Significant Difference In Treatment Effect Research Articles

Heterogeneity of Treatment Effects of Laser Epilation on Pilonidal Disease Recurrence: A Randomized Clinical Trial.

To investigate the heterogeneity of treatment effects (HTE) of laser epilation in preventing pilonidal disease recurrence through analysis of prespecified clinical factors. Pilonidal disease is a common, painful disease affecting 1% of the population aged 15 to 30 years with postoperative recurrence rates as high as 30% to 40%. Single-institution randomized controlled trial from September 2017 to September 2022 with 1-year follow-up, including patients aged 11 to 21 years with pilonidal disease undergoing gluteal cleft laser epilation and standard care (improved hygiene and mechanical or chemical depilation) or standard care alone. In total, 302 patients were enrolled with 151 randomized to each intervention. 1-year follow-up was available for 96 patients in the laser group and 134 in the standard care group. There were no significant differences in treatment effects based on sex, body mass index, previous disease, prior surgical excision, or annual household income (all P > 0.05). HTE was identified by race and ethnicity (P = 0.005) and health insurance type (P = 0.001). Recurrence among non-Hispanic white patients was 4% (3/75) with laser treatment and 31.6% (31/98) with standard care versus 38.9% (7/18) with laser treatment and 38.2% (13/34) with standard care among all other racial/ethnic groups. Recurrence rates among privately insured patients were 4.0% (3/75) with laser treatment and 33.3% (29/87) with standard care versus 36.8% (7/19) with laser treatment and 29.7% (11/37) with standard care in patients with public insurance. The effectiveness of laser epilation to reduce pilonidal disease recurrence rates may vary based on race and ethnicity and insurance type. Additional studies are warranted to investigate this potential HTE.

Childhood Trauma Questionnaire-based child maltreatment profiles to predict efficacy of the Cognitive Behavioral Analysis System of Psychotherapy versus non-specific psychotherapy in adults with early-onset chronic depression: cluster analysis of data from a randomised controlled trial

Child maltreatment is a broadly confirmed risk factor for mental and physical illness. Some psychological treatments specifically target mental health conditions associated with child maltreatment. For example, the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) focuses on maladaptive interpersonal behaviours in chronic depression. However, how the assessment of child maltreatment could inform personalised treatment is unclear. We used data from a previously published clinical trial to investigate whether a pre-established child maltreatment clustering approach predicts differential outcomes after CBASP versus non-specific supportive psychotherapy in patients with early-onset chronic depression. We did a cluster analysis of data from a previous randomised controlled trial of unmedicated adult outpatients with early-onset chronic depression who were treated at eight university clinics and psychological institutes in Germany with 32 sessions of CBASP or non-specific supportive psychotherapy. Participants were eligible for the original trial if they were aged 18-65 years; had major depressive disorder (MDD) with an early onset and duration of at least 2 years, current MDD superimposed on a pre-existing dysthymic disorder, or recurrent MDD with incomplete remission between episodes as defined by DSM-IV; and had a score of at least 20 points on the 24-item Hamilton Rating Scale for Depression (HRSD-24). Participants were included in the current study if they had completed the short form of the Childhood Trauma Questionnaire (CTQ) at trial baseline. We used an agglomerative hierarchical clustering approach to derive child maltreatment clusters from individual patterns across the five domains of the CTQ. We used linear mixed models to investigate whether clustering could predict differential clinical outcomes (change in symptom severity on the HRSD-24) up to 2 years after treatment onset. People with lived experience were involved in the current study. 253 patients (129 [51%] treated with CBASP and 124 [49%] with supportive psychotherapy) had complete CTQ records and were included in the analysis. 169 (67%) participants were women, 84 (33%) were men, and the mean age was 45·9 years (SD 11·7). We identified seven child maltreatment clusters and found significant differences in treatment effects of CBASP and supportive psychotherapy between the clusters (F(6,948·76)=2·47; p=0·023); differences were maintained over the 2-year follow-up. CBASP was superior in distinct clusters of co-occurring child maltreatment: predominant emotional neglect (change in β -6·02 [95% CI -11·9 to -0·13]; Cohen's d=-0·98 [95% CI -1·94 to -0·02]; p=0·045), predominant emotional neglect and abuse (-6·39 [-10·22 to -2·56]; -1·04 [-1·67 to -0·42]; p=0·0011), and emotional neglect and emotional and physical abuse (-9·41 [-15·91 to -2·91]; -1·54 [-2·6 to -0·47]; p=0·0046). CTQ-based cluster analysis can facilitate identification of patients with early-onset chronic depression who would specifically benefit from CBASP. Child maltreatment clusters could be implemented in clinical assessments and serve to develop and personalise trauma-informed care in mental health. The German Research Foundation and the German Federal Ministry of Education and Research.

