Association between sex and survival after non-traumatic out of hospital cardiac arrest: A systematic review and meta-analysis.

BACKGROUND: Existing studies have shown conflicting results regarding the relationship of sex with survival after out of hospital cardiac arrest (OHCA). This systematic review evaluates the association of female sex with survival to discharge and survival to 30 days after non-traumatic OHCA. METHODS: We searched Medline, Embase, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from inception through June 2021 for studies evaluating female sex as a predictor of survival in adult patients with non-traumatic cardiac arrest. Random-effects inverse variance meta-analyses were performed to calculate pooled odds ratios (ORs) with 95% confidence intervals (CI). The GRADE approach was used to assess evidence quality. RESULTS: Thirty studies including 1,068,788 patients had female proportion of 41%. There was no association for female sex with survival to discharge (OR 1.03, 95% CI 0.95-1.12; I2 = 89%). Subgroup analysis of low risk of bias studies demonstrated increased survival to discharge for female sex (OR 1.20, 95% CI 1.18-1.23; I2 = 0%) and with high certainty, the absolute increase in survival was 2.2% (95% CI 0.1-3.6%). Female sex was not associated with survival to 30 days post-OHCA (OR 1.02, 95% CI 0.92-1.14; I2 = 79%). CONCLUSIONS: In adult patients experiencing OHCA, with high certainty in the evidence from studies with low risk of bias, female sex had a small absolute difference for the outcome survival to discharge and no difference in survival at 30 days. Future models that aim to stratify risk of survival post-OHCA should focus on sex-specific factors as opposed to sex as an isolated prognostic factor.

HDAC6 Inhibition Promotes Transcription Factor EB Activation and Is Protective in Experimental Kidney Disease.

To contend with the deleterious effects of accumulating misfolded protein aggregates or damaged organelles cells rely on a system of quality control processes, among them the autophagy-lysosome pathway. This pathway is itself controlled by a master regulator transcription factor termed transcription factor EB (TFEB). When TFEB localizes to the cell nucleus it promotes the expression of a number of genes involved in protein clearance. Here, we set out to determine (1) whether TFEB expression is altered in chronic kidney disease (CKD); (2) whether inhibition of the cytosolic deacetylase histone deacetylase 6 (HDAC6) affects TFEB acetylation and nuclear localization; and (3) whether HDAC6 inhibition, in turn, alters the natural history of experimental CKD. TFEB mRNA and protein levels were observed to be diminished in the kidneys of humans with diabetic kidney disease, accompanied by accumulation of the protein aggregate adaptor protein p62 in tubule epithelial cells. In cultured NRK-52E cells, HDAC6 inhibition with the small molecule inhibitor Tubastatin A acetylated TFEB, increasing TFEB localization to the nucleus and attenuating cell death. In a rat model of CKD, Tubastatin A prevented the accumulation of misfolded protein aggregates in tubule epithelial cells, attenuated proteinuria progression, limited tubule cell death and diminished tubulointerstitial collagenous matrix deposition. These findings point to the common occurrence of dysregulated quality control processes in CKD and they suggest that TFEB downregulation may contribute to tubule injury in CKD. They also identify a regulatory relationship between HDAC6 and TFEB. HDAC6 inhibitors and TFEB activators both warrant further investigation as treatments for CKD.

EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease.

The therapeutic targeting of prostanoid subtype receptors may slow the development of chronic kidney disease (CKD) through mechanisms that are distinct from those of upstream COX inhibition. Here, employing multiple experimental models of CKD, we studied the effects of inhibition of the EP4 receptor, one of four receptor subtypes for the prostanoid prostaglandin E2. In streptozotocin-diabetic endothelial nitric oxide synthase knockout mice, EP4 inhibition attenuated the development of albuminuria, whereas the COX inhibitor indomethacin did not. In Type 2 diabetic db/db mice, EP4 inhibition lowered albuminuria to a level comparable with that of the ACE inhibitor captopril. However, unlike captopril, EP4 inhibition had no effect on blood pressure or hyperfiltration although it did attenuate mesangial matrix accumulation. Indicating a glucose-independent mechanism of action, EP4 inhibition also attenuated proteinuria development and glomerular scarring in non-diabetic rats subjected to surgical renal mass ablation. Finally, in vitro, EP4 inhibition prevented transforming growth factor-ß1 induced dedifferentiation of glomerular podocytes. In rodent models of diabetic and non-diabetic CKD, EP4 inhibition attenuated renal injury through mechanisms that were distinct from either broadspectrum COX inhibition or "standard of care" renin angiotensin system blockade. EP4 inhibition may represent a viable repurposing opportunity for the treatment of CKD.

Janus Kinase 2 Regulates Transcription Factor EB Expression and Autophagy Completion in Glomerular Podocytes.

