Citations

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

AbstractBackgroundAs low titer group O whole blood (LTOWB) increases in popularity, blood centers are finding innovative ways of maintaining the supply. One potential way is collecting LTOWB from parous female donors without testing for HLA antibodies. This in silico simulation predicted the risk of an LTOWB unit containing an HLA antibody and the subsequent risk for an HLA‐incompatible transfusion.MethodsAn LTOWB blood bank with 1 million units was simulated consisting of male, nulliparous, and parous female donors. The proportion of each donor type was modeled after the sex distribution at US blood centers. The parity of female donors was calculated based on the average number of live births per female depending on her age. HLA‐alloimmunization risk was determined by her parity status. The HLA haplotypes of the simulated recipients were derived from the 100 most common HLA haplotypes in the US National Marrow Registry Program database. The proportion of different race/ethnic groups in the US was used to simulate 100,000 LTOWB recipients to whom between 1 and 10 units were administered.ResultsOverall, the risk of an LTOWB unit containing at least one HLA antibody was 12.2% and the rate of receiving an HLA‐incompatible unit was 21.3%. The risk of receiving an HLA‐incompatible unit rose from 4.8% after receipt of one unit to 36.5% after 10 units.ConclusionBlood collectors and hospitals should evaluate the potential TRALI risk against the benefit of a potentially expanded inventory of LTOWB before collecting plasma‐containing products from non‐HLA‐tested parous female donors.

AbstractAimWe investigated whether a commercial bi‐level positive airway pressure (BPAP) device, would improve peripheral oxygen saturation (SpO2) during recreational aviation up to 12,500 feet without supplemental oxygen. Ten adults with recreational flight experience (age:47 ± 14; female = 5) completed a standardized flight profile in an unpressurised aircraft, involving randomized crossover design at 8,000 feet and 12,500 feet with BPAP or control. SpO2, middle cerebral artery velocity (MCAv), heart rate (HR), respiratory rate (RR), and relative tidal volume (TV) index were measured continuously. Psychomotor vigilance test (3‐min) assessed reaction time halfway through taxi and altitude stages. Altitude significantly (p < 0.05) decreased mean SpO2, MCAv, and RR, and increased TV index and HR. There was no effect of altitude (p > 0.05) on reaction time. BPAP increased mean SpO2 at 8,000 feet [Control: 92 ± 1%; BPAP: 94 ± 2%; mean difference (MD) = 2 ± 2%; p = 0.002] and 12,500 feet [Control: 86 ± 4%; BPAP: 89 ± 4%; MD = 2 ± 3%; p = 0.013]. BPAP lowered MCAv at 8,000 feet [Control: 53 ± 10 cm/s; BPAP: 50 ± 9 cm/s; MD = ‐3 ± 2 cm/s; p = 0.001] and 12,500 feet [Control: 52 ± 10 cm/s; BPAP: 50 ± 8 cm/s; MD = ‐2 ± 3 cm/s; p = 0.041]. BPAP increased TV index at 8,000 feet (Control: 6.6 ± 1.3; BPAP:8.1 ± 1.8; MD = 1.9 ± 0.8; p < 0.001) but not 12,500 feet, without effect on RR or reaction time. This study provides preliminary results that BPAP may improve mean SpO2 for recreational aviators up to 12,500 feet without supplemental oxygen.