Early Prostate-Specific Antigen Response by 6 Months Is Predictive of Treatment Effect in Metastatic Hormone Sensitive Prostate Cancer: An Exploratory Analysis of the TITAN Trial.

Early PSA response has been found to be prognostic of outcomes in metastatic hormone sensitive prostate cancer. We performed a secondary analysis of the TITAN trial to determine if early PSA response was predictive of treatment efficacy in metastatic hormone sensitive prostate cancer patients. Early PSA response was defined as achieving a PSA level of ≤ 0.2 ng/mL by 6 months of random assignment. A Cox proportional hazard model was constructed in a landmark population with an interaction term between the treatment and early PSA response to determine differential treatment effect on overall survival (OS). We applied multivariable Cox proportional hazard regression model with time to early PSA response fitted with restricted cubic spline to determine the association of time to early PSA response with OS. Approximately 24% (124/524) of patients in the androgen deprivation therapy (ADT) alone group and 61% (321/524) in the apalutamide group had PSA response ≤ 0.2 ng/mL by 6 months. Longer time to early PSA response was associated with significantly superior OS in the apalutamide group. There was a significant difference in treatment effect from apalutamide on OS (P = .03 for interaction) among 6-month PSA responders (HR: 0.66; 95% CI: 0.44-1.00) vs nonresponders (HR: 1.14; 95% CI: 0.89-1.46). This difference in treatment effect was not statistically significant at 3 months (P = .17 for interaction). Among 6-month PSA responders, 3-year confounder-adjusted OS was 84% (80%-88%) for the apalutamide group and 74% (66%-82%) for the ADT alone group. Among nonresponders, 3-year adjusted OS for the 2 treatment arms were 58% (52%-65%) and 56% (51%-60%), respectively. Early PSA response by 6 months was a predictor of treatment efficacy from ADT plus apalutamide on OS. Longer time to early PSA response was associated with superior OS in the apalutamide arm.

Recurrent Hospitalizations and Response to Vericiguat in Heart Failure and Reduced Ejection Fraction

BackgroundIn VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction. ObjectivesThis study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization. MethodsThe treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro–B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported. ResultsThere were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro–B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo. ConclusionsAdditional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)

Impact of anticancer drugs on the therapeutic efficacy and side effects of hepatic arterial embolization for hepatocellular carcinoma.

Transcatheter arterial chemoembolization (TACE) using various anticancer drugs is often performed to treat hepatocellular carcinoma (HCC). We aimed to compare the therapeutic efficacy and side effects of TACE with anticancer drugs versus transcatheter arterial embolization (TAE) without anticancer drugs for HCC. Patients with HCC were randomized to either the TACE or TAE group. Up to five target nodules were treated in each patient. Lipiodol (Lp; 10 mL), contrast media (CM; 10 mL), epirubicin (40 mg), mitomycin C (10 mg), miliplatin (70 mg), and 1-2-mm 2-day soluble gelatin sponge particles (2D-SGS) were injected into the TACE group, whereas Lp (10 mL), CM (10 mL), and 2D-SGS were injected into the TAE group. Treatment effect (TE) of the target nodules was graded (TE1-TE4) and patient responses were assessed. Three months after treatment, blood tests were performed to compare tumor markers and adverse events. Fifty-four patients and 161 target nodules were included; 75 nodules in 28 patients were treated by TACE, and 86 nodules in 26 patients were treated by TAE. The number of nodules graded TE1, TE2, TE3, and TE4 was 1, 28, 7, and 39, respectively, in the TACE group and 2, 25, 7, and 52, respectively, in the TAE group. The response rates were 89% (25/28) and 73% (19/26) in the TACE and TAE groups, respectively. There were no significant differences in TE, response rates, or blood test results between the two groups. In hepatic arterial embolization for HCC, anticancer drugs did not have any impact on the therapeutic efficacy or side effects at 3 months after embolization.

