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Background For acute proximal intracranial artery occlusions, contact aspiration may be more effective than stent‐retriever for first‐line reperfusion therapy. Due to the lack of data regarding medium vessel occlusion thrombectomy, we evaluated outcomes according to first‐line technique in a large, multicenter registry. Methods Imaging, procedural, and clinical outcomes of patients with acute proximal medium vessel occlusions (M2, A1, or P1) or distal medium vessel occlusions (M3, A2, P2, or further) treated at 37 sites in 10 countries were analyzed according to first‐line endovascular technique (stent‐retriever versus aspiration). Multivariable logistic regression and propensity‐score matching were used to estimate the odds of the primary outcome, expanded Thrombolysis in Cerebral Infarction score of 2b–3 (“successful recanalization”), as well as secondary outcomes (first‐pass effect, expanded Thrombolysis in Cerebral Infarction 2c‐3, intracerebral hemorrhage, and 90‐day modified Rankin scale, 90‐day mortality) between treatment groups. Results Of the 440 included patients (44.5% stent‐retriever versus 55.5% aspiration), those treated with stent‐retriever had lower baseline Alberta Stroke Program Early Computed Tomography Scale scores (median 8 versus 9; P <0.01), higher National Institutes of Health Stroke Scale scores (median 13 versus 11; P =0.02), and nonsignificantly fewer medium‐distal occlusions (M3, A2, P2, or other: 17.4% versus 23.8%; P =0.10). Use of a stent‐retriever was associated with 15% lower odds of successful recanalization (odds ratio [OR], 0.85; [95% CI 0.74–0.98]; P =0.02), but this was not significant after multivariable adjustment in the total cohort (adjusted OR, 0.88; [95% CI 0.72–1.09]; P =0.24), or in the propensity‐score matched cohort (n=105 in each group) (adjusted OR, 0.94; [95% CI 0.75–1.18]; P =0.60). There was no significant association between technique and secondary outcomes in the propensity‐score matched adjusted models. Conclusion In this large, diverse, multinational medium vessel occlusion cohort, we found no significant difference in imaging or clinical outcomes with aspiration versus stent‐retriever thrombectomy.

AbstractContextInhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED).ObjectiveWe report the first clinical studies of an FcRn inhibitor, batoclimab, in TED.DesignProof-of-concept (POC) and randomized, double-blind placebo-controlled trials.SettingMulticenter.ParticipantsPatients with moderate-to-severe, active TED.InterventionIn the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks.Main OutcomeChange from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial).ResultsThe randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P &lt; .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P &lt; .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P &lt; .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation.ConclusionsThese results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

Background: The renin-angiotensin-aldosterone system (RAAS) has been associated with gastrointestinal inflammation and fibrosis, suggesting that RAAS blockade may be beneficial in patients with inflammatory bowel disease. Using retrospective analysis, we aimed to compare the disease course of patients with Crohn’s disease (CD) taking two commonly prescribed classes of RAAS-blocking agents. Study: Patients with CD initiated on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) between 2000 and 2016 were enrolled. Data on clinical, radiologic, and procedural surrogate markers of inflammatory bowel disease were collected in the subsequent 3, 5, and 10 years and compared with matched controls using univariate and multivariate analyses. Results: Compared with controls, patients taking ARBs had fewer instances of corticosteroid use (1.06 vs 2.88, P < 0.01) at 10 years. Patients taking ACEIs had an overall worse disease course, with more imaging studies (3.00 vs 1.75, P = 0.03) and endoscopic procedures (2.70 vs 1.78, P = 0.01) at 5 years, and more imaging studies (6.19 vs 3.50, P < 0.01), endoscopic procedures (5.91 vs 3.78, P < 0.01), and gastrointestinal operations (0.59 vs 0.18, P < 0.02) at 10 years. Results remained significant on multivariate analysis, adjusting for CD characteristics and the use of other antihypertensive medications. Conclusions: Our study provides insight into the long-term use of RAAS-blocking agents in patients with CD, suggesting that differences exist among commonly prescribed medication classes. While ACEIs were associated with an overall worse disease course at 5 and 10 years, patients taking ARBs were noted to have fewer instances of corticosteroid use at 10 years. Future large-scale studies are needed to further explore this association.

