Independent Treatment Effects Research Articles

Has a fast treatment transition from surgical to endovascular operations improved the survival of aneurysmal subarachnoid hemorrhage?

BackgroundSeveral studies have attributed decreasing case fatality rates (CFRs) of aneurysmal subarachnoid hemorrhage (aSAH) to the gradually increasing use of endovascular treatment without considering improvements in other outcome-affecting factors. To assess the independent effect of a treatment modality on CFRs, we investigated CFR changes in a high-volume center rapidly transitioning from surgical to endovascular operations as the first-line treatment for all aSAH patients except those with middle cerebral artery (MCA) aneurysms.MethodsWe identified all surgically/endovascularly treated aSAH patients in Helsinki University Hospital (HUH) during 2012–2017. As the treatment shift occurred in 2015, we defined two treatment eras: surgical (2012–2014) and endovascular (2015–2017). We compared time-dependent changes in 1-year CFRs between non-MCA and MCA patients using a Poisson regression model. To analyze consistency in operation rates, we also identified sudden-death and conservatively treated aSAHs in the HUH catchment area via two externally validated registers.ResultsOf all 665 hospitalized aSAH cases in the HUH catchment area, 557 (84%) received operative treatment; 367 (66%) underwent surgical and 190 (34%) endovascular operations. Between the treatment eras, endovascular treatment for non-MCA cases increased from 21 to 79%, whereas 99% of the MCA cases were treated surgically during the whole study-period. Among the operatively treated patients, the 1-year CFRs decreased similarly in patients with non-MCA (42%; from 14 to 8%; adjusted risk ratio (aRR) = 0.66 (95% CI 0.37–1.19)) and MCA aneurysms (42%; from 15 to 9%; aRR = 0.66 (0.16–1.60)). The proportion of operatively treated patients, their clinical condition on admission, and amount of bleeding on the first CT-scan remained unchanged over time.ConclusionsWe found similar CFR decreases in aSAH groups with and without undergoing a fast transition from surgery to endovascular operations, providing real-world evidence on the small independent effect of endovascular treatment on the decreasing CFRs in high-volume centers.

Comparative Effectiveness of Buprenorphine/Naloxone and Methadone on Methamphetamine/Amphetamine Use Among People with Opioid Use Disorder in Canada.

It has been suggested that opioid agonist therapy (OAT) may have a secondary benefit of reducing methamphetamine/amphetamine use. However, current evidence is limited and conflicting, and little is known on the impacts of different OATs on methamphetamine/amphetamine use. The aim of this study was to examine the comparative effectiveness of buprenorphine/naloxone and methadone on methamphetamine/amphetamine use among individuals with opioid use disorder (OUD) initiating OAT in Canada. Data for this study were derived from a 24-week pan-Canadian pragmatic trial conducted between 2017 and 2020 comparing supervised methadone versus flexible take-home dosing buprenorphine/naloxone models of care among OUD. Generalized linear mixed models were used to evaluate the independent effect of treatment (ie, methadone or buprenorphine/naloxone) and time in treatment (ie, week 2 through 24, continuous) on methamphetamine/amphetamine use (measured by urine drug test and self-report using Timeline Follow-Back). The sample included 210 participants that initiated OAT, of which 130 (61.9%) were using methamphetamine/amphetamine at baseline. In multivariable analysis, neither treatment nor time in treatment were significantly associated with the odds of methamphetamine/amphetamine use (adjusted odds ratio [AOR] = 0.61, 95% confidence interval [CI] = 0.34-1.08, P = .092; and AOR = 0.73, CI = 0.40-1.28, P = .283, respectively). No interaction between treatment and time in treatment was observed for methamphetamine/amphetamine use (P = .367). Methamphetamine/amphetamine use was common among this sample of people with OUD initiating OAT in Canada. Over the 24-week study period, buprenorphine/naloxone and methadone were not associated with a quantifiable change in methamphetamine/amphetamine use among this sample population. The observation of less methamphetamine/amphetamine use in the buprenorphine/naloxone arm warrants further research.