A novel Corynebacterium species, strain BD556T, isolated from blood, was identified at Mayo Clinic, Rochester, MN, USA. After failing definitive identification using MALDI-ToF MS and partial 16S rRNA gene sequencing, BD556T was characterized using a polyphasic approach, including phenotypic, biochemical and whole-genome sequencing methods. BD556T was a Gram-positive rod with clubbed ends, facultatively anaerobic, catalase-positive, oxidase-negative and non-motile. Colonies were white, opaque and non-haemolytic with halo-like edges. BD556T grew at 35 °C in room air, with CO2 and under anaerobic conditions. BD556T grew well in 0 and 6% NaCl and weakly in 10% NaCl. The genome size was 2 349 779 bp with a G+C content of 60.39%. Phylogenetic analysis using 16S rRNA gene sequence analysis, average nucleotide identity and digital DNA–DNA hybridization between the genome of BD556T and the closest type strains from the Type Strain Genome Server database yielded separation values well beyond those required for species delineation. Chemotaxonomic analyses of BD556T revealed ribose, arabinose and galactose as whole-cell sugars and an A1γ meso-diaminopimelic acid-direct peptidoglycan type. The major cellular fatty acids were C15 : 0 (21.0%), C16 : 0 (14.8%), C17 : 1 ω9c (26.2%), C17 : 0 (13.3%) and C18 : 1 ω9c (18.3%). Polar lipids included diphosphatidylglycerol, phosphatidylglycerol and unidentified glycolipids and phospholipids. BD556T also contained mycolic acids (32–36 carbons) typical of corynebacteria. The respiratory quinones were dominated by MK-8(H2) (71.2%) and MK-9(H2) (25.9%), with smaller amounts of MK-7(H2) and MK-10(H2). The results presented support the tenet that BD556T (=TSD 427T=NCTC 15078T) is a novel species for which the name Corynebacterium mayonis sp. nov. is proposed.

Background and Objectives: Angioedema is a non-pitting edema of the submucosal layer which can be acquired or inherited and usually presents with hives. Intestinal angioedema is rare and can mimic other acute gastrointestinal disorders. It is typically associated with a lack or dysfunction of C1-inhibitor, with a small number of cases having normal C1-inhibitor function. We present a rare case of chronic recurrent intestinal angioedema in a patient with normal C1-inhibitor function who did not respond to icatibant therapy. Case presentation: A 56-year-old woman presented with 3 days of abdominal pain, nausea, vomiting, and diarrhea. She denied a history of allergies and reported a 30-year history of similar episodes requiring hospitalization. Initial evaluation demonstrated normal C4 and C1 esterase inhibitor function with negative gastrointestinal bacterial and viral panel. A CT of the abdomen and pelvis demonstrated acute diffuse bowel thickening and prominent mesenteric lymph nodes. MRI demonstrated inflammation of the small and large bowel. EGD and colonoscopy findings were normal. She was diagnosed with intestinal angioedema and started on icatibant without significant improvement. Her symptoms resolved after 3 days of supportive therapy and resolution of inflammation was noted on imaging. She was discharged home with allergy and immunology follow-up. Conclusions: Intestinal angioedema is under-recognized and presentation can overlap with other pathologies of the GI tract. Extensive work up is needed during the first episode of an attack and complement levels should be checked in all patients. Appropriate classification is important as it dictates therapy. However, ambiguous cases like ours sometimes cannot be classified into any specific category.

Ultrasound imaging is vital for musculoskeletal assessment due to its real‐time, high‐resolution capabilities and safety. While protocols exist for rotator cuff evaluation, comprehensive guidelines for imaging the latissimus dorsi and teres major muscles are lacking. This article fills this gap by presenting a detailed ultrasound protocol for these muscles, essential for shoulder stability and movement in overhead athletes. We review their anatomy, propose a standardized examination approach, and discuss clinical indications, aiming to improve diagnostic accuracy and management of these injuries.