Long-term incidence of haematological cancer after bariatric surgery or usual care in the Swedish Obese Subjects study: a prospective cohort study

Bariatric surgery in people with obesity is associated with a reduced overall cancer risk. Retrospective studies indicate that bariatric surgery specifically might reduce the risk of haematological cancers, but there is an absence of data from long-term, prospective studies. We therefore studied the association between bariatric surgery and haematological cancer in the Swedish Obese Subjects study. The prospective controlled Swedish Obese Subjects study was designed to compare overall mortality in people who underwent bariatric surgery (n=2007) and usual care (n=2040). Participants were recruited through campaigns in mass media and at 480 primary health-care centres all over Sweden. The inclusion criteria were an age of 37-60 years and a BMI of 34 kg/m2 or more in men and 38 kg/m2 or more in women before or at the time of the examination. Haematological cancer events, including malignant lymphoma, myeloma, myeloproliferative neoplasms, as well as acute and chronic leukaemias, were captured from the Swedish Cancer Registry. The main outcome of this study was haematological cancer incidence and mortality. This study is registered with ClinicalTrials.gov (NCT01479452) and is ongoing. A total of 4047 individuals with obesity were enrolled between Sept 1, 1987, and Jan 31, 2001. Overall, 34 participants in the surgery group and 51 participants in the usual care control group were diagnosed with haematological cancer during follow-up (hazard ratio [HR] 0·60; 95% CI 0·39-0·92; p=0·020). Moreover, there were three deaths by haematological cancer in the surgery group and 13 deaths in the control group (0·22; 0·06-0·76; p=0·017). Surgery was also associated with a reduced incidence of lymphoma (0·45; 0·23-0·88; p=0·020). A significant difference in treatment effect between men and women was found; bariatric surgery was associated with reduced incidence of haematological cancer in women (0·44; 0·26-0·74; p=0·002), but not in men (1·35; 0·58-3·17; p=0·489; interaction p=0·031). Bariatric surgery is associated with a reduced incidence of haematological cancer, specifically in women. Health-care providers and policy makers working in the field of cancer prevention should consider bariatric surgery a primary prevention resource for people with obesity. The Swedish Research Council, the Swedish State under the agreement between the Swedish Government and the county councils, the Avtal om Läkarutbildning och Forskning agreement, the Health & Medical Care Committee of the Region Västra Götaland, the Swedish Heart Lung Foundation, Gothenburg Medical Society, and the Adlerbert Research Foundation. For the Swedish translation of the abstract see Supplementary Material section.

A scoping review of statistical methods in studies of biomarker-related treatment heterogeneity for breast cancer

BackgroundMany scientific papers are published each year and substantial resources are spent to develop biomarker-based tests for precision oncology. However, only a handful of tests is currently used in daily clinical practice, since development is challenging. In this situation, the application of adequate statistical methods is essential, but little is known about the scope of methods used.MethodsA PubMed search identified clinical studies among women with breast cancer comparing at least two different treatment groups, one of which chemotherapy or endocrine treatment, by levels of at least one biomarker. Studies presenting original data published in 2019 in one of 15 selected journals were eligible for this review. Clinical and statistical characteristics were extracted by three reviewers and a selection of characteristics for each study was reported.ResultsOf 164 studies identified by the query, 31 were eligible. Over 70 different biomarkers were evaluated. Twenty-two studies (71%) evaluated multiplicative interaction between treatment and biomarker. Twenty-eight studies (90%) evaluated either the treatment effect in biomarker subgroups or the biomarker effect in treatment subgroups. Eight studies (26%) reported results for one predictive biomarker analysis, while the majority performed multiple evaluations, either for several biomarkers, outcomes and/or subpopulations. Twenty-one studies (68%) claimed to have found significant differences in treatment effects by biomarker level. Fourteen studies (45%) mentioned that the study was not designed to evaluate treatment effect heterogeneity.ConclusionsMost studies evaluated treatment heterogeneity via separate analyses of biomarker-specific treatment effects and/or multiplicative interaction analysis. There is a need for the application of more efficient statistical methods to evaluate treatment heterogeneity in clinical studies.

What Is the Added Benefit of Combining Cognitive Behavioral Therapy and Selective Serotonin Reuptake Inhibitors in Youth with Obsessive Compulsive Disorder? A Bayesian Hierarchical Modeling Meta-Analysis.