Application of nano Fe on the growth of rice under drought stress

Climate change is indicated by extreme weather changes, namely drought on agricultural land, thus limiting crop growth. The availability of rice as a food source in developing countries has not met the increasing food needs of the population. The low planting area and productivity, which are said to be the triggers for the problem, can be overcome by nutrient management on dry land. Iron serves a function in the physiology and metabolism of plants. Iron sprayed on the leaves in the form of nano Fe2O3 can increase the efficiency of nutrient absorption by plants. This study aims to evaluate the effect of the application of nano Fe concentration on rice growth in drought-stress conditions. The study was conducted in the Sleman experimental field using the Split Plot Design method with two factors (water content of 100; 50% and nano-Fe concentration of 0; 0.5; 1; 1.5; 2 ppm). Based on the results of the study showed that there was an independent effect of treatment on growth. Spraying nano Fe 0.5-1 and 1.5-2 ppm reduced membrane damage by 3.27% and 8.25% respectively, and there was a negative correlation between membrane damage and growth parameters.

343 Dupilumab efficacy on itch and skin lesions in adult patients with prurigo nodularis may be observed concurrently or independently over 24 weeks: results from two phase 3 trials

Abstract Prurigo nodularis (PN) is a chronic inflammatory and pruritic skin disease. Clinically it is characterized by intense pruritus accompanied by hyperkeratotic nodules often associated with a very low quality of life including sleep disruption. The FDA has recently approved dupilumab as the only treatment for PN, but it is unknown to what extent within-patient categorical improvements in itch and skin lesions occurred concurrently or independently. Two phase 3 clinical trials, LIBERTY-PN PRIME and PRIME2, demonstrated dupilumab efficacy and safety in patients with PN. To report the efficacy of dupilumab on signs and symptoms in adult patients with PN who did and did not achieve the multicomponent endpoint. LIBERTY-PN PRIME (NCT04183335) and PRIME2 (NCT04202679) were randomized, double-blind, placebo-controlled, multicentre, parallel-group, phase 3 trials in adult patients with PN with ≥20 PN lesions and severe itch, inadequately controlled with topical prescription therapies or for whom these are inadvisable. Here, data were pooled from the two studies. Patients received 300 mg dupilumab subcutaneously (600 mg loading dose; n = 153) or matched placebo (n = 158) every 2 weeks for 24 weeks. This abstract assesses efficacy in patients who did and those who did not achieve the stringent multicomponent endpoint of ≥4-point improvement from baseline in Worst Itch Numerical Rating Scale (WI-NRS, range: 0–10) and Investigator’s Global Assessment PN Stage (IGA PN-S, score range: 0–4) score 0 or 1 (clear or almost clear; defined as 5 or fewer nodules) at week 24. Endpoints include a proportion of patients with concomitant ≥4-point reduction in WI-NRS from baseline and IGA PN-S score 0 or 1 at week 24; the proportion of patients with ≥4-point reduction in WI-NRS from baseline or IGA PN-S score 0 or 1 at week 24; and proportion of patients not achieving ≥4-point reduction in WI-NRS from baseline and IGA PN-S score 0 or 1 at week 24. Safety was also assessed. Baseline demographic and clinical characteristics were generally balanced between subgroups. The proportion of patients treated with dupilumab and placebo who achieved the multicomponent endpoints was 35.3% and 8.9%, respectively; and who achieved WI-NRS reduction of ≥4 points from baseline or IGA PN-S score 0 or 1 at week 24 was 69.9% and 27.2%, respectively. Among multicomponent nonresponders in the dupilumab group (n = 99), 36.4% achieved WI-NRS reduction of ≥4 points and 17.2% achieved IGA PN-S score 0 or 1; in the placebo group (n = 144), corresponding values were 11.1% and 9.0%, respectively. In the dupilumab group, 23.5% achieved only WI-NRS ≥4-point reduction from baseline at week 24, and 11.1% achieved only IGA PN-S score 0 or 1 at week 24. In the placebo group, corresponding data were 10.1%, and 8.2%, respectively. Safety findings were consistent with the known dupilumab safety profile. More than one-third of dupilumab-treated patients achieved the multicomponent endpoint at week 24, constituting concurrent responses on both itch and skin lesions. However, more than two-thirds had clinically meaningful improvement by week 24, defined as either ≥4-point reduction in WI-NRS from baseline, IGA PN-S score 0/1, or both. Almost one-quarter of dupilumab-treated patients met only WI-NRS ≥4-point improvement at week 24, suggesting that skin lesion improvement may lag behind the improvement of itch. Conversely, one-ninth met only IGA PN-S score of 0 or 1 at week 24 suggesting that, in addition to the overlapping mechanisms by which dupilumab ameliorates pruritus and skin lesions, there are independent treatment effects on itch and skin remodelling. Safety was consistent with the known safety profile of dupilumab across approved indications.

