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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.

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.

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.

Introduction Further prolapse in the same or a different vaginal compartment is common, particularly following native tissue surgery. This study aims to report the rates of reoperations for prolapse and subjective recurrence after native tissue and mesh‐augmented surgeries. Additionally, it seeks to describe the methods of repeat surgery for prolapse and to evaluate long‐term mesh complications. Material and Methods This is a follow‐up study of the nationwide cohort (ClinicalTrials.gov [NCT02716506]) of pelvic organ prolapse surgeries performed in 2015 in Finland. Prolapse recurrence, reoperations and mesh complications were studied utilizing data from patient questionnaires and the national register. Reoperation rates, timing, methods of repeat surgery, and rates of subjective recurrence were compared among native tissue, transvaginal mesh and abdominal mesh surgeries. Predictive factors for reoperation were studied with logistic regression analysis. Mesh‐related complications were evaluated after transvaginal and abdominal mesh repair. Results The mean follow‐up of 3321 women was 7.4 years, during which 443 (13%) underwent reoperation for prolapse; 13.9% after native tissue, 10.1% after transvaginal mesh, and 12.1% after abdominal mesh repair (p = 0.09). Up to one third of women reported symptoms of vaginal bulging during follow‐up, with significantly lower rates after transvaginal mesh surgery at 2‐ and 5‐year follow‐ups. The majority of reoperations for prolapse were single‐site; anterior or apical repair was most common after native tissue and abdominal mesh surgery, while reoperations after transvaginal repair involved mainly posterior or apical compartments. Mesh was used in 40% of all reoperations. Prolapse surgery involving both posterior and apical compartments was the only factor associated with increased risk for reoperation (aOR 1.95 CI 1.30–2.92). Only 1.6% of women had a surgically treated mesh complication based on the register data, while the rates of patient‐reported mesh exposures and mesh‐related reoperations were 6.5% and 6.4%, with no significant difference between the two mesh groups. Conclusions The long‐term risk of reoperation for prolapse was similar after native tissue and mesh‐augmented surgery, while the site of reoperation differed based on the type of surgical treatment. Mesh complication rates were similar after transvaginal and abdominal mesh repair, and the majority of mesh exposures did not require surgical treatment. Similar rates of women undergo re‐treatment for prolapse after surgery with native tissue and mesh, while subjective recurrence is common, and the site of reoperation varies depending on prior surgical treatment. Only a minority of mesh exposures requires surgical treatment.

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.

Purpose Given an increasingly overweight population, unicompartmental knee replacements (UKRs) are being performed in patients with higher body mass indices (BMIs). There are concerns that cemented fixation will not last. Cementless fixation may offer a solution, but the long term results in different BMI groups has not been assessed. We studied the effect of BMI on the outcomes of cementless UKRs. Methods A prospective cohort of 1000 medial cementless mobile-bearing UKR with a mean follow up of 6.6 years (SD 2.7) were analysed. UKRs were categorised into four BMI groups: (1) ≥ 18.5 to < 25 kg/m 2 (normal), (2) 25 to < 30 kg/m 2 (overweight), (3) 30 to < 35 kg/m 2 (obese class 1) and (4) ≥ 35 kg/m 2 (obese class 2). Implant survival was assessed using endpoints reoperation and revision. Functional outcomes were assessed. Results Ten-year cumulative revision rate for the normal ( n  = 186), overweight ( n  = 434), obese class 1 ( n  = 213) and obese class 2 ( n  = 127) groups were 1.8% (CI 0.4–7.4), 2.6% (CI 1.3–5.1), 3.8% (CI 1.5–9.2) and 1.7% (CI 0.4–6.8) with no significant differences between groups ( p  = 0.79). The 10-year cumulative reoperation rates were 2.7% (CI 0.8–8.2), 3.8% (CI 2.2–6.6), 5.2% (CI 2.5–10.7) and 1.7% (CI 0.4–6.8) with no significant differences between groups ( p  = 0.44). The 10-year median Oxford Knee Score were 43.0, 46.0, 44.0 and 38.0 respectively. Conclusion Cementless mobile-bearing UKR has low 10-year reoperation and revision rates across in all BMI groups, and there are no significant differences between the groups. Although higher BMI groups had slightly worse functional outcomes, the improvement in function compared to preoperatively  tended to be better. This study suggests that BMI should not be considered a contraindication for the cementless mobile-bearing UKR.

