Direct Treatment Effects Research Articles

Neutrophil Elastase Facilitates Cancer Cell Motility via Induction of Akt Signaling Pathway

Cancer cells create a microenvironment favoring growth of the primary tumor and cancer dissemination. We and others have demonstrated that immune cells recruited to a primary tumor actively contribute to pro‐tumorigenic and pro‐metastatic conditions. Neutrophils, one of the first inflammatory leukocytes infiltrating a developing tumor, facilitate intratumoral angiogenesis and tumor cell dissemination via newly formed blood vessels. Upon arrival to the site of primary tumor, the recruited neutrophils release their potent enzymes, including neutrophil MMP‐9, a structurally unique metalloproteinase strongly inducing angiogenesis. Herein, we demonstrate that a neutrophil‐derived serine protease, neutrophil elastase (NE), enhances cancer cell motility, which is essential for efficient cancer cell dissemination from primary tumors to secondary sites. We have shown that the treatment of tumor cells with purified NE significantly increased their migration in a chemotactic Transwell assay. Our data show significant (by 2‐fold) increase in migration rates of NE‐treated over non‐treated control for both epidermoid HEp3 and prostate PC3 carcinoma cells. We found no direct effect of NE treatment on cell proliferation, thus excluding cell division from the causes of NE‐mediated increase in rates of cell migration. However, we found that NE treatment induced activation of Akt, a protein kinase that regulates many important cell functions. We have demonstrated that NE‐mediated activation of Akt was sensitive to the specific NE inhibitor, α1PI, implicating the catalytic activity of NE in the enhancement of cell migration. Furthermore, NE‐induced cell migration was completely abrogated if tumor cells were pre‐treated with inhibitors of Akt signaling, Dasatinib and Wortmannin, before NE treatment. Together, our findings indicate that neutrophil‐specific protease, NE, is a potent inducer of tumor cell migration, and that Akt‐activation signaling constitutes an essential mechanism for NE‐enhancing effects on tumor cell migration.

Maternal Differential Treatment and Psychological Well-Being: The Mediating Role of Marital Tension and Sibling Tension?

Past research used equity theory and social comparison theory to explain the direct effect of maternal differential treatment (MDT) on psychological well-being. However, this focus on psychological pathways ignores possible social pathways, such as indirect effects of MDT on well-being through disrupting other family relationships. This study uses stress proliferation theory to argue that MDT, as a primary stressor in mother-child relationships, can produce secondary stressors in other family relationships (e.g., sibling tension and marital tension), which in turn leads to lower psychological well-being. To investigate this mechanism, we conducted multilevel mediation analysis using data collected from 720 adult children nested within 308 families, as part of the Within-Family Differences Study. We found that sibling tension mediates the association between adult children's perceptions of maternal disfavoritism and their psychological well-being-a process we call the stress proliferation of maternal disfavoritism. In contrast, adult children's perceptions of maternal favoritism cannot trigger this stress proliferation process of producing marital tension nor sibling tension. The evaluation of the stress proliferation process of maternal favoritism and disfavoritism can help us to understand the difference in effects across various dimensions of MDT. This study contributes to the literature on social relationships as social determinants of health by investigating how intergenerational relationships are connected to other family relationships to affect family members' health.

New principles of treatment of vaginal dysbiosis in reproductive aged womеn

Purpose of the study. To investigate the efficiency and safety of combined treatment and prevention of bacterial vaginosis recurrence in women of reproductive age.Materials and methods. 78 women of reproductive age with diagnosed bacterial vaginosis were examined. 50 women are included in the main group, 28 women are included inthe comparison group. Women in the main group were offered complex therapy: Samitol (secnidazole 500 mg) 1 g 2 times a day per os for 3 days, Gynex Forte (1 vaginal suppository contains metronidazole 750 mg, miconazole nitrate 200 mg) 1 time a day (overnight) for 7 days, Serrata (serratiopeptidase tablets) 1 tablet (10 mg) 3 times a day for 20 days. After Gynex Forte treatment women received a probiotic per vaginum for 7 days. Comparison group received standard two-step therapy.Results. Clinical effect of treatments was achieved in 49 (98%) patients of the main group in contrast to the comparison group where the effectiveness of treatment was 12 (42.9%). A direct positive treatment effect on 15th day in the main group was reported in 33 cases (66%) compared with control group – 9 (32.1%). 6 months after treatment main group did not have recurrence of bacterial vaginosis, while in the comparison group recurrence was diagnosed in 8 (28.6%) women.Conclusions. The results showed the high efficacy and safety of complex therapy, which included drug Samitol (secnidazole), vaginal suppositories Gynex Forte (a combination of metronidazole and miconazole) and proteolytic drug Serrata (serratiopeptidase tablets) in women of reproductive age in the bacterial vaginosis treatment. The results of this clinical study suggest the recommended treatment of bacterial vaginosis in women of reproductive age for common use in gynecological practice

