Reconsidering stepped wedge cluster randomized trial designs with implementation periods: Fewer sequences or the parallel-group design with baseline and implementation periods are potentially more efficient.

BACKGROUND/AIMS: When designing a cluster randomized trial, advantages and disadvantages of tentative designs must be weighed. The stepped wedge design is popular for multiple reasons, including its potential to increase power via improved efficiency relative to a parallel-group design. In many realistic settings, it will take time for clusters to fully implement the intervention. When designing the HEALing (Helping to End Addiction Long-termSM) Communities Study, implementation time was a major consideration, and we examined the efficiency and practicality of three designs. Specifically, a three-sequence stepped wedge design with implementation periods, a corresponding two-sequence modified design that is created by removing the middle sequence, and a parallel-group design with baseline and implementation periods. In this article, we study the relative efficiencies of these specific designs. More generally, we study the relative efficiencies of modified designs when the stepped wedge design with implementation periods has three or more sequences. We also consider different correlation structures. METHODS: We compare efficiencies of stepped wedge designs with implementation periods consisting of three to nine sequences with a variety of corresponding designs. The three-sequence design is compared to the two-sequence modified design and to the parallel-group design with baseline and implementation periods analysed via analysis of covariance. Stepped wedge designs with implementation periods consisting of four or more sequences are compared to modified designs that remove all or a subset of 'middle' sequences. Efficiencies are based on the use of linear mixed effects models. RESULTS: In the studied settings, the modified design is more efficient than the three-sequence stepped wedge design with implementation periods. The parallel-group design with baseline and implementation periods with analysis of covariance-based analysis is often more efficient than the three-sequence design. With respect to stepped wedge designs with implementation periods that are comprised of more sequences, there are often corresponding modified designs that improve efficiency. However, use of only the first and last sequences has the potential to be either relatively efficient or inefficient. Relative efficiency is impacted by the strength of the statistical correlation among outcomes from the same cluster; for example, the relative efficiencies of modified designs tend to be greater for smaller cluster auto-correlation values. CONCLUSION: If a three-sequence stepped wedge design with implementation periods is being considered for a future cluster randomized trial, then a corresponding modified design using only the first and last sequences should be considered if sole focus is on efficiency. However, a parallel-group design with baseline and implementation periods and analysis of covariance-based analysis can be a practical, efficient alternative. For stepped wedge designs with implementation periods and a larger number of sequences, modified versions that remove 'middle' sequences should be considered. Due to the potential sensitivity of design efficiencies, statistical correlation should be carefully considered.

Equity of overdose education and naloxone distribution provided in the Kentucky HEALing Communities Study.

Background: Opioid overdoses differentially affect demographic groups. Strategies to reduce overdose deaths, specifically overdose education and naloxone distribution (OEND), are not consistently delivered equitably. Methods: The HEALing Communities StudySM (HCS) is a cluster-randomized trial designed to implement evidence-based practices, including OEND, to reduce overdose deaths across communities. Individuals receiving OEND in eight Kentucky counties between January 2020 and June 2022 provided demographics and overdose history. Recipient characteristics were compared to opioid overdose decedent characteristics to evaluate whether OEND was equitably delivered to the target population. Recipient characteristics were also analyzed based on whether OEND was delivered in criminal justice, behavioral health, or health care facilities. Results: A total of 26,273 demographic records were analyzed from 137 partner agencies. Most agencies were in behavioral health (85.6 %) or criminal justice sectors (10.4 %). About half of OEND recipients were male (50.6 %), which was significantly lower than the 70.3 % of overdose decedents who were male, (p<0.001). OEND recipients tended to be younger than overdose decedents, but there were not significant differences in race/ethnicity between OEND recipients and overdose decedents. Over 40 % of OEND recipients had overdosed, and 68.9 % had witnessed a prior overdose. There were notable differences across facility types, as males and Black individuals accounted for fewer OEND recipients in addiction treatment facilities compared to jails. Conclusion: Although OEND recipients' demographics resembled those of decedents, specific attention should be paid to ensuring equitable OEND access. Variation in OEND uptake by facility type may reflect biases and barriers to care.

