Differential Treatment Effects Research Articles

Pharmacological interventions for co-occurring psychopathology in people with borderline personality disorder: secondary analysis of the Cochrane systematic review with meta-analyses.

Medications are commonly used to treat co-occurring psychopathology in persons with borderline personality disorder (BPD). To systematically review and integrate the evidence of medications for treatment of co-occurring psychopathology in people with BPD, and explore the role of comorbidities. Building on the current Cochrane review of medications in BPD, an update literature search was done in March 2024. We followed the methods of this Cochrane review, but scrutinised all identified placebo-controlled trials post hoc for reporting of non BPD-specific ('co-occurring') psychopathology, and explored treatment effects in subgroups of samples with and without defined co-occurring disorders. GRADE ratings were done to assess the evidence certainty. Twenty-two trials were available for quantitative analyses. For antipsychotics, we found very-low-certainty evidence (VLCE) of an effect on depressive symptoms (standardised mean difference (SMD) -0.22, P = 0.04), and low-certainty evidence (LCE) of an effect on psychotic-dissociative symptoms (SMD -0.28, P = 0.007). There was evidence of effects of anticonvulsants on depressive (SMD -0.44, P = 0.02; LCE) and anxious symptoms (SMD -1.11, P < 0.00001; VLCE). For antidepressants, no significant findings were observed (VLCE). Exploratory subgroup analyses indicated a greater effect of antipsychotics in samples including participants with co-occurring substance use disorders on psychotic-dissociative symptoms (P = 0.001). Our findings, based on VLCE and LCE only, do not support the use of pharmacological interventions in people with BPD to target co-occurring psychopathology. Overall, the current evidence does not support differential treatment effects in persons with versus without defined comorbidities. Medications should be used cautiously to target co-occurring psychopathology.

Cardiovascular and kidney benefits of SGLT-2is and GLP-1RAs according to baseline blood pressure in type 2 diabetes: a systematic meta-analysis of cardiovascular outcome trials

Objectives: Using a systematic meta-analysis, we investigated if patients with type 2 diabetes (T2D) and with varying baseline blood pressure (BP) differ in the cardiorenal benefits received from sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs). Design: Randomized, placebo-controlled, cardiovascular outcome trials (CVOTs) of SGLT-2is and GLP-1RAs were identified from MEDLINE, Embase, and the Cochrane Library up to April 2024. Hazard ratios (HRs) with 95% CIs were pooled. The differential treatment effect by baseline BP category within each trial was estimated as the ratio of the HR (RHR) and pooled. Results: Seventeen publications based on 9 unique CVOTs (4 SGLT-2is and 5 GLP-1RAs) were eligible. In participants with normal baseline BP, comparing SGLT-2is with placebo, the HRs (95% CIs) were 0.88 (0.79-0.97) for major adverse cardiovascular events (MACE), 0.73 (0.59-0.91) for heart failure (HF) hospitalization, 0.78 (0.65-0.94) for composite CVD death/HF hospitalization, and 0.55 (0.41-0.73) for composite renal outcome. The corresponding estimates for participants with higher baseline BP were 0.88 (0.81-0.96), 0.67 (0.57-0.79), 0.73 (0.65-0.82), and 0.61 (0.48-0.77), respectively. In participants with normal baseline BP, GLP-RAs had no strong effect on MACE, stroke and nephropathy, but reduced stroke and nephropathy risk in those with higher baseline BP. Estimated RHRs showed no statistical evidence that baseline BP modified the cardiorenal benefits of SGLT-2is and GLP-1RAs. Conclusions: In patients with T2D, the cardiorenal benefits of treatment with SGLT2-Is and GLP1-RAs were similar in patients with normal baseline BP compared to those with a higher baseline BP.

Influence of Emulsion Lipid Droplet Crystallinity on Postprandial Endotoxin Transporters and Atherogenic And Inflammatory Profiles in Healthy Men - A Randomized Double-Blind Crossover Acute Meal Study.