Abstract Background Pharmacokinetics of beta-lactams vary widely in neonatal and pediatric patients due to developmental biology and critical illness. Cefepime (FEP), meropenem (MEM), and piperacillin/tazobactam (TZP) are highly susceptible to pharmacokinetic changes as hydrophilic, small molecules with renal clearance. Subtherapeutic levels are associated with clinical and microbiologic failure, and supratherapeutic levels associated with toxicity. Beta-lactam therapeutic drug monitoring (TDM) may optimize the effectiveness and safety of these agents. The purpose of this investigation is to describe the % of pediatric and neonatal patients with beta-lactam serum levels within target range. Methods In August 2023, TDM launched at the Mayo Clinic Children’s Center for select patients treated with FEP, MEM, or TZP with expected durations ≥ 48 hours, or who were on kidney replacement therapy (KRT), extracorporeal membrane oxygenation (ECMO), weighed &gt; 120 kg, had a BMI &gt; 95th percentile, or at the discretion of pediatric ID team. Validated drug assays were performed daily, Monday through Friday. A two-level sampling strategy was preferred with a peak 1 hour after the end of the infusion and a trough 30 minutes before the next dose. Empiric trough target ranges were set at FEP 8-50 mg/L, MEM 2-30 mg/L, and piperacillin 16-150 mg/L. These target ranges were adjusted with confirmed microbiology to a time above the minimum inhibitory concentration of the organism for 100% of the dosing interval (100%T &gt; MIC). Results From August 2023 to April 2024, 74 episodes of TDM were performed on 45 patients. Thirty-seven (82%) patients were in an intensive care unit (ICU) at the time of TDM, 8/45 (22%) of whom were in the neonatal ICU. Target range was achieved in 67% of patients on FEP, 50% on MEM, and 52% on TZP. Median (IQR) trough values were 22.1 (8.6, 44.2) mg/L for FEP, 0.6 (0, 4.1) mg/L for MEM, and 15.5 (3.8, 27.1) mg/L for TZP. Seven levels were above target for FEP and 0 for MEM and TZP. Seven levels were below target for FEP, 4 for MEM, and 11 for TZP. Conclusion Implementation of a TDM program for FEP, MEM and TZP in pediatric and neonatal patients revealed drug levels frequently outside target range. TDM may facilitate dose individualization to optimize medication efficacy and minimize toxicity. Disclosures Raymond Stetson, MD, MS, Moderna: Grant/Research Support Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Board Member Erin F. Barreto, PharmD, MSc, Baxter Health: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant

Objectives: Many individuals with dementia with Lewy bodies (DLB) die of disease-related complications, but predicting the end of life can be challenging. We identified a phenotype associated with approaching end of life. Methods: We present 4 exemplar cases where individuals with DLB experienced refractory psychosis before death. We reviewed codebooks and quotes from 3 studies regarding end-of-life experiences in DLB to identify experiences that aligned with this phenotype. Results: In addition to the 4 cases, family caregivers in prior studies described prominent worsening of psychosis before death in some individuals with DLB. The worsening often occurred several months before death and was sometimes associated with rapid deterioration. Worsening psychosis was the prominent symptom and was not initially accompanied by cognitive or physical decline. In many cases, the refractory psychosis resulted in inpatient psychiatric hospitalization or residential care, but these scenarios were challenging because of the individual’s behavior. Conclusion: Refractory psychosis in DLB, particularly out of proportion to other symptoms, may be a signal of approaching the end of life. More research is needed to understand this phenomenon and to develop effective and safe treatments for psychosis in DLB.

ABSTRACT Symmetry refers to properties that remain invariant upon mathematical transformations. The principles of symmetry have guided numerous important discoveries in physics and chemistry but not in biology and medicine. Here, we aim to explore the presence of symmetry relationships at the gene expression level as a mean to distinguish between healthy and disease states. We deployed Learning-Based Invariant Feature Engineering - LIFE, a hybrid machine learning approach implemented with two symmetric invariant feature functions (IFFs) to identify Invariant Feature Genes (IFGs), which are gene pairs whose IFF single-value outputs remain invariant across individual samples in a given biological phenotype. Our multiclass classification results across the transcriptomes of 25 normal organs, 25 cancer types, and blood samples obtained from 4 different types of neurodegenerative diseases revealed the presence of unique phenotype-specific IFGs. We constructed networks using these IFGs (IF-Nets) and intriguingly, we demonstrated that the hubs could serve as information encoders, capable of reconstructing sample-wise expression values in relation to their counterpart genes. More importantly, we found that hubs of cancer IF-Nets were enriched with both approved and clinical trial drugs, highlighting “symmetry breaking” as a novel approach for treating diseases.