Competing indirect effects in a comparative psychotherapy trial for generalized anxiety disorder.

In a randomized trial for generalized anxiety disorder, cognitive-behavioral therapy (CBT) and CBT integrated with motivational interviewing (MI) promoted comparable worry reduction at posttreatment, whereas MI-CBT outperformed CBT over 12-month follow-up (Westra, Constantino, & Antony, 2016). Secondary analyses revealed competing mediators of the long-term treatment effect: MI-CBT related to lower patient resistance to the treatment, which promoted lower follow-up worry, whereas CBT related to greater increases in patient friendly submissiveness (FS), or compliance, which also promoted lower follow-up worry (that suppressed an even greater long-term advantage of MI-CBT). In this study, we tested these competing, though theoretically consistent, variables as mediators of the nonsignificant treatment effect on posttreatment worry, as there could also be treatment-specific means to arriving to these comparable ends. Eighty-five patients received 15 sessions of MI-CBT or CBT. Therapists rated patient FS through treatment, observers rated resistance at midtreatment, and patients rated worry at posttreatment. Bootstrap analyses indicated that MI-CBT patients exhibited less resistance, which promoted lower posttreatment worry, whereas CBT patients had greater increases in FS, which also promoted lower worry. CBT and MI-CBT achieved comparable posttreatment outcomes through separate indirect paths that each conferred an advantage for one treatment over the other (and had canceled out a direct treatment effect immediately after therapy). The composite trial findings have significance for understanding different pathways to personal change in both the short- and long terms, and for the importance of testing indirect effects both when direct treatment effects do and do not emerge. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Abstract 276: TAT-PTEN9c Targets Heart Directly to Improve Survival From Cardiac Arrest

Introduction: It is well established that hypothermia enhances cardiac arrest (CA) survival due, in part, to a mechanism of enhanced Akt activation. In this study we investigate whether the biosynthetic PTEN inhibitor (TAT-PTEN9c) provides therapeutic protection on survival due to direct effects on heart. Hypothesis: We hypothesized that TAT-PTEN9c interferes with endogenous PTEN binding at its cell membrane adaptor and leads to enhanced Akt activation, mouse survival and cardiac functional recovery. The improved CA survival is due in part to the improved contractile functional recovery of heart by TAT-PTEN9c. We also tested if the treatment targets the heart directly to enhanced recovery in isolated perfused rat heart after a period of global arrest. Methods: TAT-PTEN9c (7.5 mg/kg) was given intravenously (IV) after CA in mouse to determine protective effects of the treatment on survival and heart function. Western blot was used to determine the efficacy of TAT-PTEN9c for Akt activation. In the isolated rat heart, direct effect of treatment (1-10 μm) on cardiac function (HR, LVDP, RPP) were measured for 20 min following 20 min global ischemia. Results: In the mouse model of cardiac arrest, survival was significantly increased in the TAT-PTEN9c treated group compared to saline controls at 4 h (10/15, 67% vs. 6/15, 40%, P < 0.05) after CPR. TAT-PTEN9c improved MAP at both R30 min and R2h. The treated mice had increased Akt phosphorylation at R15 min in both heart and brain tissues with significantly decreased sorbitol content and reduced release of taurine and glutamate into blood, suggesting improved metabolic recovery and glucose utilization. For the isolated heart model, RPP was reduced by 25% for both TAT vehicle and non-treatment groups following arrest. With TAT-PTEN9c treatment, cardiac contractile function was completely recovered (pre-arrest RPP 29.1k+/- 4.8; post-arrest 28.0K +/- 5.0). Conclusion: TAT-PTEN9c enhances Akt activation and decrease glucose shunting to the polyol pathway in critical organs, preventing osmotic injury and early cardiovascular collapse and death. The improved survival by this treatment is in part due to its direct effect on heart functional recovery.