Pharmacological interventions for the treatment of disordered and problem gambling.

Pharmacological interventions for the treatment of disordered and problem gambling.

33028 Direct and indirect treatment effect of guselkumab on anxiety and depression in patients with psoriasis by adjusting for Psoriasis Area and Severity Index (PASI) – A mediation analysis

Introduction: Guselkumab effectively treats psoriasis and is associated with improvements in anxiety and depression symptoms. Whether improvements in anxiety and depression are due to resolution of skin symptoms or the direct result of guselkumab treatment is unclear. Methods: Patients received guselkumab at Week(W)0, W4, then Q8W; placebo (W16→guselkumab); or adalimumab for moderate-to-severe psoriasis. Mediation analysis evaluated direct effects of guselkumab on change from baseline in Hospital Anxiety and Depression Scale (HADS) score at W24, after adjusting for indirect effects mediated by clinical assessment of skin clearance using Psoriasis Area and Severity Index (PASI) improvement and achievement of ≥90% improvement from baseline (PASI90). Regression analyses were used to determine 95% confidence interval (CI). Results: Improvements in HADS were partially mediated indirectly through skin response among guselkumab-treated patients at W24. Compared with adalimumab, HADS anxiety score was mediated through PASI improvement by 25.5%, with independent treatment effect of -0.74 (95% CI -1.22,-0.27; P < .002), or 74.5% of total effect. Similarly, treatment effect was mediated by 24% through PASI90 response, with independent treatment effect of -0.76 (95% CI -1.24, -0.28; P < .002), or 76% of total effect. Treatment effect of guselkumab (versus adalimumab) on change in HADS depression total score was mediated through PASI improvement by 49.8%; through PASI90, 40.5%. Guselkumab and adalimumab had similar natural direct effects on changes in depression score. Conclusions: Guselkumab demonstrated an independent treatment response in reducing anxiety and depression after adjusting for clinical response of skin clearance. The mechanism of the direct effect of guselkumab beyond skin clearance warrants additional research.

The effect of multistrain probiotics on functional constipation in the elderly: a randomized controlled trial

Background and objectivesConstipation is one of the most common gastrointestinal conditions, particularly among older individuals. This study aimed to evaluate the efficacy and safety of selected multistrain probiotics on functional constipation and laboratory blood parameters in the elderly living in a nursing home.Subjects and methodsSixty participants (42 females and 18 males) aged 77.9 ± 8.84 years with functional constipation, who met the eligibility criteria, completed the study. In a double-blind, placebo-controlled, parallel design, each participant was randomized to receive either the selected probiotic mixture (N = 28) or placebo (N = 32) for 12 weeks as an adjunct to their usual diet and medications. The liquid probiotic formulation containing Bifidobacterium animalis subsp. lactis BLC1, Lactobacillus acidophilus LA3 and Lactobacillus casei BGP93 was tested for the first time.ResultsSupplementation of selected probiotics resulted in a slight but nonsignificant increase in cumulative stool frequency compared with placebo. However, after the 71st day of the treatment, the cumulative number of stools was significantly higher in the probiotic group (P < 0.05) when the influence of laxative was excluded. The trend towards an increase in the difference between the two groups, which began 1 week after the probiotic intervention, pointed out to their prolonged effect. There were no significant dependent or independent effects of treatment and time on most of the 27 laboratory blood parameters tested.ConclusionsMultistrain probiotic supplementation was found to be efficacious, safe and well tolerated in the elderly with functional constipation.