The nonreceptor kinase Janus kinase 2 (JAK2) has garnered attention as a promising therapeutic target for the treatment of CKD. However, being ubiquitously expressed in the adult, JAK2 is also likely to be necessary for normal organ function. Here, we investigated the phenotypic effects of JAK2 deficiency. Mice in which JAK2 had been deleted from podocytes exhibited an elevation in urine albumin excretion that was accompanied by increased podocyte autophagosome fractional volume and p62 aggregation, which are indicative of impaired autophagy completion. In cultured podocytes, knockdown of JAK2 similarly impaired autophagy and led to downregulation in the expression of lysosomal genes and decreased activity of the lysosomal enzyme, cathepsin D. Because transcription factor EB (TFEB) has recently emerged as a master regulator of autophagosome-lysosome function, controlling the expression of several of the genes downregulated by JAK2 knockdown, we questioned whether TFEB is regulated by JAK2. In immortalized mouse podocytes, JAK2 knockdown decreased TFEB promoter activity, expression, and nuclear localization. In silico analysis and chromatin immunoprecipitation assays revealed that the downstream mediator of JAK2 signaling STAT1 binds to the TFEB promoter. Finally, overexpression of TFEB in JAK2-deficient podocytes reversed lysosomal dysfunction and restored albumin permselectivity. Collectively, these observations highlight the homeostatic actions of JAK2 in podocytes and the importance of TFEB to autophagosome-lysosome function in these cells. These results also raise the possibility that therapeutically modulating TFEB activity may improve podocyte health in glomerular disease.

The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease.

Recent years have witnessed an emergence of a new class of therapeutic agents, termed histone deacetylase 6 (HDAC6) inhibitors. HDAC6 is one isoform of a family of HDAC enzymes that catalyse the removal of functional acetyl groups from proteins. It stands out from its cousins in almost exclusively deacetylating cytoplasmic proteins, in exerting deacetylation-independent effects and in the success that has been achieved in developing relatively isoform-specific inhibitors of its enzymatic action that have reached clinical trial. HDAC6 plays a pivotal role in the removal of misfolded proteins and it is this role that has been most successfully targeted to date. HDAC6 inhibitors are being investigated for use in combination with proteasome inhibitors for the treatment of lymphoid malignancies, whereby HDAC6-dependent protein disposal currently limits the cytotoxic effectiveness of the latter. Similarly, numerous recent studies have linked altered HDAC6 activity to the pathogenesis of neurodegenerative diseases that are characterized by misfolded protein accumulation. It seems likely though that the function of HDAC6 is not limited to malignancy and neurodegeneration, the deacetylase being implicated in a number of other cellular processes and diseases including in cardiovascular disease, inflammation, renal fibrosis and cystogenesis. Here, we review the unique features of HDAC6 that make it so appealing as a drug target and its currently understood role in health and disease. Whether HDAC6 inhibition will ultimately find a clinical niche in the treatment of malignancy or prevalent complex chronic diseases remains to be determined.

Prostaglandin I2 Receptor Agonism Preserves ß-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms.

Discovery of common pathways that mediate both pancreatic ß-cell function and end-organ function offers the opportunity to develop therapies that modulate glucose homeostasis and separately slow the development of diabetes complications. Here, we investigated the in vitro and in vivo effects of pharmacological agonism of the prostaglandin I2 (IP) receptor in pancreatic ß-cells and in glomerular podocytes. The IP receptor agonist MRE-269 increased intracellular 3',5'-cyclic adenosine monophosphate (cAMP), augmented glucose-stimulated insulin secretion (GSIS), and increased viability in MIN6 ß-cells. Its prodrug form, selexipag, augmented GSIS and preserved islet ß-cell mass in diabetic mice. Determining that this preservation of ß-cell function is mediated through cAMP/protein kinase A (PKA)/nephrin-dependent pathways, we found that PKA inhibition, nephrin knockdown, or targeted mutation of phosphorylated nephrin tyrosine residues 1176 and 1193 abrogated the actions of MRE-269 in MIN6 cells. Because nephrin is important to glomerular permselectivity, we next set out to determine whether IP receptor agonism similarly affects nephrin phosphorylation in podocytes. Expression of the IP receptor in podocytes was confirmed in cultured cells by immunoblotting and quantitative real-time PCR and in mouse kidneys by immunogold electron microscopy, and its agonism 1) increased cAMP, 2) activated PKA, 3) phosphorylated nephrin, and 4) attenuated albumin transcytosis. Finally, treatment of diabetic endothelial nitric oxide synthase knockout mice with selexipag augmented renal nephrin phosphorylation and attenuated albuminuria development independently of glucose change. Collectively, these observations describe a pharmacological strategy that posttranslationally modifies nephrin and the effects of this strategy in the pancreas and in the kidney.

Psychosocial needs assessment post kidney transplant: Feasibility of a post-transplant specific support group.

This project assessed unmet psychosocial needs of kidney transplant recipients and the feasibility of a support group located at an urban Canadian hospital to meet those needs. A survey assessed transplant recipient concerns about psychosocial issues related to transplantation, interest in a support group, desired group composition, facilitation, leadership, barriers and alternative forms of support. Most respondents were more than two years since transplant and were more concerned about medical complications, returning to normalcy, and had a greater desire to talk to other transplant recipients. Forty per cent of respondents indicated they would be interested in a support group. However, 60% indicated that a support group hosted in the hospital setting would be a deterrent to attending, citing time and transportation as the greatest barriers. More research is needed to assess the feasibility of post-kidney transplant support groups closer to recipients' homes and the feasibility of alternative forms of support.