Background: Treatment of obsessive-compulsive disorder (OCD) in children and adolescents frequently involves cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs), or their combination. However, how adding CBT to SSRIs affects the trajectory and magnitude of improvement has not been evaluated meta-analytically. Methods: We performed a meta-analysis using weekly data from prospective randomized parallel group trials of CBT and SSRIs in pediatric patients with OCD. Response was modeled for the change in the Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) using a Bayesian hierarchical model over 12 weeks. Results: Fourteen studies included pharmacotherapy arms, 4 studies included combined pharmacotherapy and psychotherapy, and 10 studies included a placebo or control arm. The studies included 1146 patients (mean age 12.7 ± 1.3 years, mean 42.1% female). In the logarithmic model of response, statistically significant differences in treatment effects for CBT+SSRI and SSRI monotherapy were observed compared with placebo (SSRI β = -3.59, credible interval [95% CrI]: -4.13 to -3.02, p < 0.001; SSRI+CBT β = -4.07, 95% CrI: -5.05 to -3.04, p < 0.001). Adding CBT to an SSRI produced numerically (but not statistically significantly) greater improvement over 12 weeks. Greater improvement was observed in studies with more boys (p < 0.001), younger patients (p < 0.001), and in studies with greater baseline symptom severity (p < 0.001). Conclusions: In children and adolescents with OCD, compared with placebo, both SSRIs and SSRI+CBT produced early and sustained improvement over 12 weeks, although the improvement was also related to sample characteristics. Longer term studies are needed to determine when the additive benefit of CBT emerges relative to SSRI monotherapy.

Effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on cardiovascular and kidney outcomes in Asian versus White patients with type 2 diabetes mellitus

BackgroundThe study aimed to assess the treatment effects of the two medications on cardiovascular and kidney outcomes in Asian compared with White patients with type 2 diabetes mellitus (T2DM). MethodsMEDLINE, EMBASE, and CENTRAL were searched up to October 31, 2022. We included the trials that assessed the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus placebo in Asian and White patients with T2DM on major adverse cardiovascular events (MACE) and kidney outcomes. The Bucher method was used to perform an indirect comparison for estimating the differences in treatment effects of GLP-1 RA and SGLT2i between Asian versus White patients. Interaction tests were also performed for treatment-by-race to assess the potential effect modification by race. ResultsWe included 22 publications from 13 randomized trials. For MACE, there were no differences in treatment effects of GLP-1 RA (HR = 0.84, 95% CI: 0.68–1.04) or SGLT2i (HR = 0.90, 95% CI: 0.72–1.13) in Asian versus White patients. No differences in treatment effects of SGLT2i on kidney outcomes in Asian versus White patients were found (HR = 1.01, 95% CI: 0.75–1.36). There was no significant effect modification by race on cardiovascular and kidney outcomes. ConclusionsThere were no significant differences in treatment effects of GLP-1 RA or SGLT2i for MACE between Asian and White patients with T2DM. Likewise, no significant differences in treatment effects of SGLT2i on kidney outcomes were found between Asian and White patients.

Effect of Organic and Mineral Soil Additives on Asparagus Growth and Productivity in Replant Soils

The repeated cultivation of asparagus in the same field can severely reduce yield. A complex of predominantly microbial causes is suspected. Limited plant development, establishment problems, and yield loss may occur, particularly in light sandy soils. In order to address this replant problem and evaluate alternative cultivation conditions, two asparagus fields were treated with different supplements and were cultivated for 5 years to investigate their impact on yield. The results from the pot trials using soils from these fields are presented, along with the field trial findings. The trials included the incorporation of mushroom substrate (champost), Fimonit (clay mineral), mustard meal (biofumigation), and Micosat F Uno (including arbuscular mycorrhizal fungi, Trichoderma viride, and rhizosphere bacteria species). In the pot trials, the sterilised soil exhibited a growth benefit over the original soil. However, the tested additives had no significant effects in the short period of 8 weeks. At one of the tested field sites, the marketable asparagus yields following champost, Fimonit, biofumigation, and Micosat treatments were 14, 6, 16 and 12% higher than that of the control soil, respectively, but no significant differences in treatment effect were observed in the second test field. Biofumigation using mustard meal and champost was most successful in reducing the impact of replanting on yields.