Estimation of Controlled Direct Effects in Longitudinal Mediation Analyses with Latent Variables in Randomized Studies

In a randomized study with longitudinal data on a mediator and outcome, estimating the direct effect of treatment on the outcome at a particular time requires adjusting for confounding of the association between the outcome and all preceding instances of the mediator. When the confounders are themselves affected by treatment, standard regression adjustment is prone to severe bias. In contrast, G-estimation requires less stringent assumptions than path analysis using SEM to unbiasedly estimate the direct effect even in linear settings. In this article, we propose a G-estimation method to estimate the controlled direct effect of treatment on the outcome, by adapting existing G-estimation methods for time-varying treatments without mediators. The proposed method can accommodate continuous and noncontinuous mediators, and requires no models for the confounders. Unbiased estimation only requires correctly specifying a mean model for either the mediator or the outcome. The method is further extended to settings where the mediator or outcome, or both, are latent, and generalizes existing methods for single measurement occasions of the mediator and outcome to longitudinal data on the mediator and outcome. The methods are utilized to assess the effects of an intervention on physical activity that is possibly mediated by motivation to exercise in a randomized study.

Gonadal Histopathological Disorders in Mytilus galloprovincialis Male Exposed to Tars Used in Mussel Farms

Polycyclic aromatic hydrocarbons (PAHs) and trace metals are pollutants widely distributed in the marine environment with toxic effects on live organisms, but few laboratory studies have proved their causal relationship with histopathologic alterations from invertebrates. We analyse the histopathologic effects of a tar mixture used in mussel farms on the gonad of male mussels. Mussels were exposed to water-accommodated fractions from different sub-lethal concentrations of that tar mixture during different times. The accumulation of PAHs and metals in mussels was quantified in each one tar exposure condition, and a comparative histological and morphometric analysis of the male gonad was performed, as well as of the gametogenic disorders and the cellular pathologies induced. Spermatogenesis disruption and alterations of somatic and germinal cells were observed as a direct effect of treatment. The pathologies observed followed an increasing malignity sequence depending on dose and exposure time: spawning induction; arrest of spermatogenesis and spermiogenesis; suppression of immune response; dysplasia of Sertoli and connective cells and finally, severe disorders of germinal cells. We demonstrate for the first time that tar used in waterproofing of floating rafts from the mussel farms causes severe effects on male mussel gonad, constituting a direct risk to the health of these organisms, affecting gametogenesis, quality of gametes and, ultimately, the sustainability of this resource and their quality for human consumption. Moreover, we propose the pathologies described in mussel as biomarkers of marine pollution and the mussel gonad as study model of testicular toxicity mechanisms in male reproduction.

Treatment for Word Retrieval in Semantic and Logopenic Variants of Primary Progressive Aphasia: Immediate and Long-Term Outcomes

Purpose Recent studies confirm the utility of speech-language intervention in primary progressive aphasia (PPA); however, long-term outcomes, ideal dosage parameters, and relative benefits of intervention across clinical variants warrant additional investigation. The purpose of this study was to determine whether naming treatment affords significant, lasting, and generalized improvement for individuals with semantic and logopenic PPA and whether dosage manipulations significantly affect treatment outcomes. Method Eighteen individuals with PPA (9 semantic and 9 logopenic variant) underwent lexical retrieval treatment designed to leverage spared cognitive-linguistic domains and develop self-cueing strategies to promote naming. One group (n = 10) underwent once-weekly treatment sessions, and the other group (n = 8) received the same treatment with 2 sessions per week and an additional "booster" treatment phase at 3 months post-treatment. Performance on trained and untrained targets/tasks was measured immediately after treatment and at 3, 6, and 12 months post-treatment. Results Outcomes from the full cohort of individuals with PPA showed significantly improved naming of trained items immediately post-treatment and at all follow-up assessments through 1 year. Generalized improvement on untrained items was significant up to 6 months post-treatment. The positive response to treatment was comparable regardless of session frequency or inclusion of a booster phase. Outcomes were comparable across PPA subtypes, as was maintenance of gains over the post-treatment period. Conclusion This study documents positive naming treatment outcomes for a group of individuals with PPA, demonstrating strong direct treatment effects, maintenance of gains up to 1 year post-treatment, and generalization to untrained items. Lexical retrieval treatment, in conjunction with daily home practice, had a strong positive effect that did not require more than 1 clinician-directed treatment session per week. Findings confirm that strategic training designed to capitalize on spared cognitive-linguistic abilities results in significant and lasting improvement, despite ongoing disease progression, in PPA.