Objective To systematically evaluate the clinical application and long‐term efficacy of ear molding devices and to explore future treatment strategies for auricular morphological deformity (AMD). Methods Clinical data of patients with AMDs who visited our department between 2017 and 2022 were retrospectively collected. This study included 102 cases who underwent noninvasive ear molding correction and were followed up for more than 3 years. The correction of different types of AMDs—such as prominent ear, cup ear, cryptotia, and lop ear—was analyzed in detail. Correction outcomes were recorded. Results The overall success rate of correction was 85.29%. No significant differences were found in total wear time among different deformity types. Similarly, no significant differences were observed in correction outcomes across different morphological types of AMDs. The age at treatment initiation was positively correlated with total wear time. Both the age at treatment initiation and total wear time influenced the correction outcomes. Age ≤ 7 days and total correction time ≤ 28 days were independently associated with better treatment outcomes, each exerting a significant and non‐confounding effect on prognosis. Notably, only one case developed relatively severe eczema, which interrupted device wear for approximately 1 week; this complication was not associated with the use of domestic or imitation correction devices. Conclusion While different correction approaches may vary in their application across deformity types, the long‐term correction outcomes are comparable among different morphological classifications. The final outcome is influenced by the age at which correction is initiated and the total wear time. Only a small proportion of patients experienced complications that affected device wear. Noninvasive ear molding is an effective treatment modality with favorable long‐term outcomes. Level of Evidence 4.

Purpose The purpose was to summarize evidence of long‐term outcomes of children, 2 years and older, exposed to opioids in‐utero. Design This was a systematic review. Studies were identified by searching the following electronic databases: PubMed, EBSCO HOST/Medline, and Web of Science. Articles were published between 1979 and 2019. Methods This systematic review was reported according to the Preferred Reporting Items for Systematic Review and Meta‐Analysis. Two sets of two independent reviewers extracted data and assessed study quality according to National Institutes of Health quality assessment tools. Results Forty‐three articles met inclusion criteria. Synthesis of articles identified trends toward worse outcomes for children with in‐utero opioid exposure in all areas, most notably related to academic success, behavior, cognition, hospitalizations, and vision. Conclusions Findings reinforce the necessity of continued research in this area with improved study design. Despite limitations in the current body of evidence, findings from this review are vital knowledge for clinicians, because children exposed to opioids in‐utero are clearly vulnerable to a wide variety of suboptimal health and developmental outcomes. Clinical Relevance Recognition of all outcomes across childhood associated with in‐utero opioid exposure will inform improved identification and interventions tailored to the most pressing needs of affected children. Despite the need for continued research, there is sufficient evidence to necessitate close, individualized follow‐up throughout childhood.

Background Studies regarding the long‐term outcomes of endoscopic submucosal dissection (ESD) performed in older patients with colorectal tumors are limited. Therefore, in this study, we aimed to analyze the long‐term outcomes of older patients with colorectal tumors who underwent ESD and identify prognostic factors. Methods The data of patients aged ≥ 75 years who underwent ESD for colorectal tumors (adenoma and Tis/T1 colorectal cancer) at a single center were retrospectively analyzed. Prognostic factors for overall survival were analyzed using the Kaplan–Meier method and the Cox proportional hazard model. Results Of the 156 patients included, 51 patients died during the follow‐up period, among whom two deaths were due to colorectal cancer. The univariate analysis revealed that an age ≥83 years, Charlson Comorbidity Index ≥2, prognostic nutritional index <46, and neutrophil‐to‐lymphocyte ratio (NLR) ≥3 were associated with poor overall survival. The multivariate analysis identified Charlson Comorbidity Index ≥2 (hazard ratio: 2.26; 95% confidence interval (CI): 1.24–4.13; p = 0.0008) and NLR ≥3 (hazard ratio, 1.98; 95% CI: 1.02–3.81; p = 0.042) as independent prognostic factors. Conclusions CCI and NLR may be useful parameters for decision‐making in older patients undergoing colorectal ESD.