Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a complex clinical phenotype associated with the presence of multiple comorbidities including diabetes, obesity, and metabolic syndrome. A major challenge in the search of new therapies for HFpEF is the development of relevant animal models. The Spontaneously Diabetic Torii (SDT) fatty rat is a well-established type2 diabetic model with multiple diabetes-related comorbidities such as nephropathy, neuropathy, and retinopathy. However, the onset and spontaneous progression of cardiac dysfunction is not yet reported in this model. Purpose To validate the SDT fatty rat as a type2 diabetes related HFpEF model, we assessed the natural evolution, i.e., without any diet or surgical intervention, of cardiac function in SDT fatty at different ages starting at 7-week of age. Methods The cardiovascular phenotyping of male SDT fatty rats was assessed by echocardiography at 7, 12 and 17-week of age and invasive left intraventricular and blood pressure measurements at 17-week of age. Vascular function of isolated thoracic aortas was also evaluated at 17-week of age. Renal function was investigated by measuring the Glomerular Filtration Rate (GFR) and urine parameters at 7, 12 and 17-week of age. A group of Sprague Dawley (SD) rats was included as a negative control. Results Compared to SD rats, echocardiography in SDT fatty showed cardiac remodeling starting at 7 weeks and persistent with age. Systolic function and ejection fraction were preserved, while diastolic function was impaired as early as 7-week of age and worsened with time. E/A was comparable in SDT fatty and SD rats at 7-week of age and then increased with age to reach 1.8±0.1 vs 1.2±0.05 in SD (p<0.001) at 17 weeks, while E’/A’ was already inverted at 7 weeks (0.9± 0.02 vs 1.3±0.03 in SD, p<0.001), and lasted with age which is a sign of relaxation default and suggestive of a restrictive filling pattern. E/E’ was significantly higher at 7-week of age (16.1± 0.9 vs 12.1±0.6 in SD, p<0.01) and further increased at 17 weeks (23.1± 0.8 vs 12.1±0.8 in SD, p<0.001) indicating higher filling pressure. Intraventricular and arterial pressure were also increased (p<0.05). As well, SDT fatty rats showed altered endothelium vasodilating properties. As expected, SDT fatty rats were hyperglycemic and showed renal impairment expressed by higher proteinuria, urine albumin/creatinine ratio, KIM-1 and cystatin-C levels and a hyperfiltration state (80% higher GFR, p<0.05). Conclusions The present data demonstrate that the SDT fatty rats developed diastolic dysfunction characterized by a restrictive profile combining compliance and relaxation impairments as well as higher filling pressure along with hypertension. This type2 diabetic model seems as a very promising model to translate the hypertension/kidney dysfunction and cardiometabolic clinical HFpEF phenogroups and is consequently a relevant model to evaluate drugs targeting HFpEF.

The quest for fascinating quantum states arising from the interplay between correlation, frustration, and topology is at the forefront of condensed-matter physics. Recently discovered nonmagnetic kagome metals $A$V${_3}$Sb${_5}$ ($A=$ K, Cs, Rb) with charge density wave (CDW) and superconducting instabilities may host such exotic states. Here we report that an odd electronic nematic state emerges above the CDW transition temperature ($T_{\rm CDW}=94$ K) in CsV${_3}$Sb${_5}$. High-resolution torque measurements reveal a distinct twofold in-plane magnetic anisotropy that breaks the crystal rotational symmetry below $T^*\approx130$ K. However, no relevant anomalies are detected in the elastoresistance data near $T^*$, which excludes the even-parity ferro-orbital nematicity often found in other superconductors. Moreover, in the temperature range between $T_{\rm CDW}$ and $T^*$, conical rotations of magnetic field yield a distinct first-order phase transition, indicative of time-reversal symmetry breaking. These results provide thermodynamic evidence for the emergence of an odd-parity nematic order, implying that an exotic loop-current state precedes the CDW in CsV$_3$Sb$_5$.