Consumption of high-fat meals is associated with increased endotoxemia, inflammation, and atherogenic profiles, with repeated postprandial responses suggested as contributors to chronically elevated risk factors. However, effects of lipid solid versus liquid state specifically have not been investigated. This exploratory randomized crossover study tests the impact of lipid crystallinity on plasma levels of endotoxin transporters (lipopolysaccharide [LPS] binding protein [LBP] and soluble cluster of differentiation 14 [sCD14]) and select proinflammatory and atherogenic markers (tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP], interleukin-1-beta [IL-1β], interferon-gamma [IFN-γ], interleukin-6 [IL-6], soluble intercellular adhesion molecule [sICAM], soluble vascular cell adhesion molecule [sVCAM], monocyte chemoattractant protein-1 [MCP-1/CCL2], plasminogen activator inhibitor-1 [PAI-1], and fibrinogen). Fasted healthy men (n = 14, 28 ± 5.5 years, 24.1 ± 2.6kgm-2) consumed two 50g palm stearin oil-in-water emulsions tempered to contain either liquid or crystalline lipid droplets at 37°C on separate occasions with blood sampling at 0, 2-, 4-, and 6-h post-meal. Timepoint data, area under the curve, and peak concentration values are compared. Overall, no treatment effects are seen (p > 0.05). There are significant effects of time, with values decreasing from baseline, for TNF-α, MCP-1/CCL2, PAI-1, and fibrinogen (p < 0.05). Responder analysis pointed to differential treatment effects associated with some participant baseline characteristics but, overall, palm-stearin emulsion droplet crystallinity does not acutely affect plasma endotoxin transporters nor select inflammatory and atherogenic markers.

DIFFERENTIAL TREATMENT EFFECTS OF STANDARD AND HYPOFRACTIONATED RADIATION REGIMENS IN GLIOBLASTOMA PATIENTS.

The identification of the subgroups with differential treatment effects (DTE) is important for decisionmaking in personalized treatment. The DTE analysis assists in identifying patients who are more likely to benefit from a particular treatment regimen. The aim of the study was to analyze DTE in terms of the survival of glioblastoma (GBM) patients in the groups of standard radiotherapy (SRT) and hypofractionated radiotherapy (HRT) by the multicluster modeling of homogenous groups while retaining the statistical characteristics of the overall primary study cohort. The cohort of 159 patients with newly diagnosed GBM stratified according to the radiotherapy regimen (HRT group (n = 110/69.2%); SRT group (n = 49/30.8%)) was evaluated retrospectively. Forty-eight subgroups (multiclusters) were created by enumerating all possible combinations of 5 significant covariates (age, sex, the radicality of the surgical resection, chemotherapy, and Karnofsky performance status) of the Cox model. The DTE for the cancerspecific survival (CSS) within 48 modeled multiclusters were studied by comparing the interpolated Weibull CSS curves according to the Kolmogorov - Smirnov test. The findings showed that the SRT group was superior to the HRT group by CSS only in 3 of the modeled clusters presenting clinical scenarios with a non-radical tumor resection, no chemotherapy, and low Karnofsky functional status (≤ 70 scores) (Cluster 10: male aged < 60; Cluster 21: female aged ≥ 60; Cluster 22: male aged ≥ 60). Most of the studied clinical variants (45 of 48 multiclusters) did not demonstrate a significant difference when comparing the interpolated Weibull curves of the CSS for the SRT and HRT groups according to the Kolmogorov - Smirnov test (p ≥ 0.05). We propose a novel multicluster modeling approach that addresses DTE in relatively small samples of GBM patients receiving SRT or HRT. This original analytical method can be taken into consideration while designing new well-powered prospective trials aimed at the subgroup analysis in GBM patients who will be most beneficial from personalized treatment strategies.

