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Immunological mechanisms have come into the focus of current translational stroke research, and the modulation of neuroinflammatory pathways has been identified as a promising therapeutic approach to protect the ischemic brain. However, stroke not only induces a local neuroinflammatory response but also has a profound impact on systemic immunity. In this review, we will summarize the consequences of ischemic stroke on systemic immunity at all stages of the disease, from onset to long‐term outcome, and discuss underlying mechanisms of systemic brain‐immune communication. Furthermore, since stroke commonly occurs in patients with multiple comorbidities, we will also overview the current understanding of the potential role of systemic immunity in common stroke‐related comorbidities, such as cardiac dysfunction, atherosclerosis, diabetes, and infections. Finally, we will highlight how targeting systemic immunity after stroke could improve long‐term outcomes and alleviate comorbidities of stroke patients. Graphical Abstract This Review discusses the impact of ischemic stroke on systemic immunity, its interaction with common comorbidities, and the underlying mechanisms of systemic brain‐immune communication.

Background & Aims Sustained virological response (SVR) by direct‐acting antivirals (DAAs) may reverse the hypercoagulable state of HCV cirrhosis and the portal vein thrombosis (PVT) risk. We evaluated the incidence and predictive factors of de novo, non‐tumoral PVT in patients with cirrhosis after HCV eradication. Methods Patients with HCV‐related cirrhosis, consecutively enrolled in the multi‐center ongoing PITER cohort, who achieved the SVR using DAAs, were prospectively evaluated. Kaplan‐Meier and competing risk regression analyses were performed. Results During a median time of 38.3 months (IQR: 25.1–48.7 months) after the end of treatment (EOT), among 1609 SVR patients, 32 (2.0%) developed de novo PVT. A platelet count ≤120,000/μL, albumin levels ≤3.5 mg/dL, bilirubin >1.1 mg/dL, a previous liver decompensation, ALBI, Baveno, FIB‐4, and RESIST scores were significantly different (p < 0.001), among patients who developed PVT versus those who did not. Considering death and liver transplantation as competing risk events, esophageal varices (subHR: 10.40; CI 95% 4.33–24.99) and pre‐treatment ALBI grade ≥2 (subHR: 4.32; CI 95% 1.36–13.74) were independent predictors of PVT. After HCV eradication, a significant variation in PLT count, albumin, and bilirubin (p < 0.001) versus pre‐treatment values was observed in patients who did not develop PVT, whereas no significant differences were observed in those who developed PVT (p > 0.05). After the EOT, esophageal varices and ALBI grade ≥2, remained associated with de novo PVT (subHR: 9.32; CI 95% 3.16–27.53 and subHR: 5.50; CI 95% 1.67–18.13, respectively). Conclusions In patients with HCV‐related cirrhosis, a more advanced liver disease and significant portal hypertension are independently associated with the de novo PVT risk after SVR.

This study evaluated the feasibility, complications and long-term outcomes of using a cannulated drill system combined with intraoperative imaging to place a transcondylar screw for the management of canine humeral intracondylar fissure. Thirteen dogs were enrolled, with one dog undergoing staged bilateral surgery. No intraoperative complications occurred. Five minor (36%) and three major (21%) postoperative complications occurred, giving an overall complication rate of 57%. None of the screws placed penetrated the articular surface. The mean duration of surgery was 28 min (SD ±3.5) for dogs that developed a major complication versus 46 min (SD ±18.1) for those that did not (p=0.015). The duration of preoperative lameness was significantly shorter for cases which suffered a major complication (2 days; SD ±2.8) than those that did not (34 days; SD ±31.7, p=0.008). None of the variables assessed were significantly associated with minor complications. Median time from surgery to last follow-up was 5.8 years (range 3.5–8.5 years). Median Liverpool Osteoarthritis in Dogs questionnaire score at the final point of follow-up was 16 (range 7–27). A significant number of patients were found to require analgesia at long-term follow-up.