Delivery room interventions to prevent bronchopulmonary dysplasia in preterm infants: a protocol for a systematic review and network meta-analysis

IntroductionAs gestational age decreases, incidence of bronchopulmonary dysplasia (BPD) and chronic lung disease increases. There are many interventions used in the delivery room to prevent acute lung injury and consequently...

Cost‐effectiveness analysis of empagliflozin treatment in people with Type 2 diabetes and established cardiovascular disease in the EMPA‐REG OUTCOME trial

AimIn the EMPA‐REG OUTCOME trial, empagliflozin therapy reduced cardiovascular death by 38% compared with placebo when added to standard of care. Using the trial results, we created a discrete‐event simulation model to assess lifetime health economic outcomes in people with Type 2 diabetes and established cardiovascular disease.MethodsTime‐dependent survival regression analysis was performed on data from EMPA‐REG OUTCOME for 10 cardiovascular and renal events (e.g. stroke, heart failure hospitalization, macroalbuminuria, cardiovascular mortality) to capture event rates over time, and interaction between events. Model performance was assessed by comparing predicted and observed outcomes at 3 years. Costs in the United Kingdom (UK) and health utilities were obtained from published literature. Outcomes included cumulative event rates, life‐years, costs and quality‐adjusted life‐years (QALYs).ResultsThe model predicted an 18% relative increase (by 2.1 life‐years) in survival for empagliflozin (14.0 life‐years) vs. standard of care (11.9 life‐years), attributable to direct treatment effect on cardiovascular mortality, and to indirect effect via reductions in other events. Participants treated with empagliflozin may experience improved quality of life (1.0 QALY) and higher costs (£3737/participant), yielding an incremental cost‐effectiveness ratio (ICER) of £4083/QALY. Sensitivity analyses confirmed the robustness of these results to changes in input parameters.ConclusionsBased on extrapolation of EMPA‐REG OUTCOME trial data using a participant‐level simulation model, empagliflozin in addition to standard of care is projected to be highly cost‐effective using UK healthcare costs. The impact in other countries will vary due to differences in drug pricing and accrual of other costs. (Clinical Trial Registry No: NCT01131676)

Estimating and testing the microbial causal mediation effect with high-dimensional and compositional microbiome data.

Recent microbiome association studies have revealed important associations between microbiome and disease/health status. Such findings encourage scientists to dive deeper to uncover the causal role of microbiome in the underlying biological mechanism, and have led to applying statistical models to quantify causal microbiome effects and to identify the specific microbial agents. However, there are no existing causal mediation methods specifically designed to handle high dimensional and compositional microbiome data. We propose a rigorous Sparse Microbial Causal Mediation Model (SparseMCMM) specifically designed for the high dimensional and compositional microbiome data in a typical three-factor (treatment, microbiome and outcome) causal study design. In particular, linear log-contrast regression model and Dirichlet regression model are proposed to estimate the causal direct effect of treatment and the causal mediation effects of microbiome at both the community and individual taxon levels. Regularization techniques are used to perform the variable selection in the proposed model framework to identify signature causal microbes. Two hypothesis tests on the overall mediation effect are proposed and their statistical significance is estimated by permutation procedures. Extensive simulated scenarios show that SparseMCMM has excellent performance in estimation and hypothesis testing. Finally, we showcase the utility of the proposed SparseMCMM method in a study which the murine microbiome has been manipulated by providing a clear and sensible causal path among antibiotic treatment, microbiome composition and mouse weight. https://sites.google.com/site/huilinli09/software and https://github.com/chanw0/SparseMCMM. Supplementary data are available at Bioinformatics online.