Prior Local Therapy and First-Line Apalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Preclinical studies suggest that exposure to prostate-directed local therapy (LT) may influence the efficacy of subsequent systemic therapy including androgen receptor pathway inhibitors. However, there is insufficient clinical evidence to support this premise in patients with nonmetastatic castrate-resistant prostate cancer (nmCRPC). To determine whether exposure to prior prostate-directed LT (radical prostatectomy [RP], radiation therapy [RT], or both) played any effect-modifying role in the treatment effect of apalutamide on metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC. This post hoc secondary analysis used individual patient data from SPARTAN (Study of Apalutamide [ARN-509] in Men With Non-Metastatic Castration-Resistant Prostate Cancer), a phase 3, double-blinded, placebo-controlled randomized clinical trial conducted at 332 sites in 26 countries. Between October 14, 2013, and December 15, 2016, patients with nmCRPC and a prostate-specific antigen doubling time of 10 months or less were randomly assigned to apalutamide vs placebo; all patients received androgen deprivation therapy. The final data analysis was performed on December 31, 2023. Prior prostate-directed LT. Separate Cox proportional hazards regression models were constructed for OS and MFS, which included prior LT, treatment group, and an interaction term, in addition to a minimally sufficient set of confounders. Adjusted hazard ratios (HRs) with 95% CIs for MFS and OS were determined for the apalutamide groups with or without prior LT. Among the 1179 evaluable patients included in this analysis, 795 received prior LT and 384 did not. The median age of patients with and without prior LT was 70 (IQR, 45-90) years and 75 (IQR, 50-95) years, respectively. The median follow-up was 52.0 (IQR, 51.5-52.8) months. A differential treatment effect of apalutamide on MFS was observed between patients with and without prior LT (P for interaction = .009), with greater benefits for those with prior LT (adjusted HR, 0.22 [95% CI, 0.17-0.27]) compared with those without prior LT (adjusted HR, 0.35 [95% CI, 0.25-0.51]). However, there was insufficient evidence of a differential treatment effect on OS among subgroups stratified by exposure to prior LT (P for interaction = .23), with improved OS in the subgroup with prior LT (adjusted HR, 0.72 [95% CI, 0.57-0.92]) but no significant difference in OS in the subgroup without prior LT (adjusted HR, 0.92 [95% CI, 0.64-1.31]). This post hoc analysis of the SPARTAN trial provides evidence of an interaction between prior LT and apalutamide in patients with nmCRPC, with a clinically significant and more favorable treatment effect from apalutamide on MFS among patients with prior LT. Further studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT01946204.

Differential effects of mindfulness treatment and mobile neurofeedback on event-related potentials in early posterior negativity in cancer patients: a clinical-experimental parallel group design.

Cancer frequently leads to psychological challenges, among them emotion regulation problems. These can be alleviated with the help of mindfulness therapies or neurofeedback (NF) interventions. Possible intervention effects on emotion procession can be detected in clinical EEG studies by exploring event-related potentials, e.g., early posterior negativity (EPN), which recently has been established to investigate emotional processing and represents very early attention to affective stimuli. Therefore, this clinical-experimental study investigated the efficacy of mindfulness and NF (10 sessions each) on the EPN in oncology patients. The study enrolled 42 cancer patients (age: 31-73 years; gender: 28 female, 14 male). The study design was an RCT with a parallel group [NF (n = 21) versus mindfulness (n = 21)] waitlist paradigm. EEG recordings in an oddball task with neutral, rare positive and negative valence and high and low arousal stimuli were performed at three measurement time points (T0 = before waitlist, T1 = before intervention, T2 = after intervention). Following preprocessing, data from electrodes O1, Oz and O2 were analyzed for EPN amplitudes. Response time did not differ across groups and conditions. Comparing EPN at T1 and T2, there was a significant interaction of time, valence, and intervention (p = 0.042). Descriptive statistics showed increased EPN for negative stimuli after the NF intervention (T1 to T2), while EPN for positive stimuli only slightly increased. For mindfulness, positive stimuli evoked stronger amplitudes after the intervention, while EPN for negative stimuli increased from T1 to T2. Distinct effects were observed for the EPN for pictures with negative valence. Here, it is presumed that mindfulness treatment led to a refocusing of attention with a focus on positive valence, whereas NF seems to entail a different processing of images with negative valence and is therefore to be seen more in the sense of a confrontational approach. Our results suggest that both interventions are suitable for modulating EPN. However, it is not clear to what extent the effects are due to the interventions alone and how other factors might have affected the amplitudes, which highlights the need for further research in this area.

Exploratory Post Hoc Analysis of the CONVINCE Randomized Controlled Trial: Differential Treatment Effects of Hemodiafiltration (HDF) and Hemodialysis (HD) on Quality of Life

Exploratory Post Hoc Analysis of the CONVINCE Randomized Controlled Trial: Differential Treatment Effects of Hemodiafiltration (HDF) and Hemodialysis (HD) on Quality of Life

Heterogeneous Treatment Effects in the Incredible Years Teacher Classroom Management Programme - A Latent Profile Approach.

