Intraretinal Hyper-Reflective Foci Are Almost Universally Present and Co-Localize With Intraretinal Fluid in Diabetic Macular Edema.

Purpose: In diabetic macular edema (DME), hyper-reflective foci (HRF) has been linked to disease severity and progression. Using an automated approach, we aimed to investigate the baseline distribution of HRF in DME and their co-localization with cystoid intraretinal fluid (IRF). Methods: Baseline spectral-domain optical coherence tomography (SD-OCT) volume scans (N = 1527) from phase III clinical trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) were segmented using a deep-learning-based algorithm (developed using B-scans from BOULEVARD NCT02699450) to detect HRF. The HRF count and volume were assessed. HRF distributions were analyzed in relation to best-corrected visual acuity (BCVA), central subfield thickness (CST), and IRF volume in quartiles, and Diabetic Retinopathy Severity Scores (DRSS) in groups. Co-localization of HRF with IRF was calculated in the central 3-mm diameter using the en face projection. Results: HRF were present in most patients (up to 99.7%). Median (interquartile range [IQR]) HRF volume within the 3-mm diameter Early Treatment Diabetic Retinopathy Study ring was 1964.3 (3325.2) pL, and median count was 64.0 (IQR = 96.0). Median HRF volumes were greater with decreasing BCVA (nominal P = 0.0109), and increasing CST (nominal P < 0.0001), IRF (nominal P < 0.0001), and DRSS up to very severe nonproliferative diabetic retinopathy (nominal P < 0.0001). HRF co-localized with IRF in the en face projection. Conclusions: Using automated HRF segmentation of full SD-OCT volumes, we observed that HRF are a ubiquitous feature in DME and exhibit relationships with BCVA, CST, IRF, and DRSS, supporting a potential link to disease severity. The spatial distribution of HRF closely followed that of IRF.

Sodium Phenylbutyrate and Taurursodiol: A New Therapeutic Option for the Treatment of Amyotrophic Lateral Sclerosis.

OBJECTIVE: To review the safety and efficacy of sodium phenylbutyrate and taurursodiol (SP + T) in slowing progression of amyotrophic lateral sclerosis (ALS) compared with pre-existing therapies. DATA SOURCES: A PubMed (from January 1, 2009, to April 13, 2023) and ClinicalTrials.gov search conducted using sodium phenylbutyrate, taurursodiol, AMX0035, riluzole, and edaravone. Additional articles were identified by hand from references. DATA SELECTION AND DATA EXTRACTION: This included English-language articles evaluating SP + T efficacy or safety in humans for decreasing neuronal death and slowing the progression of ALS. DATA SYNTHESIS: In one phase II clinical trial that encompassed an open-label extension phase, disease severity, assessed by the rate of decline in overall score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised with higher scores indicating more functional ability, was -1.24 points per month with active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = 0.03). Post hoc analysis found survival benefit of median 4.8 months with active medication compared with placebo. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: SP + T is a new US Food and Drug Administration-approved oral suspension for the treatment of ALS. Patients who received active medication through the phase II trial showed decreased rates of disease progression. Overall, SP + T could be considered a potential agent for the treatment of ALS which has a high unmet need. CONCLUSION: SP + T is an option for the treatment of ALS; however, additional data regarding efficacy in phase III trials with long-term safety profile considerations, as well as trials to compare current therapy with SP + T, are needed.

Lecanemab: A Humanized Monoclonal Antibody for the Treatment of Early Alzheimer Disease.