Patient-Level Meta-Analysis of Low-Dose Hydrocortisone in Adults with Septic Shock

BackgroundTrials and study-level meta-analyses have failed to resolve the role of corticosteroids in the management of patients with septic shock. Patient-level meta-analyses may provide more precise estimates of treatment effects, particularly subgroup effects.MethodsWe pooled individual patient data from septic shock trials investigating the adjunctive use of intravenous hydrocortisone. The primary outcome was 90-day all-cause mortality, and it was also analyzed across predefined subgroups. Secondary outcomes included mortality at intensive care unit and hospital discharge, at 28 and 180 days, and vasopressor-, ventilator-, and organ failure–free days. Adverse events included superinfection, muscle weakness, hyperglycemia, hypernatremia, and gastroduodenal bleeding.ResultsOf 24 eligible trials (n=8528), 17 (n=7882) provided individual patient data, and 7 (n=5929) provided 90-day mortality. The marginal relative risk (RR) for 90-day mortality of hydrocortisone versus placebo was 0.93 (95% confidence interval [CI], 0.82 to 1.04; P=0.22; moderate certainty). It was 0.86 (9% CI, 0.79 to 0.92) for hydrocortisone with fludrocortisone and 0.96 (95% CI, 0.82 to 1.12) without fludrocortisone. There was no significant differential treatment effect across subgroups. Hydrocortisone was associated with little to no difference in any of the secondary outcomes except vasopressor-free days (mean difference, 1.24 days; 95% CI, 0.74 to 1.73; high certainty). Hydrocortisone may not be associated with an increase in the risk of superinfection (RR, 1.04; 95% CI, 0.95 to 1.15; low certainty), hyperglycemia (RR, 1.05; 95% CI, 0.98 to 1.12; low certainty), or gastroduodenal bleeding (RR, 1.11; 95% CI, 0.83 to 1.48; low certainty). Hydrocortisone may be associated with an increase in the risk of hypernatremia (RR, 2.01; 95% CI, 1.56 to 2.60; low certainty) and muscle weakness (n=2647; RR, 1.73; 95% CI, 1.49 to 1.99; low certainty).ConclusionsIn this patient-level meta-analysis, hydrocortisone compared with placebo was not associated with reduced mortality for patients with septic shock. (Funded by “Programme d’Investissements d’Avenir,” a research Professorship from the National Institute of Health and Care Research, Leadership Fellowships from the National Health and Medical Research Council of Australia, and Emerging Leaders Fellowship from the National Health and Medical Research Council of Australia; PROSPERO registration number, CRD42017062198.)

Ethnic Variations in Cardiovascular and Renal Outcomes From Newer Glucose-Lowering Drugs: A Meta-Analysis of Randomized Outcome Trials.

Background Hispanic populations are more likely to develop diabetes and its related diseases than non-Hispanic White populations. Little evidence exists to support whether the cardiovascular and renal benefits of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are generalizable to the Hispanic populations. Methods and Results We included the cardiovascular and renal outcome trials (up to March 2021) that reported the major adverse cardiovascular events (MACEs), cardiovascular death/hospitalization for heart failure, and composite renal outcomes by ethnicity in individuals with type 2 diabetes (T2D), calculated pooled hazard ratios (HRs) with 95% CIs using fixed-effects models, and tested the differences between Hispanic and non-Hispanic populations (P for interaction [Pinteraction]). In 3 sodium-glucose cotransporter 2 inhibitor trials, there was a statistically significant difference between Hispanic (HR, 0.70 [95% CI, 0.54-0.91]) and non-Hispanic (HR, 0.96 [95% CI, 0.86-1.07]) groups in treatment effects on MACE risk (Pinteraction=0.03), except for risks of cardiovascular death/hospitalization for heart failure (Pinteraction=0.46) and composite renal outcome (Pinteraction=0.31). In 5 glucagon-like peptide-1 receptor agonist trials, there was no statistically significant difference in treatment effect on MACE risk between Hispanic (HR, 0.82 [95% CI, 0.70-0.96]) and non-Hispanic (HR, 0.92 [95% CI, 0.84-1.00]) populations (Pinteraction=0.22). In 3 dipeptidyl peptidase-4 inhibitor trials, the HR for MACE risk appeared greater in Hispanic (HR, 1.15 [95% CI, 0.98-1.35]) than non-Hispanic (HR, 0.96 [95% CI, 0.88-1.04]) populations (Pinteraction=0.045). Conclusions Compared with non-Hispanic individuals, Hispanic individuals with T2D appeared to obtain a greater benefit of lowered MACE risk with sodium-glucose cotransporter 2 inhibitors.