Comparing Outcomes between Liposomal Daunorubicin/Cytarabine (CPX-351) and HMA+Venetoclax As Frontline Therapy in Acute Myeloid Leukemia

Comparing Outcomes between Liposomal Daunorubicin/Cytarabine (CPX-351) and HMA+Venetoclax As Frontline Therapy in Acute Myeloid Leukemia

27078 Mediation analysis of independent treatment effect of guselkumab on health-related quality of life in patients with moderate to severe plaque-type psoriasis: Results from 2 phase 3 studies VOYAGE-1&2

Background: VOYAGE-1&2 were randomized, double-blind, phase-3 studies exploring guselkumab for moderate-to-severe plaque-type psoriasis. Previous analyses demonstrated that among patients with a psoriasis area and severity index (PASI) 100 response, guselkumab-treated patients had greater improvement in dermatology life quality index (DLQI) score than adalimumab-treated patients. Understanding the independent treatment effect on patient-reported outcomes (PROs) beyond clinical assessments would provide insights on the importance of HRQoL in the treatment of psoriasis patients.

27594 Impact of guselkumab on fatigue and mediation analysis of independent treatment effect of guselkumab on fatigue in patients with active psoriatic arthritis: Results from DISCOVER-1&2

Introduction: Guselkumab(GUS) demonstrated efficacy in the Ph3 DISCOVER-1&2 trials in patients with psoriatic arthritis. Here, the effect of GUS on fatigue is evaluated in these trials using Functional Assessment of Chronic Illness Therapy-Fatigue(FACIT-F).

Guselkumab demonstrated an independent treatment effect in reducing fatigue after adjustment for clinical response\u2014results from two phase 3 clinical trials of 1120 patients with active psoriatic arthritis

BackgroundThe interleukin-23p19-subunit inhibitor guselkumab effectively treats signs and symptoms of psoriatic arthritis (PsA). We evaluated the effect of guselkumab on fatigue.MethodsAcross two phase 3 trials of guselkumab (DISCOVER-1, DISCOVER-2), patients with active PsA despite standard therapy were randomized to subcutaneous injections of guselkumab 100 mg every 4 weeks (Q4W, N = 373); guselkumab 100 mg at week 0, week 4, and then Q8W (N = 375); or placebo (N = 372) through week 24, after which patients in the placebo group crossed over to guselkumab Q4W. Fatigue was measured as a secondary endpoint using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue instrument (range 0–52, higher scores indicate less fatigue). Least-squares mean changes in FACIT-Fatigue scores were compared between treatments using a mixed-effect model for repeated measures. Mediation analysis was used to adjust for indirect effects on fatigue deriving from improvement in other outcomes, including ≥20% improvement in American College of Rheumatology criteria (ACR20; prespecified), minimal disease activity (MDA; post hoc), or C-reactive protein (CRP; post hoc).ResultsBaseline mean (SD) FACIT-Fatigue scores in DISCOVER-1 (N = 381) and DISCOVER-2 (N = 739), ranging from 29.1 (9.5) to 31.4 (10.1), indicated substantial levels of fatigue relative to the United States general population (43.6 [9.4]). Across studies, mean improvements, and proportions of patients with ≥4-point improvements, in FACIT-Fatigue scores at week 24 with guselkumab Q4W and Q8W (5.6–7.6 and 54–63%, respectively) were larger vs placebo (2.2–3.6 and 35–46%). Improvement in FACIT-Fatigue scores with guselkumab was sustained from week 24 to week 52, with moderate-to-large effect sizes (Cohen’s d = 0.52–0.81 at week 24; 0.66–0.91 at week 52). Mediation analyses demonstrated that substantial proportions of the effects of guselkumab vs placebo on fatigue were direct effect, after adjusting for achievement of ACR20 (Q4W 69–70%, Q8W 12–36% direct effect) or MDA (72–92% across dosing regimens) response or for change in serum CRP concentrations (82–88% across dosing regimens).ConclusionsIn patients with active PsA, guselkumab 100 mg Q4W or Q8W led to clinically meaningful and sustained improvements in fatigue through 1 year. A substantial portion of the improvement in FACIT-Fatigue scores induced by guselkumab was independent of effects on the achievement of other select outcomes.Trial registrationName of the registry: ClinicalTrials.govTrial registrations: DISCOVER-1, NCT03162796; DISCOVER-2, NCT03158285Date of registration: DISCOVER-1, May 22, 2017; DISCOVER-2, May 18, 2017URLs of the trial registry record:DISCOVER-1, https://clinicaltrials.gov/ct2/show/NCT03162796?term=NCT03162796&draw=1&rank=1DISCOVER-2, https://clinicaltrials.gov/ct2/show/NCT03158285?term=NCT03158285&draw=2&rank=1