OBJECTIVE: To review current pharmacology, pharmacokinetics/pharmacodynamics, safety, and efficacy of lecanemab in patients with Alzheimer disease. DATA SOURCES: A literature search of PubMed (April 1, 2016-November 15, 2023) and ClinicalTrials.gov search were conducted using the following search terms: lecanemab and BAN2401. Additional articles were identified by hand from references. STUDY SELECTION AND DATA EXTRACTION: We included English-language clinical trials, randomized controlled trials, reviews, and systematic reviews evaluating lecanemab pharmacology, efficacy, or safety in humans for the management of Alzheimer disease. DATA SYNTHESIS: In the Clarity AD phase III trial, lecanemab led to a decrease in brain amyloid levels and showed moderate improvement in clinical measures of cognition and function. At 18 months, lecanemab 10 mg/kg biweekly exhibited a lower least squares mean change from baseline (1.21) compared to placebo (1.66) of Clinical Dementia Rating-Sum of Boxes score, signifying a significant difference of -0.45 (95% CI, -0.67 to -0.23; P < 0.001). In a subset of 698 participants, lecanemab reduced brain amyloid burden by -59.1 Centiloids (95% CI, -62.6 to -55.6). Lecanemab demonstrated favorable differences in Alzheimer Disease Assessment Scale-cognitive subscale 14, Alzheimer Disease Composite Score, and Alzheimer Disease Cooperative Study-Mild Cognitive Impairment-Activities of Daily Living scores. Adverse events included infusion-related reactions (26.4%) and amyloid-related imaging abnormalities (12.6%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Lecanemab reduces cognitive decline but raises concerns about intravenous administration, cost, and magnetic resonance imaging needs. Ongoing trials exploring subcutaneous dosing and positron emission tomography scans may offer solutions. CONCLUSION: Lecanemab is a humanized monoclonal antibody that is selective for soluble amyloid-beta (Aß) aggregates. Lecanemab has exhibited a decrease in brain Aß plaques and moderately less decline on clinical measures of cognitive function.

Black Youth Suicide Crisis: Prevalence Rates, Review of Risk and Protective Factors, and Current Evidence-Based Practices.

Suicide is the second leading cause of death among adolescents and young adults. Historically, Black youths have experienced lower rates of suicide; however, recent data point to significant racial disparities. In this article, the authors review current suicide rates, including alarming new data suggesting that suicide rates are two times higher among Black children ages 5-12 compared with White children in that age range. A clinically focused summary of socioecological risk and protective factors associated with suicide among Black youths, with particular attention on structural drivers and culturally relevant factors, is provided. Current evidence-based reviews suggest that dialectical behavior therapy is the only well-established treatment against self-harm and suicide among youths. However, it is unknown whether current established treatments work for Black youths, because Black youths are rarely included in randomized controlled trials. The authors conclude by reviewing emerging treatments developed and tested specifically for Black youths.

Trauma Takeaways: Reception and Utilization of a Postsimulation Newsletter.

BACKGROUND: Simulation is incorporated into medical education to reinforce practical skills. Instructor methodologies allow for reflective practice through debriefing; however, this is limited to real-time audiences. Few studies have described education via supplemental materials. OBJECTIVE: This educational initiative demonstrates the reception and use of a postsimulation newsletter for both participating and nonparticipating trauma team members. METHODS: After each case, the Trauma Takeaways newsletter was distributed to all trauma team members at our Level I pediatric trauma center. The newsletter included a brief case summary, objectives, and debrief highlights regarding communication, medical management, and practical logistics. A survey was conducted to assess its utility 6 months after its introduction. RESULTS: Of 69 interdisciplinary respondents, 46 reviewed the newsletter. The majority (69%) reported their trauma education is directly from simulation sessions. Thirty-nine percent of respondents found the newsletter most useful as a review when unable to attend, and 35% found it equally useful as compared with being an active participant. The majority of respondents found the newsletter either very helpful or extremely helpful. CONCLUSIONS: Medical simulation cases traditionally capture a select audience during educational debriefing sessions. However, because the majority of our respondents receive their trauma education from simulation sessions, the need for supplementation is paramount. Our team members found the Takeaways similarly useful both as a direct participant or as an indirect participant as a helpful reference for communication, management, and practical logistics in pediatric trauma care.

Testing for and identification of Multisystem Inflammatory Syndrome in children in the pediatric emergency department.