Abstract The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1x10− 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

Importance Given the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed. Objective To examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population. Design, Setting, and Participants This cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020. Individuals were matched using propensity score matching according to the following criteria: age, sex, body mass index, ethnicity, diabetes with or without insulin or biguanide use, hypertension, ischemic heart disease, dyslipidemia, aspirin use, and number of medications taken (UKB only). Data analysis was performed from April 2021 to April 2023. Exposure Regular statin use. Main Outcomes and Measures Primary outcomes were liver disease and HCC development as well as liver-associated death. Results A total of 1 785 491 individuals were evaluated after matching (aged 55 to 61 years on average, up to 56% men, and up to 49% women). A total of 581 cases of liver-associated death, 472 cases of incident HCC, and 98 497 new liver diseases were registered during the follow-up period. Individuals were aged 55-61 years on average, with a slightly higher proportion of men (up to 56%). In UKB individuals (n = 205 057) without previously diagnosed liver disease, statin users (n = 56 109) had a 15% lower hazard ratio (HR) for the association of developing a new liver disease (HR, 0.85; 95% CI, 0.78-0.92; P &amp;lt; .001). In addition, statin users demonstrated a 28% lower HR for the association with liver-related death (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and a 42% lower HR for the development of HCC (HR, 0.58; 95% CI, 0.35-0.96; P = .04). In TriNetX individuals (n = 1 568 794), the HR for the association of HCC was reduced even further for statin users (HR, 0.26; 95% CI, 0.22-0.31; P = .003). The hepatoprotective association of statins was time and dose dependent, with a significant association in PMBB individuals (n = 11 640) for incident liver diseases after 1 year of statin use (HR, 0.76; 95% CI, 0.59-0.98; P = .03). Taking statins was particularly beneficial in men, individuals with diabetes, and individuals with a high Fibrosis-4 index at baseline. Carriers of the heterozygous minor allele of PNPLA3 rs738409 benefited from statin use and had a 69% lower HR for the association with HCC (UKB HR, 0.31; 95% CI, 0.11-0.85; P = .02). Conclusions and Relevance This cohort study indicates substantial preventive associations of statins against liver disease, with an association with duration and dose of intake.

Abstract The landmark NUTRIREA‐2 and NUTRIREA‐3 trials compared the route and dose of nutrition, respectively, in critically ill patients with circulatory shock. The results of both trials support a “less‐is‐more” paradigm shift in the early acute phase of critical illness. In this review, the authors outline and appraise the results of the NUTRIREA‐2 and NUTRIREA‐3 trials, introduce the concept of identifying the “sweet spot” for nutrition dose based on severity of illness/nutrition risk and nutrition dose, and identify the unintended consequences of delivering full‐dose nutrition in sicker critically ill patients during the early acute phase of critical illness.