Background Components of physical frailty cluster into subtypes, but it remains unknown how these might be associated with age‐related functional declines and multimorbidities. This study aims to investigated associations of physical frailty subtypes with functional declines and multimorbidity in a 10 year longitudinal cohort survey. Methods Complementary longitudinal cohort study used group‐based multitrajectory modelling to verify whether frailty subtypes discovered in Taiwan are presented in another aging cohort, then investigated associations of these subtypes with cognitive decline and multimorbidity. Participants aged ≥50 years were recruited from the third to sixth waves (May 2002 to July 2010) of the National Institute for Longevity Sciences‐Longitudinal Study of Aging, in Japan. People with incomplete data, pre‐frail/frail status before their index wave, and those with incomplete data or who died during follow‐up, were excluded. Group‐based trajectory analysis denoted five established physical frailty criteria as time‐varying binary variables in each wave during follow‐up. Incident frailty was classified as mobility subtype (weakness/slowness), non‐mobility subtype (weight loss/exhaustion), or low physical activity subtype. General linear modelling investigated associations of these frailty subtypes with activities of daily living, digit symbol substitution test (DSST) and Charlson Comorbidity Index (CCI) at 2 year follow‐up. Results We identified four longitudinal trajectories of physical frailty, which corroborated the distinct subtypes we discovered previously. Among 940 eligible participants, 38.0% were robust, 18.4% had mobility subtype frailty, 20.7% non‐mobility subtype, and 20.1% low physical activity subtype. People with mobility subtype frailty were older than those with other frailty subtypes or robust status and had higher prevalence of hypertension, diabetes, and heart failure. In the multivariable‐adjusted general linear models, mobility‐subtype frailty was associated with a significantly lower DSST score (point estimate −2.28, P = 0.03) and higher CCI (point estimate 0.82, P < 0.01) than the other groups. Conclusions Mobility‐subtype frailty was associated with functional declines and progression of multimorbidity; the long‐term effects of physical frailty subtypes deserve further investigation.

To extend the discussion on the use of real-world evidence (RWE) in conveying the clinical value of treatment beyond trial data, the primary objective of this study was to assess if efficacy gains in progression-free survival (PFS) observed in randomized controlled trials (RCT) correlate with efficacy gains in the real-world setting. For this, we assessed the treatment benefit of three tyrosine kinase inhibitors (TKIs) in aNSCLC. Using matched cohorts identified in the Flatiron Health database (2011-2020), we mimicked the following cohorts of TKI versus platinum-based chemotherapy (PBC) from the following trials: (1) erlotinib, EURTAC; (2) afatinib, LUX-Lung 3; and (3) crizotinib, PROFILE 1014. Time to treatment discontinuation (TTD) hazard ratio (HR) was used as a proxy for PFS HR, the primary endpoint in the selected RCTs. HRs were calculated via Cox proportional hazard models. Overall, 1,118 patients were included across the three RWE cohorts. Frontline TKI regimens had statistically significantly better real-world TTD than their matched PBC comparator group (HR 0.37, 95% confidence interval [CI] 0.30-0.44 for erlotinib; HR 0.42, 95% CI 0.32-0.55 for afatinib; HR 0.37, 95% CI 0.26-0.53 for crizotinib). The benefit in real-world OS was not different between TKIs and PBC patients, attributed to a high proportion of switching to subsequent therapy. Study findings of relative treatment benefit (HR) for real-world TTD and OS were deemed similar to those for PFS and OS from the pivotal RCTs. The relative treatment effect, measured as real-world TTD HR over the long term, was similar to trial-based PFS HR, implying that the clinical benefit of aNSCLC treatments conveyed in trials translated into the clinical setting. This is important, given that OS data interpretation is limited, even with longer follow-up. Additionally, our RWE analysis endorses TTD as a relevant endpoint to measure clinical benefit.

BackgroundFecal calprotectin (FC) concentration is a useful surrogate marker for mucosal healing (MH) during tumor necrosis factor alpha (TNFα)-blocking therapy for inflammatory bowel disease (IBD). Our aim was to evaluate whether a normal FC after induction therapy with TNFα antagonist predicts the outcome of IBD patients during maintenance therapy.MethodsSixty IBD patients (34 Crohn's disease [CD], 26 ulcerative colitis [UC]), treated with TNFα antagonists, either infliximab (n = 42) or adalimumab (n = 18), and having a documented FC level at baseline and after induction therapy were included. Disease activity was evaluated by partial Mayo score without endoscopy or Harvey–Bradshaw index at baseline, after induction, and at 12 months during maintenance therapy.ResultsAfter induction, FC was normalized (≤100 μg/g) in 31 patients (52%, median 42 μg/g, range 0–97), whereas the level remained elevated in 29 patients (48%, median 424 μg/g, range 116–5859). At ≈12 months, 26/31 (84%, 18 CD, 8 UC) of the patients with normal FC after induction were in clinical remission, whereas only 11/29 (38%, 9 CD, 2 UC) of those with an elevated (≥100 μg/g) postinduction FC were in clinical remission, P < 0.0001. After induction therapy with TNFα antagonists, a cutoff concentration of 139 μg/g for FC had a sensitivity of 72% and a specificity of 80% to predict a risk of clinically active disease after 1 year.ConclusionsA normal FC after induction therapy with TNFα antagonists predicts sustained clinical remission in the majority of patients on scheduled therapy with active luminal disease.