PURPOSE OF REVIEW: The current article summarizes updates on multisystem inflammatory syndrome in children (MIS-C) research and focuses on strategies to diagnose and manage these patients in the emergency department. RECENT FINDINGS: MIS-C is an inflammatory syndrome that occurs approximately 4-5 weeks after severe acute respiratory syndrome coronavirus 2 infection. It is associated with symptoms such as fever, shock, abdominal pain, rash, and conjunctivitis along with laboratory abnormalities such as elevated inflammatory markers, coagulation factors, and cytokines. Patients fall into the following three subcategories: first, classic or incomplete Kawasaki; second, cardiogenic or distributive shock; or third, an inflammatory response that does not initially meet criteria of the other subcategories. Immediate treatment largely focuses on supportive care through fluid resuscitation and pressor support; however, inpatient management may also include intravenous immunoglobulin, steroids, anticoagulation and at times anti-inflammatory biologics. SUMMARY: Overall fatality rate remains low and short-term research has demonstrated self-limited sequelae. Pediatricians should focus on the timely diagnosis and identification of this inflammatory disease via clinical findings and laboratory evidence to best treat these patients.

Safety and Pharmacokinetic Characterization of Nacubactam, a Novel ß-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers.

Nacubactam is a novel ß-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine ß-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential ß-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].).

Use of a historical control group in a noninferiority trial assessing a new antibacterial treatment: A case study and discussion of practical implementation aspects.

When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice. In this paper, we compare the existing methods based on a confirmatory phase III study design exercise done for a new antibacterial therapy with a binary endpoint and a single historical dataset. A procedure to assess the relative performance of the different methods for borrowing information from historical control data is proposed, and practical questions related to the selection and implementation of methods are discussed. Based on our examination, we found that the methods have a comparable performance, but we recommend the robust mixture prior for its ease of implementation.

Increases in hip and spine bone mineral density are predictive for vertebral antifracture efficacy with ibandronate.

The relationship between bisphosphonate-induced bone mineral density (BMD) gains and antifracture efficacy remains to be fully elucidated. Data from two antifracture studies were analyzed. Postmenopausal osteoporotic women received oral (2.5 mg daily, 20 mg intermittent) or intravenous (0.5 mg, 1 mg quarterly) ibandronate. Outcome measures included moving averages plots and logistic regression analyses of the relationship between BMD change and vertebral fracture rate. In moving averages plots, ibandronate-induced BMD gains were consistently associated with decreased fracture rates. In the oral study, total-hip BMD increases at years 2 and 3 and lumbar spine BMD increases at year 3 were associated with 3-year vertebral fracture rate (relative risk reduction [RRR] at year 3 for 1% change from baseline: hip, 7.9% [95% CI 2.1-13.5%, P = 0.0084]; lumbar spine, 4.7% [-0.1% to 9.3%, P = 0.0565]). In the intravenous study, total-hip BMD increases at years 1, 2, and 3 and lumbar spine BMD increases at years 2 and 3 were significantly associated with vertebral fracture rate (RRR at year 3 for 1% change from baseline: hip, 11.6% [7.0-16.0%, P < 0.0001]; lumbar spine, 6.9% [2.9-10.6%, P = 0.0008]). In a pooled analysis, changes in total-hip and lumbar spine BMD were associated with 3-year vertebral fracture risk reduction and explained a substantial proportion of the antifracture effect (23-37% at 2 and 3 years). This analysis suggests that ibandronate-induced BMD gain in postmenopausal osteoporotic women is associated with vertebral fracture risk reduction.

Comparing proportional hazards and accelerated failure time models: an application in influenza.

The proportional hazards (PH) model is routinely employed for the analysis of time-to-event data in medical research when it is required to assess the effect of an intervention in the presence of covariates. The assumption of PH required for the PH approach may not hold, especially in circumstances where the effect of the intervention is to delay or accelerate the onset of an event rather than to reduce or increase the overall proportion of subjects who observe the event through time. If the assumption of PH is violated, the results from a PH model will be difficult to generalize to situations where the length of follow-up is different to that used in the analysis. It is also difficult to translate the results into the effect upon the expected median duration of illness for a patient in a clinical setting. The accelerated failure time (AFT) approach is an alternative strategy for the analysis of time-to-event data and can be suitable even when hazards are not proportional and this family of models contains a certain form of PH as a special case. The framework can allow for different forms of the hazard function and may provide a closer description of the data in certain circumstances. In addition, the results of the AFT model may be easier to interpret and more relevant to clinicians, as they can be directly translated into expected reduction or prolongation of the median time to event, unlike the hazard ratio. We recommend that consideration is given to an AFT modelling approach in the analysis of time-to-event data in medical research.