Temporal Sequencing of Mental Health Symptom Severity and Suicidal Ideation in Post-9/11 Men and Women Veterans Who Recently Separated from the Military.

BACKGROUND: Despite some evidence for gender differences in associations between military veterans' mental health and suicidal ideation (SI), gender-specific prospective studies are lacking. The aims of this prospective study were to: (1) examine gender differences in veterans' initial status and trajectories of mental health severity and SI status and (2) identify temporal sequencing of mental health predictors of SI. METHODS: Surveys of 1035 US veterans were administered at 3 time-points (T1, T2, T3) over a 7-year period following military separation, with an initial assessment within 2 years of military separation. RESULTS: Men reported higher baseline PTSD and alcohol misuse severity than women. No baseline gender difference in SI prevalence was detected. Baseline gender differences in mental health severity were maintained over time. For both men and women, remittance of SI was more likely from T1 to T2 than from T2 to T3 while chronic SI was more likely from T2 to T3. The strongest predictors of T3 SI were prior SI followed by alcohol misuse, depression, and PTSD severity with stronger effects for T2 predictors than T1. CONCLUSION: The maintenance of baseline gender differences throughout trajectories of mental health predictors of SI supports the need for ongoing gender-specific mental health services. Current governmental interorganizational efforts are focused on suicide prevention during the first year after military service completion. Our findings indicate a need to extend mental health screening and treatment beyond the early post-military period to reduce risk and recurrence of SI for both men and women.

Mental Health and Psychosocial Functioning in Recently Separated U.S. Women Veterans: Trajectories and Bi-Directional Relationships.

Prior research on the relationship between veterans' mental health and psychosocial functioning has primarily relied on male samples. Here, we investigated prospective longitudinal relationships between mental health and psychosocial functioning in 554 female Iraq and Afghanistan War veterans who were surveyed three times between two- and seven-years following separation from service. Mixed effects modeling revealed that increasing depression and posttraumatic stress disorder (PTSD) severity predicted declines in work functioning. Increasing PTSD severity predicted declining parental functioning and worsening depression predicted a decline in relationship functioning. In turn, decreased work and intimate relationship functioning predicted increased PTSD and depression symptom severity suggesting bi-directional effects between mental health and psychosocial functioning. An examination of the effect of deployment stressors on psychosocial functioning revealed that deployment sexual harassment was the strongest predictor of decreased psychosocial functioning across all domains. Evidence for the reciprocal nature of relationships between mental health and psychosocial functioning underscore the need for treatment targeted at PTSD and depression, as well as work and relationship functioning to improve outcomes for women veterans.

Desulfination by 2'-hydroxybiphenyl-2-sulfinate desulfinase proceeds via electrophilic aromatic substitution by the cysteine-27 proton.

Biodesulfurization is an attractive option for enzymatically removing sulfur from the recalcitrant thiophenic derivatives that comprise the majority of organosulfur compounds remaining in hydrotreated petroleum products. Desulfurization in the bacteria Rhodococcus erythropolis follows a four-step pathway culminating in C-S bond cleavage in the 2'-hydroxybiphenyl-2-sulfinate (HBPS) intermediate to yield 2-hydroxybiphenyl and bisulfite. The reaction, catalyzed by 2'-hydroxybiphenyl-2-sulfinate desulfinase (DszB), is the rate-limiting step and also the least understood, as experimental evidence points to a mechanism unlike that of other desulfinases. On the basis of structural and biochemical evidence, two possible mechanisms have been proposed: nucleophilic addition and electrophilic aromatic substitution. Density functional theory calculations showed that electrophilic substitution by a proton is the lower energy pathway and is consistent with previous kinetic and site-directed mutagenesis studies. C27 transfers its proton to HBPS, leading directly to the release of SO2 without the formation of a carbocation intermediate. The H60-S25 dyad stabilizes the transition state by withdrawing the developing negative charge on cysteine. Establishing the desulfination mechanism and specific role of active site residues, accomplished in this study, is essential to protein engineering efforts to increase DszB catalytic activity, which is currently too low for industrial-scale application.