Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Targeting the extracellular HSP90 co-chaperone Morgana inhibits cancer cell migration and promotes anti-cancer immunity

Heat shock protein 90 (HSP90) is secreted by cancer cells into the extracellular milieu, where it exerts pro-tumoral activities by activating extracellular substrate proteins and triggering autocrine signals through cancer cell surface receptors. Emerging evidence indicates that HSP90 co-chaperones are also secreted and may direct HSP90 extracellular activities. In this study, we found that the HSP90 co-chaperone Morgana is released by cancer cells and, in association with HSP90, induces cancer cell migration through TLR2, TLR4, and LRP1. In syngeneic cancer mouse models, a monoclonal antibody targeting Morgana extracellular activity reduced primary tumor growth via macrophage-dependent recruitment of CD8+ T lymphocytes, blocked cancer cell migration, and inhibited metastatic spreading. Overall, this data defines Morgana as a new player in the HSP90 extracellular interactome and suggests that Morgana may regulate HSP90 activity to promote cancer cell migration and suppress anti-tumor immunity

Fasting renders immunotherapy effective against low-immunogenic breast cancer while reducing side effects

Immunotherapy is improving the prognosis and survival of cancer patients, but despite encouraging out-comes in different cancers, the majority of tumors are resistant to it, and the immunotherapy combinations are often accompanied by severe side effects. Here, we show that a periodic fasting-mimicking diet (FMD) can act on the tumor microenvironment and increase the efficacy of immunotherapy (anti-PD-L1 and anti-OX40) against the poorly immunogenic triple-negative breast tumors (TNBCs) by expanding early exhausted effector T cells, switching the cancer metabolism from glycolytic to respiratory, and reducing collagen depo-sition. Furthermore, FMD reduces the occurrence of immune-related adverse events (irAEs) by preventing the hyperactivation of the immune response. These results indicate that FMD cycles have the potential to enhance the efficacy of anti-cancer immune responses, expand the portion of tumors sensitive to immuno-therapy, and reduce its side effects

Lineamenti di Diritto Costituzionale della Regione Emilia-Romagna

Il Volume, intitolato "Lineamenti di Diritto Costituzionale della Regione Emilia-Romagna", si inserisce nella Collana "Diritto Costituzionale Regionale", curata dai Professori Pasquale Costanzo e Antonio Ruggeri. I Curatori del Volume hanno inteso affrontare tutti gli aspetti pi\uf9 significativi della struttura e del funzionamento della Regione Emilia-Romagna, gli aspetti, che dunque rigurdano il Diritto costituzionale di questa Regione. In particolare, dopo una introduzione di carattere storico-istituzionale, ci si \ue8 soffermati sui principi fondamentali dell'ordinamento regionale e sugli elementi costitutivi, sulla tutela dei diritti fondamentali e partecipazione popolare, sulla forma di governo regionale, affrontandone tutti gli aspetti, quali Presidente della Regione, Giunta regionale e Consiglio regionale. Ci si \ue8 poi soffermati sul sistema amministrativo, sulla finanza regionale, sui rapporti con le autonomie locali, sul sistema delle fonti del diritto, sulle garanzie e controlli (con particolare riguardo alla Consulta statutaria, al Comitato regionale per le comunicazioni e al Difensore civico). Per finire, si sono affrontati i raccordi della Regione con lo Stato e le altre Regioni, le attivit\ue0 di rilievo internazionale e i rapporti con l'Unione europea

Overview of different modified full-face snorkelling masks for intraoperative protection

Panoramica delle diverse maschere snorkelling modificate per la protezione intraoperatoria.Obiettivo: La pandemia di COVID-19 ha tuttora un impatto significativo sui sistemi sanitari di tutto il mondo. Il tasso di operatori sanitari italiani che hanno contratto linfezione e superiore al 10%. In questo drammatico scenario, la comunita scientifica si e impegnata nello sviluppo di nuovi dispositivi di protezione individuale. Il nostro studio si concentra sulluso di maschere da snorkelling modificate (MFFSM) come dispositivi di protezione individuali contro linfezione da virus COVID-19 durante procedure diagnostiche e terapeutiche sul tratto aerodigestivo superiore.Metodi: Cinque diversi tipi di MFFSM sono stati testati. I dati sono stati raccolti attraver-so un sondaggio online; solo per la maschera OceanReef Aria QR+ sono stati registrati i valori intraoperatori di pO2 e pCO2.Risultati: Tutte le MFFSM testate si sono rivelate di facile utilizzo e tutti gli operatori hanno riferito una sensazione di comfort, mantenendo una sensazione di sicurezza durante laprocedura.Conclusione: In futuro sara possibile lo sviluppo di specifiche maschere per laprotezione in sala operatoria e in terapia intensiva sulla base di una stretta collaborazione tra clinici e ingegneri. Lobiettivo per i medici sara definire con precisione le loro esigenze, mentre per le industrie produttrici sara mettere a disposizione il loro expertise per fornire dispositivi che incontrino le necessita sanitarie.Objective: The COVID-19 pandemic has caused significant impact on healthcare systems worldwide. The rate of infected healthcare workers is > 10% in Italy. Within this dramatic scenario, the development of new personal protective equipment (PPE) devices is mandatory. This study focuses on validation of modified full-face snorkel masks (MFFSM) as safe and protective equipment against SARS-CoV-2 infection during diagnostic and therapeutic procedures on the upper aerodigestive tract.Methods: Five different MFFSM were tested during otolaryngological surgery and in anaesthesia procedures. Data were collected through an online survey to assess the feedback of operators. pO2 and pCO2 monitoring values during procedures were recorded in selected cases.Results: All five MFFSM tested were easy to use and gave all operators a sound feeling of protection. All clinicians involved had common agreement regarding safety and the userfriendly format.Conclusions: In the future, specific development of different type of masks for protection in the operating room, intensive care units and/or office will be possible as a joint venture between clinicians and developers. Goals for clinicians include better definition of needs and priorities, while developers can devote their expertise to produce devices that meet medical requirements.The COVID-19 pandemic has caused significant impact on healthcare systems worldwide. The rate of infected healthcare workers is > 10% in Italy. Within this dramatic scenario, the development of new personal protective equipment (PPE) devices is mandatory. This study focuses on validation of modified full-face snorkel masks (MFFSM) as safe and protective equipment against SARS-CoV-2 infection during diagnostic and therapeutic procedures on the upper aerodigestive tract. Methods. Five different MFFSM were tested during otolaryngological surgery and in anaesthesia procedures. Data were collected through an online survey to assess the feedback of operators. pO2 and pCO2 monitoring values during procedures were recorded in selected cases. Results. All five MFFSM tested were easy to use and gave all operators a sound \u201cfeeling\u201d of protection. All clinicians involved had common agreement regarding safety and the userfriendly format. Conclusions. In the future, specific development of different type of masks for protection in the operating room, intensive care units and/or office will be possible as a joint venture between clinicians and developers. Goals for clinicians include better definition of needs and priorities, while developers can devote their expertise to produce devices that meet medical requirements

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies1. Increased RAS-mitogenactivated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations cause 50 percent of NS2-6. Here, we report that 22 of 129 NS patients without PTPN11 or KRAS mutation (17 percent) have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor (GEF). SOS1 mutations cluster at residues implicated in the maintenance of SOS1 in its autoinhibited form and ectopic expression of two NS-associated mutants induced enhanced RAS activation. The phenotype associated with SOS1 defects is distinctive, although within NS spectrum, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate for the first time gain-of-function mutations in a RAS GEF in inherited disease and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791