Octreotide versus oral dietary modification for the treatment of chylous fistula following neck dissection: A systematic review and meta-analysis.

Chylous fistula following neck surgery is a rare, but significant complication. Currently, there is no standardised treatment, which may comprise pressure dressings, oral dietary modification (ODM), surgery or a combination of such measures. Octreotide is a somatostatin analogue that has gained popularity in the management of cervical chyle leaks. The effectiveness of octreotide compared with ODM is unclear. We provide a comprehensive, systematic review of the literature pertaining to the management of chylous fistulae, comparing both treatment strategies. The bibliographic databases MEDLINE, Cochrane, PubMed, EMBASE and Google Scholar were searched from inception to October 2019. Search terms included (chyle [title/abstract]) OR (chylous [title/abstract]) AND (fistula [title/abstract]) OR (fistulae [title/abstract]) OR (leak [title/abstract]) AND (neck [title/abstract]) OR (dissection [title/abstract]). The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Risk of bias was assessed using guidelines from the Joanna Briggs Institute. Outcome measures included the proportion of chylous fistulae that spontaneously resolved without the need for surgery and time taken until resolution, for both DM and octreotide, respectively. The primary search identified 20 articles for review, comprising 313 patients. Two studies were suitable for pooled analysis. There was no statistically significant difference in the time taken for chylous fistula to resolve between groups (octreotide 10.0days; ODM 12.0days; P=.38). The overall rate of resolution was 89.6% and 81.5%, respectively (P=.25). Surgery was highly effective in cases failing to resolve following intervention with either method (96% [53/55] patients). The use of octreotide for chylous fistula following neck dissection surgery is associated with a high rate of spontaneous resolution. However, significant heterogeneity, bias and concurrent use of ODM/TPN for patients in studies investigating octreotide precludes universal recommendation at this time. Further research in the form of randomised controlled trials is required to establish an independent treatment effect.

SAT0421 GUSELKUMAB DEMONSTRATED AN INDEPENDENT TREATMENT EFFECT ON FATIGUE AFTER ADJUSTMENT FOR CLINICAL RESPONSE (ACR20) IN PATIENTS WITH PSORIATIC ARTHRITIS: RESULTS FROM PHASE-3 TRIALS DISCOVER 1 &amp; 2