Post-Prandial Cognitive and Blood Pressure Effects of a DHA-Rich Omega-3 Powder in Middle-Aged Males: A Pilot Study

The use of omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplements is increasingly common among middle-aged and older adults. Users of ω-3 PUFA supplements often report using such supplements to support cognitive health, despite mixed findings reported within the ω-3 PUFA literature. To date, very few studies have explored cognitive effects in distinctly middle-aged (40 to 60 years) adults, and none have examined the acute effects (in the hours following a single dose) on cognitive performance. The current study evaluated whether a single dose of ω-3 PUFA (4020 mg docosahexaenoic acid and 720 mg eicosapentaenoic acid) influences cognitive performance and cardiovascular function in middle-aged males. Cognitive performance and cardiovascular function were assessed before and 3.5–4 h after consumption of a high dose of ω-3 PUFA (DHA + EPA) or placebo, incorporated into a standardized meal (i.e., single serve of Greek yogurt). In this study of middle-aged males, no significant differential treatment effects were observed for cognitive performance. However, a significant reduction in aortic systolic blood pressure (pre-dose to post-dose) was apparent following consumption of the ω-3 PUFA (DHA + EPA) treatment (mean difference = −4.11 mmHg, p = 0.004) but not placebo (mean difference = −1.39 mmHg, p = 0.122). Future replication in a sample comprising females, as well as patients with hypertension, is merited.

Parent Training via Internet or in Group for Disruptive Behaviors: A Randomized Clinical Noninferiority Trial

To evaluate if an internet-delivered parent training program is noninferior to its group-delivered counterpart in reducing child disruptive behavior problems (DBP). This noninferiority randomized clinical trial enrolled families seeking treatment in primary care in Stockholm, Sweden, for DBP in a child 3-11 years of age. Participants were randomized to internet-delivered (iComet) or group-delivered (gComet) parent training. The primary outcome was parent-rated DBP. Assessments were made at baseline and 3, 6, and 12 months. Secondary outcomes included child and parent behaviors and well-being and treatment satisfaction. The noninferiority analysis was determined by a one-sided 95% CI of the mean difference between gComet and iComet using multilevel modeling. This trial included 161 children (mean age 8.0); 102 (63%) were boys. In both intention-to-treat and per-protocol analyses, iComet was noninferior to gComet. There were small differences in between-group effect sizes (d=-0.02 to 0.13) on the primary outcome with the upper limit of the one-sided 95% CI below the noninferiority margin at 3-, 6-, and 12-month follow-up. Parents were more satisfied with gComet (d= 0.49, 95% CI [0.26, 0.71]). At 3-month follow-up, there were also significant differences in treatment effect on attention-deficit/hyperactivity disorder symptoms (d= 0.34, 95% CI [0.07, 0.61]) and parenting behavior (d= 0.41, 95% CI [0.17, 0.65]) favoring gComet. At 12-month follow-up, there were no differences in any outcomes. Internet-delivered parent training was noninferior to group-delivered parent training in reducing child DBP. The results were maintained at 12-month follow-up. This study supports internet-delivered parent training being used as an alternative to group-delivered parent training in clinical settings. Randomized Controlled Trial of Comet via the Internet or in Group Format; https://www. gov/; NCT03465384.

Impact of Type2 Diabetes Duration on the Efficacy and Safety of Add-on Lixisenatide in Asian Individuals Receiving Basal Insulin: A Pooled Analysis.

This analysis investigated the efficacy and safety of add-on lixisenatide by disease duration in Asian people with type2 diabetes inadequately controlled with basal insulin ± oral antidiabetic drugs. Data for Asian participants in the GetGoal-Duo1, GetGoal-L, and GetGoal-L-C studies were pooled and categorized by diabetes duration: < 10years (group1), 10 to < 15years (group2), and ≥ 15years (group3). Efficacy and safety of lixisenatide versus placebo were evaluated by subgroup. The potential influence of diabetes duration on efficacy was examined using multivariable regression analyses. A total of 555 participants were included (mean age 53.9years, 52.4% male). No significant differences in treatment effect between the duration subgroups were observed for the changes from baseline to 24weeks in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), PPG excursion, body weight or body mass index, or the proportion of participants with HbA1c < 7% at 24weeks (all P values for interaction > 0.1). Change in insulin dosage (U/day) was significantly different between subgroups (P = 0.038). Multivariable regression analysis showed participants in group1 had a smaller change in body weight and basal insulin dose over the 24-week treatment period than participants in group3 (P = 0.014 and 0.030, respectively) and were less likely to achieve an HbA1c < 7% than participants in group2 (P = 0.047). No severe hypoglycemia was reported. A higher proportion of participants in group3 versus the other groups had symptomatic hypoglycemia, for both lixisenatide and placebo, and T2D duration had a significant effect on hypoglycemia risk (P = 0.001). Lixisenatide improved glycemic control in Asian individuals regardless of diabetes duration, without increasing the risk of hypoglycemia. Individuals with longer disease duration had a greater risk of symptomatic hypoglycemia than individuals with shorter disease duration regardless of treatment. No additional safety concerns were observed. GetGoal-Duo1, ClinicalTrials.gov record NCT00975286; GetGoal-L, ClinicalTrials.gov record NCT00715624; GetGoal-L-C, ClinicalTrials.gov record NCT01632163.