Tumour morphology (tumour burden score (TBS)) and liver function (albumin‐to‐alkaline phosphatase ratio (AAPR)) have been shown to correlate with outcomes in intrahepatic cholangiocarcinoma (ICC). This study aimed to evaluate the combined predictive effect of TBS and AAPR on survival outcomes in ICC patients. We conducted a retrospective analysis using a multicentre database of ICC patients who underwent curative surgery from 2011 to 2018. The Kaplan–Meier method was employed to examine the relationship between a new index (combining TBS and AAPR) and long‐term outcomes. The predictive efficacy of this index was compared to other conventional indicators. A total of 560 patients were included in the study. Based on TBS and AAPR stratification, patients were classified into three groups. Kaplan–Meier curves demonstrated that 124 patients with low TBS and high AAPR had the best overall survival (OS) and recurrence‐free survival (RFS), while 170 patients with high TBS and low AAPR had the worst outcomes (log‐rank p < 0.001). Multivariate analyses identified the combined index as an independent predictor of OS and RFS. Furthermore, the index showed superior accuracy in predicting OS and RFS compared to other conventional indicators. Collectively, this study demonstrated that the combination of liver function and tumour morphology provides a synergistic effect in evaluating the prognosis of ICC patients. The novel index combining TBS and AAPR effectively stratified postoperative survival outcomes in ICC patients undergoing curative resection.

Abstract Background Information is limited regarding the prevalence and importance of hepatic histologic abnormalities in dogs with gallbladder mucocele (GBM). Objectives To (a) report prevalence of hepatic histologic abnormalities in dogs with GBM (b) evaluate for association between hepatic abnormalities and outcome in dogs with GBM (c) evaluate whether neutrophil-to-lymphocyte ratio (NLR) differs in dogs with GBM with and without specific hepatic lesions. Animals Fifty-two dogs with grossly and histologically confirmed GBM. Methods Multicenter, retrospective study of dogs with GBM undergoing cholecystectomy with concurrent liver biopsy. Archived histological sections of gallbladder and liver evaluated by investigators blinded to data. Proportions of dogs with each histologic abnormality alive vs deceased at 1, 3, and 12 months post-cholecystectomy compared. Mann-Whitney U performed to determine if NLR differed in dogs with or without selected lesions. Results 51/52 (98%, 95% CI [89%, 99%]) dogs with GBM had at least 1 hepatic histologic abnormality. Hepatic fibrosis (37/51; 73%, 95% CI [59%, 83%]), biliary hyperplasia (29/52; 56%, 95% CI [42%, 68%]), and portal inflammation (25/52; 48%, 95% CI [35%, 61%]) were most common. The proportion of dogs alive vs dead differed based on the fibrosis score at 1, 3, and 12 (P ≤ .04) months post-cholecystectomy. Dogs with hepatic necrosis (P = .006) and cholangitis/cholangiohepatitis (P = .02) had higher NLRs compared to dogs without these lesions. Conclusions and Clinical Importance Histologic abnormalities of the liver are common in dogs with GBM. A higher portal fibrosis score might be associated with shortened long-term survival after cholecystectomy for dogs with GBM. An increase in NLR might predict hepatic necrosis and cholangitis/cholangiohepatitis in dogs with GBM.

Aims With the progress of thrombectomy technology, the vascular recanalization rate of patients with stroke has been continuously improved, but the proportion of futile recanalization (FR) is still quite a few. The long‐term prognosis and survival of patients with FR and its influencing factors remain unclear. Methods Consecutive patients who received endovascular treatment (EVT) for ischemic stroke were enrolled between 2013 and 2021 from a single‐center prospectively registry study. We evaluated the long‐term outcome of these patients by Kaplan–Meier survival analysis, and the multivariable logistic regression curve was performed to analyze influencing factors. Results Among 458 patients with FR, 56.4% of patients survived at 1 year, and 50.4% at 2 years. In the multivariate regression analysis, age, premorbid modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), posterior circulation infarct, general anesthesia, symptomatic intracerebral hemorrhage (sICH), and decompressive craniectomy were found to be related to unfavorable outcomes in long‐term. Age, premorbid mRS, NIHSS, general anesthesia, and sICH were predictors of long‐term mortality. Conclusions Futile recanalization accounts for a large proportion of stroke patients after thrombectomy. This study on the long‐term prognosis of such patients is beneficial to the formulation of treatment plans and the prediction of therapeutic effects. Futile recanalization accounts for a large proportion of stroke patients after thrombectomy. We evaluated the long‐term outcome of these patients by Kaplan–Meier survival analysis, and the multivariable logistic regression curve was performed to analyze influencing factors, which is beneficial to the formulation of treatment plans and the prediction of therapeutic effects.