Background:DISCOVER 1 and 2 are phase-3 trials of guselkumab (GUS, a monoclonal antibody that specifically binds the p19-subunit of IL-23) in patients with psoriatic arthritis (PsA). In both trials, treatment with GUS led to significantly more improvement than placebo (PBO) in the primary endpoint (ACR20) as well as in other measures of arthritis and psoriasis at week (W) 24.1,2Objectives:To evaluate the effect of GUS on fatigue in DISC 1 &amp; 2 using the patient reported outcome (PRO) FACIT-Fatigue, which has demonstrated content validity and strong psychometric properties in clinical trials.3Methods:DISC 1 &amp; 2 enrolled patients with active PsA, despite nonbiologic DMARDS and/or NSAIDS, who were mostly biologic naïve except for ~30% of patients in DISC 1 who had received 1-2 TNFi. Patients were randomized (1:1:1) in a blinded fashion to subcutaneous GUS 100 mg at W0 and W4 then every (q) 8W, to GUS 100 mg q4W, or to matching PBO. Concomitant treatment with select non-biologic DMARDS, oral corticosteroids, and NSAIDs was allowed. The FACIT-Fatigue is a 13-item PRO instrument assessing fatigue and its impact on daily activities and function over the past seven days, with a total score ranging from 0 to 52, higher score denoting less fatigue. A change of ≥4 points is identified as clinically meaningful.3Change from baseline in FACIT-Fatigue was analyzed using MMRM (Figure). Independence of treatment effect on FACIT-Fatigue from effect on ACR20 was assessed using Mediation Analysis4(Table) to estimate the natural direct effect (NDE) and natural indirect effect (NIE) mediated by ACR20 response.Results:At baseline in DISC 1 &amp; 2, the mean FACIT-fatigue scores (SD) were 30.4 (10.4) and 29.7 (9.7), respectively, indicating moderate to severe fatigue. In both DISCOVER 1 &amp; 2 trials, treatment with GUS led to improvements in FACIT-Fatigue scores compared with PBO as early as W8 (Figure). 54%-63% of GUS patients compared with 35%-46% of PBO patients achieved clinically meaningful improvement (≥4 points) in FACIT-Fatigue (P≤0.003). Mediation analysis revealed that the independent treatment effects on fatigue after adjustment for ACR20 response (Natural Direct Effect [NDE], Table) were 12-36% in the q8W GUS dosing group and 69% -70% in the q4W GUS group.Conclusion:In 2 phase-3 trials, treatment with GUS of patients with active PsA led to significant improvements compared to PBO in fatigue, including substantial effects on FACIT-Fatigue that were independent of the effects on ACR 20, especially for the q4W dosing group.

Progesterone-based timed AI protocols for Bos indicus cattle III: Comparison of protocol lengths

This study aimed to validate a 7d progesterone (P4)-based fixed-time AI (FTAI) protocol for Bos indicus cattle by comparing to 8 and 9 d-type protocols. The first study compared 7 vs. 8 d protocols in Nelore heifers (Exp. 1.1; n=742) and cows (Exp. 1.2; n=2488), and the second study compared 7 vs. 9 d protocols in cows (Exp. 2; n=1343). On experimental Day-10 and Day-11 the 8 and 9d groups received an intravaginal P4 implant, 2.0mg estradiol benzoate (EB) and 0.5mg cloprostenol sodium (PGF). On Day-9 the 7d group received the same treatments (P4, EB, and PGF). Then, on Day-2 all groups had the P4 implants removed, and PGF, 0.6mg estradiol cypionate, and 300 IU equine chorionic gonadotropin (eCG) was administered. Fixed-time AI was performed 48h later (Day 0) and 8.4mg buserelin acetate (GnRH) was administered to 7d-G, 8d-G and 9d-G groups, whereas 7d-0, 8d-0 and 9d-0 groups did not receive GnRH at AI. Estrus was detected using tail-chalk between Day-2 and Day 0. Pregnancy per AI (P/AI) was evaluated by ultrasound 30d after AI. Effects were considered significant when P≤0.05, whereas a tendency was designated when P≤0.10 and P>0.05. In heifers (Exp. 1.1), incidence of estrus was similar regardless of protocol length (7 or 8d). There was no independent treatment effect on P/AI or interaction between protocol length and GnRH at AI for P/AI (7d-0: 46.9, 7d-G: 51.4, 8d-0: 47.7, and 8d-G: 43.6%). Heifers in estrus had greater P/AI, and GnRH had no additional effect. More cows (Exp. 1.2) from the 8d protocol were in estrus than cows submitted to the 7d protocol. Additionally, despite no interaction between protocol length and GnRH on P/AI (7d-0: 55.9, 7d-G: 60.9, 8d-0: 56.2, and 8d-G: 60.8%), GnRH at AI increased P/AI. There was no interaction between estrus and GnRH, but cows displaying estrus had greater P/AI. Cows not expressing estrus tended (P=0.06) to have greater P/AI when receiving GnRH. In Exp. 2, more 9d cows were in estrus than 7d cows. Protocol length did not affect P/AI but tended (P=0.08) to interact with GnRH (7d-G had greater P/AI [57.9%] than 7d-0 [47.6%], but 9d-0 [54.6%] and 9d-G [55.4%] were not different from other groups). Moreover, GnRH increased P/AI only for the 7d protocol. No interaction between estrus and GnRH was detected but estrus improved P/AI, and GnRH tended (P=0.09) to improve P/AI of cows in estrus. In conclusion, despite longer protocols being more conducive to expression of estrus, there were no detectable effects of protocol length on P/AI. In addition, GnRH at FTAI may improve fertility in cows, particularly when cows are treated with shorter protocols.