Nonlinear absorption-based analysis of energy deposition in melanosomes for 532-nm short-pulsed laser skin treatment.

The clinical use of 532-nm short-pulsed lasers has provided effective treatment of epidermal pigmented lesions. However, the detection of significant differences in treatment effects between picosecond and nanosecond lasers has still varied among clinical studies. For robust evaluation of the differences based on the treatment mechanism, this study presents a nonlinear absorption-based analysis of energy deposition in melanosomes for 532-nm short-pulsed laser treatment. Nonlinear absorption by melanin is modeled based on sequential two-photon absorption. Absorption cross-sections and nonradiative lifetimes of melanin, which are necessary for the nonlinear absorption-based analysis, are determined from transmittance measurement. Using the model and parameters, energy deposition in melanosomes was calculated with varying fluence and pulse width settings, including actual clinical parameters. The energy deposition in melanosomes increased with shorter laser pulses, and subnanosecond laser pulses were found to be most efficient. The comparison of energy deposition calculated using clinical parameters demonstrated the differences in treatment effects between picosecond and nanosecond lasers reported in clinical studies. The nonlinear absorption-based analysis provides quantitative evidence for the safety and efficacy evaluation of short-pulsed laser treatments, which may lead to the establishment of numerical indices for determining treatment conditions. Future studies considering the effects of the surrounding tissue on energy deposition in melanosomes will be needed.

Adverse Events in Patients With Esophageal Cancer Treated With Nivolumab in Combination With Radiotherapy.

When nivolumab is administered as second-line therapy for esophageal cancer, radiotherapy may also be provided in cases either concurrently or sequentially. The aim of this study was to retrospectively examine whether the incidence of adverse events increases in such cases. Twenty-two esophageal cancer patients [17 males and 5 females; mean age 71 years (range=58-87 years)] treated with nivolumab were included. Patients were divided into two treatment groups: nivolumab alone (N group) (12 patients) and nivolumab combined with radiotherapy (R group) (10 patients). All patients had squamous cell carcinoma. The primary outcomes measured were the severity and frequency of adverse events. Adverse events were seen in 6 of the 12 patients in the N group and 8 of the 10 in the R group. There were significantly more adverse events in the R group (p=0.035), but no difference in Grade 3 or higher adverse events (p=0.781), indicating that the adverse events were controllable. There was no significant difference in treatment effect between the N and R groups. In this report, 50% of adverse events in the N group were grade 3-4, 25% of which were grade 4, as seen in previous reports. In the present study, the side effects were not enhanced by treatment with immune checkpoint inhibitors plus radiotherapy. Immune checkpoint inhibitors plus radiation therapy would be a relatively safe treatment and may become an option for esophageal cancer treatment in the future.

Effect of a Run-In Period on Estimated Treatment Effects in Cardiovascular Randomized Clinical Trials: A Meta-Analytic Review.

Background A run-in period may increase adherence to intervention and reduce loss to follow-up. Whether use of a run-in period affects the magnitude of treatment effects is unknown. Methods and Results We conducted a meta-analysis comparing treatment effects from 11 systematic reviews of cardiovascular prevention trials using a run-in period with matched trials not using a run-in period. We matched run-in with non-run-in trials by population, intervention, control, and outcome. We calculated a ratio of relative risks (RRRs) using a random-effects meta-analysis. Our primary outcome was a composite of cardiovascular events, and the primary analysis was a matched comparison of clinical trials using a run-in period versus without a run-in period. We identified 66 run-in trials and 111 non-run-in trials (n=668901). On meta-analysis there was no statistically significant difference in the magnitude of treatment effect between run-in trials (relative risk [RR], 0.83 [95% CI, 0.80-0.87]) compared with non-run-in trials (RR, 0.88 [95% CI, 0.84-0.91]; RRR, 0.95 [95% CI, 0.90-1.01]). There was no significant difference in the RRR for secondary outcomes of all-cause mortality (RRR, 0.97 [95% CI, 0.91-1.03]) or medication discontinuation because of adverse events (RRR, 1.05 [95% CI, 0.85-1.21]). Post hoc exploratory univariate meta-regression showed that on average a run-in period is associated with a statistically significant difference in treatment effect (RRR, 0.94 [95% CI, 0.90-0.99]) for cardiovascular composite outcome, but this was not statistically significant on multivariable meta-regression analysis (RRR, 0.95 [95% CI, 0.90-1.0]). Conclusions The use of a run-in period was not associated with a difference in the magnitude of treatment effect among cardiovascular prevention trials.

