Comparative effectiveness of an individualized model of hemodialysis vs conventional hemodialysis: a study protocol for a multicenter randomized controlled trial (the TwoPlus trial).

BACKGROUND: Most patients starting chronic in-center hemodialysis (HD) receive conventional hemodialysis (CHD) with three sessions per week targeting specific biochemical clearance. Observational studies suggest that patients with residual kidney function can safely be treated with incremental prescriptions of HD, starting with less frequent sessions and later adjusting to thrice-weekly HD. This trial aims to show objectively that clinically matched incremental HD (CMIHD) is non-inferior to CHD in eligible patients. METHODS: An unblinded, parallel-group, randomized controlled trial will be conducted across diverse healthcare systems and dialysis organizations in the USA. Adult patients initiating chronic hemodialysis (HD) at participating centers will be screened. Eligibility criteria include receipt of fewer than 18 treatments of HD and residual kidney function defined as kidney urea clearance ≥3.5 mL/min/1.73 m2 and urine output ≥500 mL/24 h. The 1:1 randomization, stratified by site and dialysis vascular access type, assigns patients to either CMIHD (intervention group) or CHD (control group). The CMIHD group will be treated with twice-weekly HD and adjuvant pharmacologic therapy (i.e., oral loop diuretics, sodium bicarbonate, and potassium binders). The CHD group will receive thrice-weekly HD according to usual care. Throughout the study, patients undergo timed urine collection and fill out questionnaires. CMIHD will progress to thrice-weekly HD based on clinical manifestations or changes in residual kidney function. Caregivers of enrolled patients are invited to complete semi-annual questionnaires. The primary outcome is a composite of patients' all-cause death, hospitalizations, or emergency department visits at 2 years. Secondary outcomes include patient- and caregiver-reported outcomes. We aim to enroll 350 patients, which provides ≥85% power to detect an incidence rate ratio (IRR) of 0.9 between CMIHD and CHD with an IRR non-inferiority of 1.20 (α = 0.025, one-tailed test, 20% dropout rate, average of 2.06 years of HD per patient participant), and 150 caregiver participants (of enrolled patients). DISCUSSION: Our proposal challenges the status quo of HD care delivery. Our overarching hypothesis posits that CMIHD is non-inferior to CHD. If successful, the results will positively impact one of the highest-burdened patient populations and their caregivers. TRIAL REGISTRATION: Clinicaltrials.gov NCT05828823. Registered on 25 April 2023.

SGLT2 inhibitors: Beyond glycemic control.

Multiple randomized controlled trials have extensively examined the therapeutic effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors, ushering in a transformative approach to treating individuals with type 2 diabetes mellitus (DM). Notably, emerging reports have drawn attention to the potential positive impacts of SGLT2 inhibitors in nondiabetic patients. In an effort to delve into this phenomenon, a comprehensive systematic literature review spanning PubMed (NLM), Medline (Ovid), and Cochrane Library, covering publications from 2000 to 2024 was undertaken. This systematic review encompassed twenty-six randomized control trials (RCTs) involving 35,317 participants. The findings unveiled a multifaceted role for SGLT2 inhibitors, showcasing their ability to enhance metabolic control and yield cardioprotective effects through a reduction in cardiovascular death (CVD) and hospitalization related to heart failure (HF). Additionally, a renalprotective effect was observed, evidenced by a slowdown in chronic kidney disease (CKD) progression and a decrease in albuminuria. Importantly, these benefits were coupled with an acceptable safety profile. The literature also points to various biological plausibility and underlying mechanistic pathways, offering insights into the association between SGLT2 inhibitors and these positive outcomes in nondiabetic individuals. Current research trends indicate a continual exploration of additional role for SGLT2 inhibitors in. Nevertheless, further research is imperative to fully elucidate the mechanisms and long-term outcomes associated with the nondiabetic use of SGLT2 inhibitors.

Tumor-specific polycistronic miRNA delivered by engineered exosomes for the treatment of glioblastoma.

BACKGROUND: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs. METHODS: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to hone in on miRs that were most likely to be clinically effective. To enhance delivery and expression of the miRs, we generated a polycistronic plasmid encoding 3 miRs (pPolymiR) and used HEK293T cells as biofactories to package pPolymiR into engineered exosomes (eExos) that incorporate viral proteins (Gag/VSVg) in their structure (eExos+pPolymiR) to enhance function. RESULTS: Our stepwise screen identified miR-124-2, miR-135a-2, and let-7i as the most effective miRs across all GBM subtypes with clinical relevance. Delivery of eExos+pPolymiR resulted in high expression of all 3 miRs in GSCs, and significantly decreased GSC proliferation in vitro. eExos+pPolymiR prolonged survival of GSC-bearing mice in vivo when compared with eExos carrying each of the miRs individually or as a cocktail. CONCLUSION: eExos+pPolymiR, which includes a pan-subtype anti-glioma-specific miR combination encoded in a polycistronic plasmid and a novel exosome delivery platform, represents a new and potentially powerful anti-GBM therapeutic.

Hepatorenal syndrome: pathophysiology and evidence-based management update.