Heterogeneous effects from interventions often remain hidden in between-group analyses, risking overgeneralized conclusions of treatment effects. In this exploratory study, we performed latent profile analysis to unveil differential treatment effects among children in The Incredible Years Teacher Classroom Management Programme (IY TCMP). This program has previously been shown to reduce behavioral problems in preschools and schools in total samples and subgroups. A total of 726 children (48.7% girls; Mage = 4.21 years; SDage = 0.86) from 92 childcare centers in Norway participated in either the intervention (n = 338) or the matched control condition (n = 388). First, by conducting latent profile analysis on baseline levels of child-teacher relationship (closeness, conflict), behavioral problems, and social competence, three distinct profiles were identified: High Risk (26.4%), Moderate Risk (42.8%), and Low Risk (30.7%) - each profile with unique characteristics. Second, we tested for within-profile, condition-by-time interactions following the intervention, showing distinct treatment responses for each profile. High-risk profiles profited most from the IY TCMP, with a substantial decrease in externalizing problems, more teacher closeness, and less teacher conflict. Moderate-risk profiles also gained better teacher-child relationships and improved social competence. The Low-Risk profiles showed no effects from the intervention. It is argued that latent profile analysis presents a feasible approach for examining within-sample heterogeneity in intervention research. It also reveals crucial information on treatment variability, as demonstrated in the Incredible Years Programme.

Wastewater and warming effects on aquatic invertebrates: Experimental insights into multi-level biodiversity consequences

Wastewater effluents and global warming affect freshwater ecosystems and impact their crucial biodiversity. Our study aimed at characterizing individual and combined impacts of wastewater effluent and increased water temperature (as one aspect of climate change) on model freshwater communities. We tested the effect of experimental treatments on genetic diversity, survival, body weight, total lipid content, lipidome and metabolome of individual species as well as community composition and phylogenetic diversity. In a 21-day mesocosm experiment we assessed the responses of a simplified freshwater food web comprising of moss and seven species of benthic macroinvertebrate shredders and grazers (mayflies, stoneflies, caddisflies and amphipods) to four treatments in a full factorial design: control, increased water temperature, wastewater and a multiple stressor treatment combining increased temperature and wastewater. Physiological responses varied among taxa, with species-specific sensitivities observed in survival and lipid content. The lowest total lipid content was observed in caddisflies and a mayfly subjected to multiple stressor treatment. The effects of stressors were reflected in the altered metabolic pathways and lipid metabolism of the individual taxa, with differential treatment effects also observed between taxa. A notable decrease in phylogenetic diversity was observed across all experimental communities. Gammarus fossarum demonstrated a high susceptibility to environmental stressors at the genetic level. Hence, while commonly used indicators of ecosystem health (e.g. community composition) remained stable, molecular indicators (e.g. phylogenetic diversity, metabolome and lipidome) responded readily to experimental treatments. These findings underscore the vulnerability of macroinvertebrates to environmental stressors, even over relatively short exposure periods. They highlight the importance of molecular indicators in detecting immediate ecological impacts, offering valuable information for conservation strategies and understanding the ecological consequences in freshwater ecosystems.

Differential Efficacy of Weight Loss Interventions in Patients with Versus Without Diabetes.

Obesity is both a major risk factor for diabetes and a serious comorbidity of the condition. The twin epidemics of obesity and diabetes have spread globally over the past few decades. Treatment of obesity in patients with diabetes provides a host of clinical benefits that encompass virtually all body systems. Despite this, multiple lines of evidence suggest that the efficacy of most therapies for weight loss is significantly reduced among patients with diabetes. With this background, we summarize the evidence of a differential effect of lifestyle, pharmacological, and surgical treatments for obesity in patients with existing diabetes, and explore the potential mechanisms involved in this phenomenon. This information is then used to formulate strategies to improve weight loss outcomes for patients with diabetes.

Differential effects of exercise and hormone treatment on spinal cord injury-induced changes in micturition and morphology of external urethral sphincter motoneurons.