Short communication: Pegbovigrastim treatment in vivo does not affect granulocyte ability to migrate to endometrial cells and kill bacteria in vitro in healthy cows

In periparturient dairy cows, immune suppression, resulting in decreased neutrophil numbers and function, leads to increased susceptibility to postpartum conditions such as mastitis, retained placenta, and metritis. Administration of polyethylene glycol-conjugated bovine granulocyte colony stimulating factor (pegbovigrastim, Imrestor; Elanco Animal Health, Greenfield, IN) 7 d before and within 24 h of calving, effectively improves granulocyte production and function in vivo as well as in milk. A recently developed coculture assay was adapted for use with endometrial epithelial cells to assess the effects of pegbovigrastim application on directed granulocyte migration and bactericidal activity in vitro on a per-cell basis in endometrial cell cultures. Granulocytes from treated and untreated periparturient cows (6 and 5 per group, respectively) were evaluated for their ability to migrate to and kill bacteria after treatment, in context of the infected endometrium. We hypothesized that in addition to increasing the absolute concentration of circulating neutrophil granulocytes, pegbovigrastim treatment in vivo alters the ability of granulocytes to migrate to endometrial cells in vitro. The results clearly show a marked increase in the total concentration of granulocytes and monocytes between the 2 treatment groups as early as 2 d after the first injection, and this increased between the samples taken 2 d after calving. No migratory or killing differences were identified between granulocytes of both groups, suggesting that pegbovigrastim-induced granulocytes were as effective as non-induced cells. This may also be due to the absence of negative energy balance in the study animals and leads us to conclude that the positive effects seen in vivo are most likely based on the larger number of granulocytes present rather than a direct effect of pegbovigrastim treatment on the functionality of cells for the parameters tested in this study.

The Intergenerational Impact of China's New Rural Pension Scheme

The Intergenerational Impact of China's New Rural Pension Scheme

Association Between Intravenous Fluid Bolus and Biomarker Trajectory During Prehospital Care

Background: Patients with acute illness who receive intravenous (IV) fluids prior to hospital arrival may have a lower in-hospital mortality. To better understand whether this is a direct treatment effect or epiphenomenon of downstream care, we tested the association between a prehospital fluid bolus and the change in inflammatory cytokines measured at prehospital and emergency department timepoints in a sample of non-trauma, non-cardiac arrest patients at risk for critical illness. Methods: In a prospective cohort study, we screened 4,013 non-trauma, non-cardiac arrest encounters transported by City of Pittsburgh Emergency Medical Services (EMS) to 2 hospitals from August 2013 to February 2014. In 345 patients, we measured prehospital biomarkers (IL-6, IL-10, and TNF) at 2 time points: the time of prehospital IV access placement by EMS and at ED arrival. We determined the relative change for marker X as: ([XED – XEMS]/XEMS). We determined the risk-adjusted association between prehospital IV fluid bolus and relative change for each marker using multivariable linear regression. Results: Among 345 patients, 88 (26%) received a prehospital IV fluid bolus and 257 (74%) did not. Compared to patients who did not receive prehospital fluids, median prehospital IL-6 was greater initially in subjects receiving a prehospital IV fluid bolus (22.3 [IQR 6.4–113] vs. 11.5 [IQR 5.5–47.6]). Prehospital IL-10 and TNF were similar in both groups (IL-10: 3.5 [IQR 2.2–25.6] vs. 3.0 [IQR 1.9–9.0]; TNF: 7.5 [IQR 6.4–10.4] vs. 6.9 [IQR 6.0–8.3]). After adjustment for demographics, illness severity, and prehospital transport time, we observed a relative decrease in IL-6 at hospital arrival in those receiving a prehospital fluid bolus (adjusted β = −10.0, 95% CI: −19.4, −0.6, p = 0.04), but we did not detect a significant change in IL-10 (p = 0.34) or TNF (p = 0.53). Conclusions: Among non-trauma, non-cardiac arrest patients at risk for critical illness, a prehospital IV fluid bolus was associated with a relative decrease in IL-6, but not IL-10 or TNF.

Hybrid Compound SA-2 is Neuroprotective in Animal Models of Retinal Ganglion Cell Death.

