Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Eosinopenia and post-hospital outcomes in critically ill non-cardiac vascular surgery patients.

BACKGROUND AND AIMS: Eosinopenia is a marker for acute inflammation. We hypothesized that eosinopenia at Intensive Care Unit (ICU) admission in vascular surgery patients who receive critical care, would be associated with increased mortality following hospital discharge. METHODS AND RESULTS: We performed a two-center observational cohort study of critically ill, non-cardiac adult vascular surgery patients who received treatment in Boston between 1997 and 2012 and survived hospital admission. The consecutive sample included 5083 patients (male 57%, white 82%, mean age [SD] 61.6 [17.4] years). The exposure was Absolute eosinophil count measured within 24 h of admission to the ICU and categorized as ≤10 cells/µL, 11-50 cells/µL, 51-100 cells/µL, 101-350 cells/µL (normal range), and >350 cells/µL. The primary outcome was all-cause mortality within 90 days of hospital discharge. The secondary outcome was discharge to home following hospitalization. 90-day post-discharge mortality was 6.7%, and 12.9% of patients were readmitted within 30 days. After multivariable adjustment, patients with eosinopenia (≤10 cells/µL) have a 90-day post-discharge mortality OR of 1.97 (95%CI 1.42, 2.73; P < 0.001) relative to patients with an absolute eosinophil count of 101-350 cells/µL. Further, after multivariable adjustment, patients with eosinopenia (≤10 cells/µL) have a 25% lower odds of discharge to home compared to patients with an absolute eosinophil count of 101-350 cells/µL [OR = 0.71 (CI 95% 0.59-0.85); P < 0.001]. CONCLUSION: Eosinopenia at ICU admission is a robust predictor of increased mortality and lower likelihood of discharge to home in vascular surgery patients treated with critical care who survive hospitalization.

Sex-Specific Catabolic Metabolism Alterations in the Critically Ill following High Dose Vitamin D.

Pharmacological interventions are essential for the treatment and management of critical illness. Although women comprise a large proportion of the critically ill, sex-specific pharmacological properties are poorly described in critical care. The sex-specific effects of vitamin D3 treatment in the critically ill are not known. Therefore, we performed a metabolomics cohort study with 1215 plasma samples from 428 patients from the VITdAL-ICU trial to study sex-specific differences in the metabolic response to critical illness following high-dose oral vitamin D3 intervention. In women, despite the dose of vitamin D3 being higher, pharmacokinetics demonstrated a lower extent of vitamin D3 absorption compared to men. Metabolic response to high-dose oral vitamin D3 is sex-specific. Sex-stratified individual metabolite associations with elevations in 25(OH)D following intervention showed female-specific positive associations in long-chain acylcarnitines and male-specific positive associations in free fatty acids. In subjects who responded to vitamin D3 intervention, significant negative associations were observed in short-chain acylcarnitines and branched chain amino acid metabolites in women as compared to men. Acylcarnitines and branched chain amino acids are reflective of fatty acid B oxidation, and bioenergesis may represent notable metabolic signatures of the sex-specific response to vitamin D. Demonstrating sex-specific pharmacometabolomics differences following intervention is an important movement towards the understanding of personalized medicine.

Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.

Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.

Metabolomic differences between critically Ill women and men.

Metabolism differs in women and men at homeostasis. Critically ill patients have profound dysregulation of homeostasis and metabolism. It is not clear if the metabolic response to critical illness differs in women compared to men. Such sex-specific differences in illness response would have consequences for personalized medicine. Our aim was to determine the sex-specific metabolomic response to early critical illness. We performed a post-hoc metabolomics study of the VITdAL-ICU trial where subjects received high dose vitamin D3 or placebo. Using mixed-effects modeling, we studied sex-specific changes in metabolites over time adjusted for age, Simplified Acute Physiology Score II, admission diagnosis, day 0 25-hydroxyvitamin D level, and 25-hydroxyvitamin D response to intervention. In women, multiple members of the sphingomyelin and lysophospholipid metabolite classes had significantly positive Bonferroni corrected associations over time compared to men. Further, multiple representatives of the acylcarnitine, androgenic steroid, bile acid, nucleotide and amino acid metabolite classes had significantly negative Bonferroni corrected associations over time compared to men. Gaussian graphical model analyses revealed sex-specific functional modules. Our findings show that robust and coordinated sex-specific metabolite differences exist early in critical illness.

Gender disparity in critical care publications: a novel Female First Author Index.

BACKGROUND: Bibliometric analyses show gender bias against women in scientific publications and citations. We hypothesized that a metric of an individual senior author's inclusivity of women as first authors in critical care publications would predict gender inequality. METHODS: Using PubMed and Web of Science, we conducted a bibliometric analysis of original research publications in critical care from 2008 to 2018 in 11 specialty and general journals. Gender for first and senior authors was assigned by a gender determination application, and manually if needed. For all senior authors we defined the novel Female First Author Index (FFA-index) = #Female first authors in publications by an individual senior author/Total # publications by that senior author. We produced a novel interactive web-based application using the R package Shiny to increase potential utilization of the FFA-index. RESULTS: Of 7370 publications, 30.4% had female first authors and 15.5% had female senior authors. After adjustment for impact factor, journal, year of publication, number of authors, country, and gender determination accuracy, female senior authorship was associated with a 1.9-fold increase in female first authorship [OR = 1.85 (95% CI 1.62, 2.11); p < 0.001] compared with male senior authorship. The mean (SD) FFA-index for all individual senior authors was 30.5 (42.9); with a significant difference in FFA-index between male and female senior authors (27.6 versus 42.5, respectively; p < 0.001). The interactive web-based application (FFA-index App) produces the same FFA-index output as our study results. CONCLUSIONS: Female representation at prominent authorship positions in critical care publications is still far from achieving gender parity. By creating an authorship index score, we propose a frame of reference for the advancement of female first authorship.

Septicemia due to Capnocytophaga canimorsus following dog bite in an elderly male.

A previously healthy, 67-year-old, man with past medical history of myocardial infarction and hypertension was rushed to the emergency room after sudden onset of fever, chills, severe rigors, hypotension, tachycardia and vomiting. The patient was diagnosed as being in septic shock, and investigations revealed intracellular gram-negative bacilli in polymorphonuclear leukocytes in the peripheral smear. A history of dog contact was elicited after this very unusual and rare finding. Cultures confirmed septicemia due to Capnocytophaga canimorsus, a normal oral and nasal flora inhabitant of cats and dogs that can cause severe and sometimes fatal septicemia in humans. We report this very interesting case because of the common prevalence of dog homeownership and the rarity of C. canimorsus inducing sepsis.