AbstractObjectivesAlthough hemispheric surgeries are among the most effective procedures for drug‐resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1‐, 2‐, and 5‐years post‐hemispherectomy.MethodsRetrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time‐to‐seizure recurrence. A multivariate Cox proportional‐hazards regression model was developed to predict the likelihood of post‐hemispheric surgery seizure freedom at three time points (1‐, 2‐ and 5‐ years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops‐calculator.com/).ResultsThe selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non‐hemispheric resective surgery, and contralateral fluorodeoxyglucose–positron emission tomography [FDG‐PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time‐to‐seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG‐PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non‐lesional MRI, non‐stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%.SignificanceOnline calculators are useful, cost‐free tools that can assist physicians in risk estimation and inform joint decision‐making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Cisplatin is the standard for the chemoradiation of squamous cell carcinoma of the head and neck (HNSCC). Many patients cannot receive cisplatin due to impaired renal function. This study investigated carboplatin as an alternative option. In total, 131 patients assigned to two courses of cisplatin (20 mg/m2/d1-–5 or 25 mg/m2/d1–4) were matched to 45 patients not suitable for cisplatin and receiving carboplatin (AUC 1.0/d1–5 or AUC 1.5/d1–4). The endpoints included loco-regional control (LRC), metastases-free survival (MFS), overall survival (OS), toxicities, and the completion of chemotherapy. The patients in the carboplatin group were significantly older and had more G3 tumors. Otherwise, the baseline characteristics were balanced. The LRC rates at 2 and 3 years were 77% and 76% in the cisplatin group vs. 69% and 65% in the carboplatin group (p = 0.21). The MFS rates were 83% and 78% vs. 78% and 74% (p = 0.34) and the OS rates 83% and 79% vs. 83% and 75% (p = 0.64), respectively. The outcomes were not significantly different in the subgroups receiving definitive or adjuvant chemoradiation. No significant differences were found regarding toxicities. Non-significantly more patients in the carboplatin group completed their chemotherapy (78% vs. 66%, p = 0.15). Carboplatin was associated with similar outcomes and toxicities as cisplatin, although these patients had worse renal function, more aggressive tumors, and were older. Given the limitations of this study, carboplatin appears an option for patients not suitable for cisplatin.

Many patients with squamous cell carcinoma of the head and neck (SCCHN) receive cisplatin-based chemoradiation. Cisplatin 100 mg/m2 every three weeks is toxic and alternative cisplatin regimens are desired. Two courses of 20 mg/m2/day 1–5 (cumulative 200 mg/m2) were shown to be similarly effective and better tolerated than 100 mg/m2 every three weeks. Previous studies suggested that cumulative doses >200 mg/m2 may further improve outcomes. In this study, 10 patients (group A) receiving two courses of 25 mg/m2/day 1–5 (cumulative 250 mg/m2) in 2022 were retrospectively matched and compared to 98 patients (group B) receiving two courses of 20 mg/m2/day 1–5 or 25 mg/m2/day 1–4 (cumulative 200 mg/m2). Follow-up was limited to 12 months to avoid bias. Group A achieved non-significantly better 12-month loco-regional control (100% vs. 83%, p = 0.27) and metastases-free survival (100% vs. 88%, p = 0.38), and similar overall survival (89% vs. 88%, p = 0.90). No significant differences were found regarding toxicities, completion of chemotherapy, and interruption of radiotherapy. Given the limitations of this study, chemoradiation with two courses of 25 mg/m2/day 1–5 appears an option for carefully selected patients as a personalized treatment approach. Longer follow-up and a larger sample size are needed to properly define its role.

Background & Aims: Early-stage HCC can be treated with thermal ablation or stereotactic body radiation therapy (SBRT). We retrospectively compared local progression, mortality, and toxicity among patients with HCC treated with ablation or SBRT in a multicenter, US cohort. Approach & Results: We included adult patients with treatment-naïve HCC lesions without vascular invasion treated with thermal ablation or SBRT per individual physician or institutional preference from January 2012 to December 2018. Outcomes included local progression after a 3-month landmark period assessed at the lesion level and overall survival at the patient level. Inverse probability of treatment weighting was used to account for imbalances in treatment groups. The Cox proportional hazard modeling was used to compare progression and overall survival, and logistic regression was used for toxicity. There were 642 patients with 786 lesions (median size: 2.1 cm) treated with ablation or SBRT. In adjusted analyses, SBRT was associated with a reduced risk of local progression compared to ablation (aHR 0.30, 95% CI: 0.15–0.60). However, SBRT-treated patients had an increased risk of liver dysfunction at 3 months (absolute difference 5.5%, aOR 2.31, 95% CI: 1.13–4.73) and death (aHR 2.04, 95% CI: 1.44–2.88, p < 0.0001). Conclusions: In this multicenter study of patients with HCC, SBRT was associated with a lower risk of local progression compared to thermal ablation but higher all-cause mortality. Survival differences may be attributable to residual confounding, patient selection, or downstream treatments. These retrospective real-world data help guide treatment decisions while demonstrating the need for a prospective clinical trial.