Determine the toxicity, bioavailability in the retina, and neuroprotective effects of a hybrid antioxidant-nitric oxide donor compound SA-2 against oxidative stress-induced retinal ganglion cell (RGC) death in neurodegenerative animal models. Optic nerve crush (ONC) and ischemia reperfusion (I/R) injury models were used in 12-week-old C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mice were treated intravitreally with either vehicle or SA-2. Retinal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The electroretinogram and pattern ERG (PERG) were used to assess retinal function. RGC survival was determined by counting RBPMS-positive RGCs and immunohistochemical analysis of superoxide dismutase 1 (SOD1) levels was carried out in the retina sections. Concentrations of SA-2 in the retina and choroid were determined using HPLC and MS. In addition, the direct effect of SA-2 treatment on RGC survival was assessed in ex vivo rat retinal explants under hypoxic (0.5% O2) conditions. Compound SA-2 did not induce any appreciable change in retinal thickness, or in a- or b-wave amplitude in naive animals. SA-2 was found to be bioavailable in both the retina and choroid after a single intravitreal injection (2% wt/vol). An increase in SOD1 levels in the retina of mice subjected to ONC and SA-2 treatment, suggests an enhancement in antioxidant activity. SA-2 provided significant (P < 0.05) RGC protection in all three of the tested RGC injury models in rodents. PERG amplitudes were significantly higher in both I/R and ONC mouse eyes following SA-2 treatment (P ≤ 0.001) in comparison with the vehicle and control groups. Compound SA-2 was effective in preventing RGC death and loss of function in three different rodent models of acute RGC injury: ONC, I/R, and hypoxia.

Growth hormone treatment and health-related quality of life in children and adolescents: A national, prospective, one-year controlled study.

Health-related quality of life (HRQOL) may improve as an additional benefit of the growth hormone treatment (GHT) in children with short stature, but this effect has not been conclusively proven. To explore the direct effect of GHT on HRQOL in children starting GHT due to isolated or multiple GH deficiency (IGHD), acquired GH deficiency (AGHD) and Turner syndrome (TS), in comparison with untreated short stature controls in 18 UK centres. We used recognized measures of HRQOL, the PedsQL, the Strengths and Difficulties Questionnaire and Youth Life Optimism Test scales to investigate the effect of GHT at 0, 6 and 12months in children and adolescents 6-16years with IGHD (n=73) and AGHD (n=45), and 22 girls with TS. 49 children with non-GHD short stature served as the controls. Children rated their HRQOL better than their parents. Those with IGHD and TS rated their overall HRQOL lower than the controls at baseline, psychosocial scores significantly lower in IGHD. After 12months, the control and TS groups scored higher than UK norms. Those with AGHD had lowest HRQOL scores at all time points, due to poorer physical functioning. The controls showed the greatest improvement in the strength and difficulties scale. All measures evaluated, whether from child, parent or teacher showed an equal improvement over the year of GHT with no discernible direct treatment effect, despite reduced numbers in some patient groups. Children with short stature resulting from GHD have lower functioning than controls but HRQOL appears to improve with GHT, most likely on account of greater attention and as a result of the retest phenomenon. We were not able to demonstrate an absolute and independent effect of GHT in itself. HRQOL should not be used as a primary measure, as in adults, to determine whether children should receive GHT.

The symptom-specific efficacy of antidepressant medication vs. cognitive behavioral therapy in the treatment of depression: results from an individual patient data meta-analysis.

A recent individual patient data meta-analysis showed that antidepressant medication is slightly more efficacious than cognitive behavioral therapy (CBT) in reducing overall depression severity in patients with a DSM-defined depressive disorder. We used an update of that dataset, based on seventeen randomized clinical trials, to examine the comparative efficacy of antidepressant medication vs. CBT in more detail by focusing on individual depressive symptoms as assessed with the 17-item Hamilton Rating Scale for Depression. Five symptoms (i.e., "depressed mood" , "feelings of guilt" , "suicidal thoughts" , "psychic anxiety" and "general somatic symptoms") showed larger improvements in the medication compared to the CBT condition (effect sizes ranging from .13 to .16), whereas no differences were found for the twelve other symptoms. In addition, network estimation techniques revealed that all effects, except that on "depressed mood" , were direct and could not be explained by any of the other direct or indirect treatment effects. Exploratory analyses showed that information about the symptom-specific efficacy could help in identifying those patients who, based on their pre-treatment symptomatology, are likely to benefit more from antidepressant medication than from CBT (effect size of .30) versus those for whom both treatments are likely to be equally efficacious. Overall, our symptom-oriented approach results in a more thorough evaluation of the efficacy of antidepressant medication over CBT and shows potential in "precision psychiatry" .