Spinal cord injury (SCI) results in lesions that destroy tissue and spinal tracts, leading to deficits in locomotor and autonomic function. We have previously shown that after SCI, surviving motoneurons innervating hindlimb muscles exhibit extensive dendritic atrophy, which can be attenuated by treadmill training or treatment with gonadal hormones post-injury. We have also shown that following SCI, both exercise and treatment with gonadal hormones improve urinary function. Animals exercised with forced running wheel training show improved urinary function as measured by bladder cystometry and sphincter electromyography, and treatment with gonadal hormones improves voiding patterns as measured by metabolic cage testing. The objective of the current study was to examine the potential protective effects of exercise or hormone treatment on the structure and function of motoneurons innervating the external urethral sphincter (EUS) after contusive SCI. Gonadally intact young adult male rats received either a sham or a thoracic contusion injury. Immediately after injury, one cohort of animals was implanted with subcutaneous Silastic capsules filled with estradiol (E) and dihydrotestosterone (D) or left blank; continuous hormone treatment occurred for 4 weeks post-injury. A separate cohort of SCI-animals received either 12 weeks of forced wheel running exercise or no exercise treatment starting two weeks after injury. At the end of treatment, urinary void volume was measured using metabolic cages and EUS motoneurons were labeled with cholera toxin-conjugated horseradish peroxidase, allowing for assessment of dendritic morphology in three dimensions. Locomotor performance was improved in exercised animals after SCI. Void volumes increased after SCI in all animals; void volume was unaffected by treatment with exercise, but was dramatically improved by treatment with E + D. Similar to what we have previously reported for hindlimb motoneurons after SCI, dendritic length of EUS motoneurons was significantly decreased after SCI compared to sham animals. Exercise did not reverse injury-induced atrophy, however E + D treatment significantly protected dendritic length. These results suggest that some aspects of urinary dysfunction after SCI can be improved through treatment with gonadal hormones, potentially through their effects on EUS motoneurons. Moreover, a more comprehensive treatment regime that addresses multiple SCI-induced sequelae, i.e., locomotor and voiding deficits, would include both hormones and exercise.

CtDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial.

The ETOP 10-16 BOOSTER study was a randomized phase II trial of osimertinib and bevacizumab therapy versus osimertinib therapy in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously. Next-generation sequencing (Guardant360) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored, and molecular alterations at progression were described. A total of 136 patients (88% of 155 randomized) had plasma samples at baseline (68 per arm), 110 (71%) at week 9, and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found to differ by smoking status (interaction P = 0.046), with the effect of smoking also differing by baseline EGFR T790M (interaction P = 0.033), whereas both TP53 at baseline and the tissue EGFR exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (P = 0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (P = 0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arms, respectively. The differential effect of treatment by smoking was not explained by TP53 mutations or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected, but no novel molecular alterations were identified in the combination arm.

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.

Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60

BackgroundOngoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher...

Sample size and power calculation for testing treatment effect heterogeneity in cluster randomized crossover designs.

The cluster randomized crossover design has been proposed to improve efficiency over the traditional parallel-arm cluster randomized design. While statistical methods have been developed for designing cluster randomized crossover trials, they have exclusively focused on testing the overall average treatment effect, with little attention to differential treatment effects across subpopulations. Recently, interest has grown in understanding whether treatment effects may vary across pre-specified patient subpopulations, such as those defined by demographic or clinical characteristics. In this article, we consider the two-treatment two-period cluster randomized crossover design under either a cross-sectional or closed-cohort sampling scheme, where it is of interest to detect the heterogeneity of treatment effect via an interaction test. Assuming a patterned correlation structure for both the covariate and the outcome, we derive new sample size formulas for testing the heterogeneity of treatment effect with continuous outcomes based on linear mixed models. Our formulas also address unequal cluster sizes and therefore allow us to analytically assess the impact of unequal cluster sizes on the power of the interaction test in cluster randomized crossover designs. We conduct simulations to confirm the accuracy of the proposed methods, and illustrate their application in two real cluster randomized crossover trials.

Clinical sub-phenotypes of Staphylococcus aureus bacteraemia.

Staphylococcus aureus bacteraemia (SAB) is a clinically heterogeneous disease. The ability to identify sub-groups of patients with shared traits (sub-phenotypes) is an unmet need that could allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically-relevant sub-phenotypes can be reproducibly identified amongst patients with SAB. We studied three cohorts of hospitalised adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n=458), the UK ARREST randomised trial (n=758), and the Spanish SAFO randomised trial (n=214). Latent class analysis was used to identify sub-phenotypes using routinely-collected clinical data, without considering outcomes. Mortality and microbiologic outcomes were then compared between sub-phenotypes. Included patients had predominantly methicillin-susceptible SAB (1366/1430,95.5%). We identified five distinct, reproducible clinical sub-phenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the sub-phenotypes. 84-day mortality was highest in sub-phenotype A, and lowest in B and E. Microbiologic outcomes were worse in sub-phenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased 84-day mortality in sub-phenotype B and improved microbiologic outcomes in sub-phenotype C. We have identified reproducible and clinically-relevant sub-phenotypes within SAB, and provide proof-of-principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these sub-phenotypes could contribute to a personalised medicine approach to SAB.