Physical Function, Pain Severity, and Fatigue in Patients with Relapsed/Refractory Multiple Myeloma: Health-Related Quality of Life Results in Patients Receiving Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone

Physical Function, Pain Severity, and Fatigue in Patients with Relapsed/Refractory Multiple Myeloma: Health-Related Quality of Life Results in Patients Receiving Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone

The costs of crime associated with stimulant use in a Canadian setting

Costs attributable to criminal activity are a major component of the economic burden of substance use disorders, yet there is a paucity of empirical evidence on this topic. Our aim was to estimate the costs of crime associated with different forms and intensities of stimulant use. Retrospective cohort study, including individuals from three prospective cohorts in Vancouver, Canada, measured biannually (2011-2015), reporting stimulant use at baseline assessment. Monthly crime costs included policing, court, corrections, and criminal victimization (2016 CAD). We estimated monthly crime costs associated with mutually exclusive categories of crack, cocaine, methamphetamine, and polystimulant use, stratified by daily/non-daily use, relative to stimulant abstinence, as well as the independent effects of treatment (opioid agonist (OAT) and other addiction treatment). We used a two-part model, capturing the probability of criminal activity and costs of crime with generalized linear logistic and gamma regression models, respectively, controlling for age, gender, education, homelessness, mental health issues, employment, prior incarceration, alcohol and opioid use. The study sample included 1599 individuals (median age 39, 65.9% male) assessed over 5299 biannual interviews. Estimates of associated monthly crime costs ranged from $5449 [95% C.I.: $2180, $8719] for non-daily polystimulant use, to $8893 [$4196, $13,589] for daily polystimulant use. Cost differences between daily/non-daily use, injection/non-injection, and stimulant type were not statistically significant. Drug treatment was not associated with lower monthly crime costs in our sample. Substantial crime-related costs were associated with stimulant use, emphasizing the urgency for development and implementation of efficacious treatment regimens.

Chemoradiation and Local Excision for T2N0 Rectal Cancer Offers Equivalent Overall Survival Compared to Standard Resection: a National Cancer Database Analysis

Local excision (LE) alone is associated with worse survival compared to radical surgery (RS) for T2 rectal cancer, but LE with additional chemoradiation (CRT) may improve outcomes. The objective of this study was to compare combined CRT and LE versus RS for T2 rectal cancer. The 2004-2014 National Cancer Database was queried for patients with T2N0M0 rectal cancer undergoing LE with neoadjuvant(NA-CRT + LE) or adjuvant(LE + Adj-CRT) CRT, or RS. The main outcome was 5-year overall survival (OS). Cox proportional hazards was used to determine the independent effect of treatment on OS. A total of 4822 patients were included (4367 RS, 242 CRT + LE, 213 LE + Adj-CRT). Mean follow-up was 48.6 (SD28.5) months. There were no differences in patient characteristics, but more high-risk features in the LE + Adj-CRT group. There were no differences in 90-day mortality. Five-year OS was similar (RS 77.4% vs. CRT + LE 76.1% vs. LE + Adj-CRT 79.7%, p=0.786). Older age, male gender, and higher Charlson score were independently associated with worse OS, whereas treatment type was not. If 90-day mortality was excluded, LE + Adj-CRT was independently associated with worse OS compared to RS. CRT with LE for T2N0M0 rectal cancer was not associated with worse OS compared to RS, and may be a viable treatment modality.