Beneficial effects of Silexan on sleep are mediated by its anxiolytic effect

Disturbed sleep is among the most prevalent hyperarousal symptoms in anxiety disorders. Most drugs recommended for anxiety and insomnia have a sedating effect which is related to their beneficial effect on disturbed sleep. Silexan is a proprietary essential oil from Lavandula angustifolia. This drug has significant anxiolytic and sleep improving properties. Interestingly, these effects are not associated with sedation. Here we asked whether the positive effects on sleep are due to primary pharmacodynamic or secondary, disease related effects. We used the data from a double-blind, randomized study in which 212 patients were analyzed for efficacy after ten weeks' treatment with 80 mg/day Silexan or placebo. Anxiety and disturbed sleep were assessed using the Hamilton Anxiety Scale (HAMA) and the Pittsburgh Sleep Quality Index (PSQI), respectively. Regression-based mediation analysis was employed to estimate direct treatment effects and indirect effects mediated by anxiety control separately for each study group. Sobel's test was used to investigate the extent to which the mediator (HAMA change) contributes to the total effect of the independent variable (treatment) on the dependent variable (PSQI change). Compared to placebo, Silexan significantly reduced the total scores of the HAMA (p < 0.001) and of the PSQI (p = 0.002) after ten weeks, with clinically meaningful treatment group differences that were observed already after two and six weeks for HAMA and PSQI, respectively. Silexan had a statistically meaningful indirect effect on sleep (mediated by the effect on anxiety; p < 0.001) but no appreciable direct effect (p = 0.958). The ratio between the indirect and the total effect was determined to be 0.984, i. e., 98.4% of the total effect of Silexan on disturbed sleep were explained by the effect of Silexan on the symptoms of anxiety whereas 1.6% were attributable to a direct effect. The results indicate that Silexan exerts a secondary sleep improving effect almost exclusively through its anxiolytic action rather than by sedation. Findings are consistent with the drug's assumed mechanism of action.

Optimising the two-stage randomised trial design when some participants are indifferent in their treatment preferences.

Outcomes in a clinical trial can be affected by any underlying preferences that its participants have for the treatments under comparison and by whether they actually receive their preferred treatment. These effects cannot be evaluated in standard trial designs but are estimable in the alternative two-stage randomised trial design, in which some patients can choose their treatment, while the rest are randomly assigned. We have previously shown that, when all two-stage trial participants have a preferred treatment, the preference effects can be evaluated, in addition to the usual direct effect of treatment. We also determined criteria by which to optimise how many participants should be given a choice of treatment vs being randomised. More recently, we extended our methodology to allow for participants who are unable or unwilling to express a treatment preference if they are assigned to the choice group. In this paper, we show how to optimise the two-stage design when some participants are undecided about their treatment. We demonstrate that the undecided group should be regarded as distinct in the analysis, to obtain valid estimates of the preference effects. We derive the optimal proportion of participants who should be offered a choice of treatment, which in many cases will be close to 50%. More generally, the optima depend on the preference rates for treatments and the proportion of undecided participants, and the parameters of primary interest. We discuss some advantages and disadvantages of the two-stage trial design in this situation and describe a practical example.

Nonparametric approaches for comparing three-period, two-treatment, four-sequence crossover designs

ABSTRACTThe paper describes nonparametric approaches for comparing three-period, two-treatment, four-sequence crossover designs through testing the hypothesis that the treatments are interchangeable. The proposed approaches are based on a model which incorporates, along with the direct treatment effects, self and mixed carryover effects. Related asymptotic results are obtained. Comparisons among the designs are made numerically with respect to type I error rate and power of the tests considering compound symmetry and autoregressive covariance structures of the response variables. Lengths of the confidence intervals of the treatment differences are also used to make comparative study among the designs.