No evidence for effects of low-intensity vestibular noise stimulation on mild-to-moderate gait impairments in patients with Parkinson’s disease

BackgroundGait impairment is a key feature in later stages of Parkinson’s disease (PD), which often responds poorly to pharmacological therapies. Neuromodulatory treatment by low-intensity noisy galvanic vestibular stimulation (nGVS) has indicated positive effects on postural instability in PD, which may possibly be conveyed to improvement of dynamic gait dysfunction.ObjectiveTo investigate the effects of individually tuned nGVS on normal and cognitively challenged walking in PD patients with mild-to-moderate gait dysfunction.MethodsEffects of nGVS of varying intensities (0–0.7 mA) on body sway were examined in 32 patients with PD (ON medication state, Hoehn and Yahr: 2.3 ± 0.5), who were standing with eyes closed on a posturographic force plate. Treatment response and optimal nGVS stimulation intensity were determined on an individual patient level. In a second step, the effects of optimal nGVS vs. sham treatment on walking with preferred speed and with a cognitive dual task were investigated by assessment of spatiotemporal gait parameters on a pressure-sensitive gait carpet.ResultsEvaluation of individual balance responses yielded that 59% of patients displayed a beneficial balance response to nGVS treatment with an average optimal improvement of 23%. However, optimal nGVS had no effects on gait parameters neither for the normal nor the cognitively challenged walking condition compared to sham stimulation irrespective of the nGVS responder status.ConclusionsLow-intensity nGVS seems to have differential treatment effects on static postural imbalance and continuous gait dysfunction in PD, which could be explained by a selective modulation of midbrain-thalamic circuits of balance control.

Metagenomic analysis reveals differential effects of sewage treatment on the microbiome and antibiotic resistome in Bengaluru, India

ABSTRACT Climate change and health are closely linked to urban wastewater used for irrigation. Sewage treatment plants (STPs) provide ideal environments and niche availability for the transmission of antibiotic resistance genes (ARGs) among pathogenic and non-pathogenic bacteria. In this study, we examined the differential effect of sewage processing methods from the inlet to the outlet on the microbial diversity and antibiotic resistomes of 26 STPs in the urban sewage network of Bengaluru, India. We screened 478 ARGs and found 273 in wastewater, including clinically relevant genes such as CTX-M, qnr, sul-1, and NDM-1, which confer resistance to six major classes of antibiotics. The richness of ARGs was higher in sewage inlets compared with outlets. We observed a downward shift in drug classes from inlet to outlet samples, except for aminoglycosides, beta-lactams, MLSB, and tetracycline. Inlet samples exhibited more complex correlations between ARGs and bacteria compared with outlet samples. Our findings serve as a baseline study that could aid in the quantification of genes from both culturable and non-culturable taxa and will assist in the development of policies and strategies to address water quality issues associated with the use of recycled water.

Evaluating Ki67 and Oncotype DX Breast Recurrence Score during neoadjuvant treatment with letrozole/abemaciclib or chemotherapy in patients with highly proliferative HR+/HER2- breast cancer participating in the GEICAM CARABELA trial.