Radical cystectomy (RC) is standard care for patients with muscle invasive bladder cancer (BC) or highest-risk non-muscle invasive BC. However, optimal care for bladder preservation or intolerance to RC remains uncertain. Atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor with synergistic antitumor activity along with radiation therapy (RT), is a promising treatment. In this multicenter, phase 2 trial, we recruited patients with clinical (c)T1-3N0M0 invasive BC who were unfit for or refused RC. Patients received RT (41.4 Gy in 23 fractions to the small pelvis and 16.2 Gy in 9 fractions to the whole bladder) combined with intravenous atezolizumab 1200mg every 3 weeks. After 24 treatment weeks, response was assessed using CT imaging and transurethral bladder resection. The secondary endpoint, pathological complete response (pCR), was evaluated before the primary endpoint (progression-free survival rate). Tumor PD-L1 expression was assessed using the tumor-infiltrating immune cell (IC) score. Forty-five patients enrolled between January 2019 and May 2021 were analyzed. The most common cT stage was T2 (73.3%), followed by T1 (15.6%) and T3 (11.1%). Most tumors were single (77.8%) or small (<3cm) (57.8%), with no concomitant carcinoma in situ (CIS) (88.9%). Thirty-eight patients (84.4%) achieved pCR after 24 weeks of treatment. Patients with high PD-L1 expression (IC score >1) had higher pCR rates than those with low expression (IC score 0) (95.8% vs. 71.4%), with low rates (60.0%) in patients with CIS. Adverse events (AEs) were observed in 93.3% of patients and the most common were diarrhea (55.6%), followed by pollakiuria (42.2%) and dysuria (20.0%). The frequency of grade 3 AEs was 13.3%, with no grade 4 events. RT combined with atezolizumab resulted in a favorable high proportion of pCR with acceptable toxicity. This protocol will provide a promising new alternative for bladder preservation in BC patients.

Combination immunotherapy with an anti-PD-1 inhibitor and an anti-CTLA-4 inhibitor is used as first-line therapy in metastatic renal cell carcinoma (mRCC). While providing the benefit of a certain population of long-term responders, the frequency of immune-related adverse events (irAEs) is known to be high with the combination therapy. Thus, predictive biomarkers of irAEs could help guide treatment strategies.

Immune check inhibitor (ICI) combination therapy with an anti-PD-1 inhibitor and an anti-CTLA-4 inhibitor is used as first-line therapy in metastatic renal cell carcinoma (mRCC). Immune-related adverse events (irAEs) are known to be associated with better survivals in various cancer types. However, the association between the irAEs and survivals remains unestablished in mRCC patients treated with ICI combination therapy.

The discovery of a useful biomarker for advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitors is expected. In this study, we aimed to investigate whether the mechanism of inflammatory makers is associated with the efficacy of nivolumab plus ipilimumab.

This study, following Japanese Registry of NeuroEndovascular Treatment 1 and 2 (JR-NET 1 & 2), shows an annual trend of cases including adverse events and clinical outcomes at 30 days after NET. JR-NET3 was registered by 749 cumulative total number of physicians, certified by the Japanese Society of Neuroendovascular Therapy in 166 centers, between 2010 and 2014. Medical information about the patients was anonymized and retrospectively registered through a website. A total of 40,177 patients were recruited, 632 patients were excluded because data of preprocedural status were not available. So we analyzed 39,545 patients retrospectively. The proportion of octogenarians is increasing year-by-year and 14.7% in 2014 compared with 10.4% in 2010. Most frequent target disease is intracranial aneurysm. For the proportion of the treatment of intracranial aneurysm, 50.0% in 2010, but that has decreased to 44.8% in 2014. However, number of procedures were increased from 3150 in 2010 to 3419 in 2014. Although before the positive clinical evidence of mechanical thrombectomy for acute ischemic stroke (AIS) was established, the proportion of endovascular treatment for AIS increased 13.8% in 2014 compared with 6.3% in 2010. The number of patients requiring neuroendovascular treatment in Japan is increasing since 2010-2013, but that declined a little in 2014 caused by study operation suspended at the end of 2013. The outcomes of such therapy are clinically acceptable. Details of each type of treatment will be investigated in sub-analyses of the database.

Background: Programmed death-ligand 1 (PD-L1) expression on tumor cells has been found to predict the response to immune checkpoint inhibitors in various cancers. PD-L1 is upregulated not only in tumor cells, but also in immune cells, such as macrophages in the tumor microenvironment. It is known that macrophages differentiate from monocytes. However, there are no data about PD-L1 expression in monocytes from patients with cancer. Whether PD-L1 expression on monocytes could serve as an alternative biomarker is of great interest.

Objective: The objective of this study is to determine the contribution of Chile’s 2005 child restraint legislation to the reduction in child severe traffic injuries.Methods: We analyzed motor vehicle injury data from Chile’s Ministry of Transport National Road Safety Commission from 2000 to 2012 to determine the effect of Chile’s 2005 mandatory child restraint legislation. Using time-series robust random effects models we assessed the effect of the law on two dependent variables:(1) child severe traffic injuries per vehicle fleet; and (2) child severe traffic injuries per population. The independent variable was the 2005 enactment of Chile’s mandatory child restraint legislation. We added the following control variables: Number of tickets per year per police officer; motor vehicle fleet; alcohol consumption; number of crashes; and unemployment rate. Results: There was a 23.6%[95% confidence interval (CI) 0.98–48.89, P< …