantly decreased CBF of all BEC cultures from T1/4 h to T24 h (p<0.05). Formoterol significantly prevented decreases in CBF induced by capsaicin. Higher concentrations of capsaicin (250-500 µM) significantly reduced TEER of BECs from nonsmokers (T2-T24 h), smokers (T24 h) and COPD patients (T2 and T24 h), which was partially prevented by roflumilast. Capsaicin (500 µM) decreased release of IL-8 (p<0.0001) and GM-CSF (p<0.05) while inducing release of LDH in BECs (p<0.05), and this was more prominent in BEC from patients with COPD. In conclusion, our findings demonstrate that capsaicin can suppress ciliary activity and cytokine release from BECs, induce BEC culture permeability and cellular toxicity and that these effects can be partially prevented by formoterol and roflumilast.

BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming.

Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes to silence existing cell-type-specific genes and activate pluripotency genes. ATP-dependent chromatin remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of recently identified Bromodomain-containing protein 9 (BRD9) and the associated non-canonical BRG1-associated factors (ncBAF) complex in reprogramming remains unknown. Here, we show that genetic or chemical inhibition of BRD9, as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, increase human somatic cell reprogramming efficiency and can replace KLF4 and c-MYC. We find that BRD9 is dispensable for human induced pluripotent stem cells under primed but not under naive conditions. Mechanistically, BRD9 inhibition downregulates fibroblast-related genes and decreases chromatin accessibility at somatic enhancers. BRD9 maintains the expression of transcriptional regulators MN1 and ZBTB38, both of which impede reprogramming. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers chromatin-based barriers to reprogramming.