The outcomes of mechanical thrombectomy in patients with acute stroke with and without intravenous injection of tissue plasminogen activator

Background: Stroke is a major health problem and leading cause of mortality worldwide. This study aimed to evaluate the consequences of intravascular interventions in patients with acute ischemic stroke with and without intravenous tissue plasminogen activator (tPA) injection. Methods: This prospective cohort study was conducted on 120 patients with acute ischemic stroke. Patients were divided into three groups based on the type of disease treatment: angiography, tPA, and combined therapy (angiography + tPA). Patients in the tPA group were treated with a standard dose of intravenous alteplase (0.9 mg/kg). The severity of acute ischemic stroke was calculated on days 0, 14, and 90 after the interventions using the National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) questionnaires. Results: All three groups were homogeneous regarding age, gender, location, job status, education, and body mass index (BMI) distribution. Coronary disease was the most common risk factor for stroke in 38.33% of patients. There was no significant difference in mean NIHSS and mRS scores between the groups on days 0, 14, and 90 after intervention (p &gt; 0.05). Mean NIHSS and mRS scores significantly decreased from the first time point (day 0), 10 days until 90 days after treatment in all three groups (p &lt; 0.001); however, there was no significant difference in treatment effect between the three groups at these time points (p &gt; 0.05). Conclusion: Treatment with angiography and tPA alone or with combined therapy significantly decreased the severity of acute ischemic stroke. A significant decrease was observed in the mean NIHSS and mRS scores in all therapy groups, indicating that these treatments were effective in mitigating acute ischemic stroke and improving functional independence in these patients. The eligibility criteria by which patients with acute ischemic stroke are selected for each specific therapy are essential to achieving better clinical outcomes.

Trends of First-Line Targeted Therapy in Korean Patients With Metastatic Clear Cell Renal Cell Carcinoma: Sunitinib Versus Pazopanib, a Multicenter Study

Purpose: There have been few reports on comparison between sunitinib and pazopanib as first-line targeted therapy in Korean metastatic clear cell renal cell carcinoma (ccRCC). We sought to analyze the treatment trends of metastatic ccRCC by comparing the effects and adverse events of sunitinib and pazopanib.Materials and Methods: Data of 357 metastatic RCC patients who received the sunitinib or pazopanib as the first-line targeted therapy from the Daegyeong Oncology Study Group database was obtained and analyzed. Among these patients, patients who only clear cell type was confirmed after needle biopsy or nephrectomy were included, and patients who underwent target therapy for less than 3 months were excluded.Results: Of 251 patients who met the inclusion criteria, sunitinib and pazopanib group were identified in 156 (62%) and 95 patients (38%), respectively. Pazopanib group was older (66 years vs. 61 years, p=0.001) and more symptomatic (65% vs. 52%, p=0.037) and had more patients with Karnofsky performance status &lt;80 (20% vs. 11%, p=0.048) and fewer number of organ metastases (p=0.004) compared to sunitinib group. There was no significant difference in disease control rate (88.5% vs. 87.3%, p=0.744), the median progression-free survival (19 months vs. 15 months, p=0.444) and overall survival (25 months vs. 19 months, p=0.721) between sunitinib and pazopanib. The most common grade 3/4 adverse events with sunitinib and pazopanib were anemia (5%) and hand-foot syndrome (3%), respectively. There was no significant difference between sunitinib and pazopanib in number of patients who experienced grade 3/4 adverse events (15% vs. 11%, p=0.275). However, there were more patients who discontinued treatment due to only adverse events in sunitinib group compared to pazopanib group (12% vs. 3%, p=0.020).Conclusions: In Korean metastatic ccRCC, pazopanib tended to be used in patients with poorer health status compared to sunitinib. Sunitinib and pazopanib had no significant difference in treatment effect and survival, but pazopanib had more tolerable adverse events.