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Frexalimab, a second-generation anti-CD40L monoclonal antibody, demonstrated safety and efficacy in participants with relapsing multiple sclerosis (pwRMS) in the12-week (W) double-blind period of a phase 2 trial (NCT04879628), with an 89% reduction in new gadolinium-enhancing lesions in the high-dose group versusplacebo. This was accompanied by a 24% reduction in plasma neurofilament light (pNfL), a biomarker of neuroaxonal damage. Here, we describe changes in pNfL levelswith frexalimab treatment until W48. 129 pwRMS were randomized 4:4:1:1 to frexalimab-high, frexalimab-low, placebo-high, or placebo-low groups; participants receiving placebo switched to respective frexalimab groups at W12. Plasma samples were collected at baseline, W12, W24 and W48, and pNfL levels were measured using the Simoa® NF-LIGHT™ assay. Here, geometric means are reported at baseline and W48. A one-way ANOVA was used to examine differences in pNfL levels across treatment groups at baseline. Differences from baseline were calculated using percent change. 125/129 (97%) participants completed the double-blind period and entered the open-label extension. At baseline (n=123), pNfL levels (geometric mean [SD]) were similar across groups (F=0.09, p=0.97): 11.9 [2.0] in frexalimab-high, 12.7 [1.8] in frexalimab-low, 12.5 [1.9] in placebo-high/frexalimab-high, and 12.2 [1.8] pg/ml in placebo-low/frexalimab-low. At W48 (n=108), pNfL levels were reduced to 6.7 [2.0] in frexalimab-high, 8.1 [1.7] in frexalimab-low, 9.6 [1.7] in placebo-high/frexalimab-high, and 7.8 [2.1] pg/ml in placebo-low/frexalimab-low corresponding to a 41%, 35%, 24%, and 33% reduction from baseline, respectively. The observed reduction in pNfL through W48 provides evidence that frexalimab markedly reduces neuroaxonal damage in pwRMS. [ABSTRACT FROM AUTHOR]

Although the impact of poorly controlled diabetes on surgical outcomes of patients undergoing lower extremity revascularization is well-known, it is not clear if immediate postoperative hyperglycemia (IPH) itself can be used as a surrogate for poor outcomes after peripheral arterial bypass. We sought to examine the effect of IPH in this patient population with its impact on short-term and long-term outcomes. Retrospective review was completed for 505 patients who underwent either suprainguinal bypass surgery or infrainguinal bypass surgery between July 2002 and April 2018 for the treatment of peripheral arterial disease. All patients were undergoing first-time open bypass grafting. Patients were stratified into those who were normoglycemic or hyperglycemic (glucose ≥ 140 mg/dL) within 24 hours after surgery. A comparative analysis was performed on comorbidities and outcomes. Of 505 patients who underwent bypass grafting, 255 patients (50.5%) were hyperglycemic. The mean age of patients was 63.5 ± 14.1 years. The median follow-up was 5.2 years (range, 0.0-15.2 years). The distribution of procedures was as follows: femoral to popliteal bypasses (29%), femoral to femoral bypasses (17%), femoral to tibial bypasses (12%), aortobifemoral bypasses (10%), iliofemoral bypasses (9%), and axillofemoral bypasses (7%). At 30 days, hyperglycemic patients had an increased incidence of limb loss (8.3% vs 4.0%) and myocardial infarction (4.8% vs 0.8%) and incurred higher costs of hospital stay ($27,701 vs $22,990) (all P <.05). At 10 years, these patients had a higher incidence of needing major amputations (15.4% vs 9.4%; P =.025). Hyperglycemia after infrainguinal bypass was associated with nearly twice the risk of limb loss at 5 years (hazard ratio, 1.91; P =.034). Among the cohort of patients who required major amputations, the time duration between index revascularization and amputation was significantly shorter as compared with normoglycemic patients (P =.003). In this single-institution study with long-term follow-up, IPH was associated with increased rates of 30-day amputation and myocardial infarction, as well as an increased cost of hospital stay. In the long term, postoperative hyperglycemia was associated with greater major limb loss. Among the cohort of patients who required major amputations, the time period between revascularization and amputation was shorter for those patients who had IPH. IPH is an independent marker for poor outcomes after lower extremity revascularization procedures. [ABSTRACT FROM AUTHOR]

Believes critical thinking and reflective thinking are distinctly different yet complementary forms of higher level thinking. Discusses topics such as: why higher level thinking is important; what the proper attitude for this form of thinking is; and why it is important. Addresses questions with examples from sociology and medicine. (Author/KDR)