Hepatorenal syndrome (HRS) is a functional renal failure that develops in patients with advanced hepatic cirrhosis with ascites and in those with fulminant hepatic failure. The prevalence of HRS varies among studies but in general it is the third most common cause of acute kidney injury (AKI) in cirrhotic patients after pre-renal azotemia and acute tubular necrosis. HRS carries a grim prognosis with a mortality rate approaching 90% three months after disease diagnosis. Fortunately, different strategies have been proven to be successful in preventing HRS. Although treatment options are available, they are not universally effective in restoring renal function but they might prolong survival long enough for liver transplantation, which is the ultimate treatment. Much has been learned in the last two decades regarding the pathophysiology and management of this disease which lead to notable evolution in the HRS definition and better understanding on how best to manage HRS patients. In the current review, we will summarize the recent advancement in epidemiology, pathophysiology, and management of HRS.

Predictors of disease severity and outcome of hospitalized renal transplant recipients with COVID-19 infection: a systematic review of a globally representative sample.

Introduction. COVID-19 presents a special challenge to the kidney transplant population.Methods. A systematic review of articles that examined COVID-19 in kidney transplant recipients was performed. Patients' demographics, clinical, laboratory and radiological presentations, immunosuppression modification, and COVID-19 specific management were abstracted and analyzed. COVID-19 severity was classified into mild, moderate, and severe. Disease outcome was classified by whether the patient was discharged, still hospitalized, or died.Results. 44 articles reporting individual data and 13 articles reporting aggregated data on 149 and 561 kidney transplant recipients respectively with COVID-19 from Asia, Europe and America fulfilled all inclusion and exclusion criteria. Among studies reporting case specific data, 76% of cases had severe disease. Compared to patients with mild/moderate disease, patients with severe disease had higher CRP, LDH, Ferritin, D-dimer and were more likely to have bilateral lung involvement at presentation and longer time since transplantation (P < 0.05 for all). Recipients' age, gender and comorbidities did not impact disease severity. Patients with severe disease had a more aggressive CNI reduction and more antiviral medications utilization. Outcome was reported on 145 cases, of those 34 (23%) died all with severe disease. Longer duration from transplant to disease diagnosis, hypoxia and higher LDH were associated with mortality (P < 0.05). Different immunosuppression reduction strategies, high dose parenteral corticosteroids use and various antiviral combinations did not demonstrate survival advantage. Similar finding was observed for studies reporting aggregated data.Conclusion. COVID-19 in kidney transplant patients is associated with high rate of disease severity and fatality. Higher LDH and longer time since transplantation predicted both disease severity and mortality. None of the COVID-19 specific treatment correlated with, or improved disease outcome in kidney transplant recipients.

Forecasting People Trajectories and Head Poses by Jointly Reasoning on Tracklets and Vislets.

In this article, we explore the correlation between people trajectories and their head orientations. We argue that people trajectory and head pose forecasting can be modelled as a joint problem. Recent approaches on trajectory forecasting leverage short-term trajectories (aka tracklets) of pedestrians to predict their future paths. In addition, sociological cues, such as expected destination or pedestrian interaction, are often combined with tracklets. In this article, we propose MiXing-LSTM (MX-LSTM) to capture the interplay between positions and head orientations (vislets) thanks to a joint unconstrained optimization of full covariance matrices during the LSTM backpropagation. We additionally exploit the head orientations as a proxy for the visual attention, when modeling social interactions. MX-LSTM predicts future pedestrians location and head pose, increasing the standard capabilities of the current approaches on long-term trajectory forecasting. Compared to the state-of-the-art, our approach shows better performances on an extensive set of public benchmarks. MX-LSTM is particularly effective when people move slowly, i.e., the most challenging scenario for all other models. The proposed approach also allows for accurate predictions on a longer time horizon.

Activity of Hospital Disinfectants against Vegetative Cells and Spores of Clostridioides difficile Embedded in Biofilms.

Clostridioides difficile spores can survive in the environment in either mono- or mixed-species biofilms. However, no previous studies have investigated chemical disinfection of C. difficile spores embedded in biofilms. Thus, the purpose of this study was to assess the in vitro effectiveness of hospital disinfectants against C. difficile spores embedded within biofilms. Five unique C. difficile strains embedded in three different biofilm types grown for 72 or 120 h were exposed to seven different hospital disinfectants. C. difficile abundance [as log(number of CFU/milliliter)] was calculated after manufacturer-determined contact times along with biofilm biomass and microscopy. The primary analysis compared differences between C. difficile vegetative cell and spore counts as well as amounts of biomass after exposure to disinfectants. C. difficile vegetative cells and spores were recovered from biofilms regardless of the type of biofilm growth or biofilm growth time. No disinfectant was able to completely eliminate C. difficile from the biofilms. Overall, Clorox, ortho-phthalaldehyde (OPA), and Virex were most effective at killing C. difficile spores regardless of biofilm age, ribotype, or wash conditions (whether biofilms are washed or unwashed) (P = 0.001, each). Clorox and OPA were also effective at killing total vegetative cell growth (P = 0.001, each), but Virex was found to be ineffective against vegetative cell growth in biofilms (P = 0.77). Clorox and Virex were most effective in reducing biomass, followed by Nixall, OPA, and Vital Oxide. No disinfectant was able to completely eliminate C. difficile embedded within biofilms although differences among disinfectants were noted. Future research will be required to determine methods to eradicate this persister reservoir.