Research Spotlight

Li, X., Wang, T., Feng, D., Xu, Z., Xu, X., Gao, H. and Chen, G. (2020). “Sex-Specific Associations of Smoking with Spontaneous Subarachnoid Hemorrhage: Findings from Observational Studies.” J Stroke Cerebrovasc Dis 29(10): 105144.

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BACKGROUND: Some studies have reported that women are at higher risk for spontaneous subarachnoid hemorrhage (SAH) compared with men, and smoking is the most important lifestyle risk factor for spontaneous SAH. However, it is still unknown whether the risk of SAH from smoking and smoking status is differential for women and men. We performed a meta-analysis to estimate the effect of smoking on SAH in women compared with men. METHODS: PubMed (January 1, 1966 to February 19, 2020) and EMBASE (January 1, 1980 to February 19, 2020) were systematically searched. Studies that estimated sex-specific relative risks (RRs) of SAH were selected. We pooled sex-specific RRs, comparing women with men using random-effects meta-analysis. RESULTS: Data from 20 observational studies that included 1,387,204 participants (563,898 women) and 7,838 SAHs (3,977 women) were analyzed. The combined women-to-men RRs of former smokers versus never smokers for SAH were 1.08 (95% confidence interval [CI] 0.62-1.89, p = 0.78). The pooled women-to-men RRs of current smokers versus never smokers were 1.39 (95% CI 1.05-1.83, p = 0.02). The combined women-to-men RRs of total smokers versus never smokers RRs were 1.15 (95% CI 0.88-1.52, p = 0.30). CONCLUSIONS: Our study shows there is not enough evidence to suggest that women who smoke have a greater risk for SAH than men; however, women who persistently smoke have a greater risk. Smoking seems to be more susceptible in the increased SAH risk in women.

Juengst, S., Rainey, E., Noorbakhsh, D. and Driver, S. (2020). “Providing equal attention: designing control groups for intensive lifestyle interventions after brain injury.” Brain Inj Oct 1;1-7. [Epub ahead of print.].

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PRIMARY OBJECTIVE: Interventions are needed to address chronic health conditions, such as obesity and diabetes, faced by adults with traumatic brain injury (TBI). The objective of this narrative is to present the justification for and an exemplar of an active attention control condition as a needed comparison group in clinical trials for intensive lifestyle interventions after TBI. RESEARCH DESIGN: Narrative review. METHODS AND PROCEDURES: N/A. MAIN OUTCOMES AND RESULTS: Despite the historical use in scientific research, integration of appropriate control conditions to account for not only the placebo effect, but also to isolate the “active ingredients” of behavioural interventions, remains a challenge. This is particularly true for intensive lifestyle interventions, especially with the increasing use of mobile health (mHealth) to augment these interventions. Herein we describe the design, content, and implementation of a group-based, attention control condition, referred to as the Brain Health Group, as an exemplar active comparison to an intensive lifestyle intervention for weight-loss among individuals with TBI (GLB-TBI). CONCLUSIONS: Intervention studies should incorporate strong scientific designs and active control conditions to assess effectiveness and aid in replication. Following recommended guidelines, we provide an active control condition for future group-based intensive lifestyle interventions post-TBI.

Ascierto, P.A., Del Vecchio, M., Mandalá, M., Gogas, H., Arance, A.M., Dalle, S., Cowey, C.L., Schenker, M., Grob, J.J., Chiarion-Sileni, V., Márquez-Rodas, I., Butler, M.O., Maio, M., Middleton, M.R., de la Cruz-Merino, L., Arenberger, P., Atkinson, V., Hill, A., Fecher, L.A., Millward, M., Khushalani, N.I., Queirolo, P., Lobo, M., de Pril, V., Loffredo, J., Larkin, J. and Weber, J. (2020). “Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.” Lancet Oncol 2020 Sep 18;S1470-2045(20)30494-0. [Epub ahead of print.].

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BACKGROUND: Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results. METHODS: This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906. FINDINGS: Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported. INTERPRETATION: At a minimum of 4 years’ follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.

Tan, E.E., Hopkins, R.A., Lim, C.K., Jamuar, S.S., Ong, C., Thoon, K.C., Koh, M.J., Shin, E.M., Lian, D.W., Weerasooriya, M., Lee, C.Z., Soetedjo, A.A.P., Lim, C.S., Au, V.B., Chua, E., Lee, H.Y., Jones, L.A., James, S.S., Kaliaperumal, N., Kwok, J., Tan, E.S., Thomas, B., Wu, L.X., Ho, L., Fairhurst, A.M., Ginhoux, F., Teo, A.K., Zhang, Y.L., Ong, K.H., Yu, W., Venkatesh, B., Tergaonkar, V., Reversade, B., Chin, K.C., Tan, A.M., Liew, W.K. and Connolly, J.E. (2020). “Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency.” J Clin Invest Sep 28;98882. [Epub ahead of print.].

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Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient’s stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient’s hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.

Collinsworth, A.W., Priest, E.L. and Masica, A.L. (2020). “Evaluating the Cost-Effectiveness of the ABCDE Bundle: Impact of Bundle Adherence on Inpatient and 1-Year Mortality and Costs of Care.” Crit Care Med Sep 20. [Epub ahead of print.].

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OBJECTIVES: Growing evidence supports the Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility (ABCDE) bundle processes as improving a number of short- and long-term clinical outcomes for patients requiring ICU care. To assess the cost-effectiveness of this intervention, we determined the impact of ABCDE bundle adherence on inpatient and 1-year mortality, quality-adjusted life-years, length of stay, and costs of care. DESIGN: We conducted a 2-year, prospective, cost-effectiveness study in 12 adult ICUs in six hospitals belonging to a large, integrated healthcare delivery system. SETTING: Hospitals included a large, urban tertiary referral center and five community hospitals. ICUs included medical/surgical, trauma, neurologic, and cardiac care units. PATIENTS: The study included 2,953 patients, 18 years old or older, with an ICU stay greater than 24 hours, who were on a ventilator for more than 24 hours and less than 14 days. INTERVENTION: ABCDE bundle. MEASUREMENTS AND MAIN RESULTS: We used propensity score-adjusted regression models to determine the impact of high bundle adherence on inpatient mortality, discharge status, length of stay, and costs. A Markov model was used to estimate the potential effect of improved bundle adherence on healthcare costs and quality-adjusted life-years in the year following ICU admission. We found that patients with high ABCDE bundle adherence (≥ 60%) had significantly decreased odds of inpatient mortality (odds ratio 0.28) and significantly higher costs ($3,920) of inpatient care. The incremental cost-effectiveness ratio of high bundle adherence was $15,077 (95% CI, $13,675-$16,479) per life saved and $1,057 per life-year saved. High bundle adherence was associated with a 0.12 increase in quality-adjusted life-years, a $4,949 increase in 1-year care costs, and an incremental cost-effectiveness ratio of $42,120 per quality-adjusted life-year. CONCLUSIONS: The ABCDE bundle appears to be a cost-effective means to reduce in-hospital and 1-year mortality for patients with an ICU stay.