When Is Pharmacotherapy Initiation Beneficial in Patients With Depressive Disorders?

Psychotherapy and pharmacotherapy are the most common treatments utilized in patients diagnosed with depressive disorders. Their efficacy in remitting symptoms and restoring patients to baseline functioning has been established throughout the literature; however, questions still remain on whether pharmacotherapy is necessary in all patients and if used, when initiation is most beneficial. Current guidelines recommend initiating only psychotherapy in patients with mild depression and advancing to pharmacotherapy as appropriate. Evidence-based literature has shown pharmacotherapy to have a significant and independent treatment effect in depressive disorders compared with psychotherapy. Combination treatment with both modalities has also shown to be beneficial for remitting depressive symptoms in this patient population. Therefore, treatment should be individualized for each specific patient based on severity of disease, history of depression and response to treatment, cost of treatment, and patient preference.

Sequential Multiple Assignment Randomized Trials: An Opportunity for Improved Design of Stroke Reperfusion Trials

Modern clinical trials in stroke reperfusion fall into 2 categories: alternative systemic pharmacological regimens to alteplase and "rescue" endovascular approaches using targeted thrombectomy devices and/or medications delivered directly for persistently occluded vessels. Clinical trials in stroke have not evaluated how initial pharmacological thrombolytic management might influence subsequent rescue strategy. A sequential multiple assignment randomized trial (SMART) is a novel trial design that can test these dynamic treatment regimens and lead to treatment guidelines that more closely mimic practice. To characterize a SMART design in comparison to traditional approaches for stroke reperfusion trials. We conducted a numerical simulation study that evaluated the performance of contrasting acute stroke clinical trial designs of both initial reperfusion and rescue therapy. We compare a SMART design where the same patients are followed through initial reperfusion and rescue therapy within 1 trial to a standard phase III design comparing 2 reperfusion treatments and a separate phase II futility design of rescue therapy in terms of sample size, power, and ability to address particular research questions. Traditional trial designs can be well powered and have optimal design characteristics for independent treatment effects. When treatments, such as the reperfusion and rescue therapies, may interact, commonly used designs fail to detect this. A SMART design, with similar sample size to standard designs, can detect treatment interactions. The use of SMART designs to investigate effective and realistic dynamic treatment regimens is a promising way to accelerate the discovery of new, effective treatments for stroke.

Prevention of Poststroke Mortality Using Problem-Solving Therapy or Escitalopram

This study re-examined patients from a 1-year randomized controlled double-blind trial of escitalopram, problem-solving therapy (PST), or placebo to prevent depression among patients less than 3 months after a stroke. The objective of the current study was to determine if preventive treatment would predict time to death over 8-10 years of follow-up. Based on the importance of depression in poststoke mortality and a previous study of this population at 18 months' follow-up showing that stopping escitalopram but not PST led to a significant increase in depression, the authors hypothesized that PST would be associated with the longest time to death. Of 129 eligible patients, 122 were contacted and 7 were lost to follow-up. Families and surviving patients were interviewed to determine current health status or the date and cause of death. Using the Weibull model of log time (years) to death, controlled for age, severity of physical illness, gender, severity of stroke, and history of depression after study entry, there was a significant independent effect of treatment. PST significantly and independently increased the time to mortality, whereas older age and major depression significantly and independently decreased the time to death. To the authors' knowledge, this is the first time a psychological antidepressant treatment administered for 1 year has been associated with increased survival among patients who have suffered a stroke.