576 Background: CARABELA (NCT04293393) is a phase 2 randomized trial comparing 12 months of neoadjuvant letrozole/abemaciclib (let/abema) vs. 6 months of neoadjuvant chemotherapy (CT) for stage II-III, Ki67≥20%, HR+/HER2- breast cancer patients. Let/abema failed to show similar residual cancer burden (RCB) 0-I rates compared to CT (13% vs. 18%), highlighting the need to identify response biomarkers to CDK4/6 inhibitors and to determine which patients cannot avoid CT. Methods: We explored the predictive role of baseline (BL) Ki67 and Recurrence Score (RS) in tumor samples, and their changes during treatment. Ki67 was centrally determined using a standardized assay (Ki67 MIB-1 pharmDx, Dako Omnis, Agilent Technologies) at BL, 2 weeks (2w), and surgery. RS result was assessed at BL and at surgery (Exact Sciences), in the case of RCB=0, RS and Ki67 was assigned a value of 0. We examined the association of BL Ki67 and RS with RCB 0-I rates as independent variables, by logistic regression (adjusting by disease stage and cN), checking for treatment interaction. Results: BL Ki67 and RS showed similar distributions between arms; median Ki67: let/abema 38% vs CT 36% ( P=0.528); median RS: let/abema 27 vs CT 30 ( P=0.188). Although we could not detect a differential treatment effect based on BL Ki67 or RS, rates of RCB0-I were higher in the CT arm both for high Ki67 (≥40%) and high RS (&gt;25) (table 1). In addition, BL Ki67 as a continuous variable was associated to RCB 0-I only in the CT arm (OR 0.954; 95%CI 0.922-0.988, P=0.006), with an interaction P=0.05. Ki67 suppression was higher in let/abema arm, with a lower median Ki67 at 2w: let/abema 0% vs. CT 21.7% ( P&lt;0.0001), but not at surgery: let/abema 0% vs. CT 2.25% ( P=0.157). In addition, rates of Ki67 &lt;2.7% were higher with let/abema compared to CT at 2w (68% vs. 6%, P&lt;0.0001), but not at surgery (53% vs. 45%, P=0.157). Moreover, 17% of patients in the let/abema arm shifted from 2w Ki67&lt;2.7% to surgery Ki67≥2.7%, while only 2% did so with CT ( P&lt;0.0001). Median RS at surgery was higher in let/abema arm (22 vs. 19 in CT, P=0.028), and CT induced higher downstaging from BL high (&gt;25) to low (≤25) RS at surgery (36% vs. let/abema 20%, P=0.024). Conclusions: Highly proliferative tumors Ki67 (≥40%) or those with high Recurrence Score (&gt;25) exhibited higher rates of RCB 0-I when treated with chemotherapy, than when treated with letrozole/abemaciclib. This suggests that relying solely on letrozole/abemaciclib as systemic treatment for these tumors may be insufficient. Clinical trial information: NCT04293393 . [Table: see text]

Effect of p16 immunohistochemical expression (exp) on irinotecan in metastatic colorectal cancer (mCRC): A translational analysis of the TRIBE and TRIBE2 studies.

3562 Background: CDKN2A encodes the inhibitor of the cyclin-dependent kinases p16 and is frequently methylated in colorectal cancer, thus reducing the exp levels of p16 protein. In pre-clinical models of colorectal cancer cells, the demethylation of CDKN2A gene induces topoisomerase I upregulation increasing the sensitivity to irinotecan. In metastatic colorectal cancer (mCRC) pts, the role of p16 expression has been poorly investigated. Methods: Tumour samples of pts randomized in the phase III TRIBE2 study comparing upfront FOLFOXIRI/bevacizumab (bev) versus (vs) FOLFOX/bev were assessed for p16 immunohistochemical exp. A validation analysis in patients treated with FOLFIRI/bev in the TRIBE study was conducted. Results: Out of 679 patients enrolled in the TRIBE2 study, 231 tumours were assessed for p16 exp. Overall, 152 (66%), and 79 (34%) were classified as positive (pos) (IHC 2+ and 3+) and negative (neg) (IHC 0 and 1+), respectively. In the p16 pos group, 69 (45%) and 83 (55%) pts received FOLFOXIRI/bev and FOLFOX/bev, respectively, while in the p16 neg cohort, FOLFOXIRI/bev was administered in 37 (47%) and FOLFOX/bev in 42 (53%) cases. Pts with p16 neg tumours had more frequently an ECOG-PS of 1-2 (16% vs 6%, p=0.0098) and a BRAF mut tumour (26% vs 7%, p=0.0002). No PFS difference was observed between p16 neg and pos patients, while a trend for a longer OS was shown in favour of p16 pos pts (25.5 vs 21.3 months; HR: 0.74, 95%CI: 0.53-1.02, p=0.068) that was not confirmed at the multivariate analysis (p=0.61). Among patients with p16 pos tumours, those treated with FOLFOXIRI/bev reported longer PFS (12.8 vs 9.4 months, HR: 0.55, 95%CI: 0.39-0.78, p=0.0008) and OS (30.0 vs 21.4 months, HR: 0.66, 95%CI: 0.46-0.95, p=0.026) than those receiving FOLFOX/bev. On the other hand, no significant difference was observed among p16 neg patients in terms of both PFS (9.0 vs 9.4 months, HR: 0.91, 95%CI: 0.57-1.46, p=0.69) and OS (21.3 vs 19.5 months, HR: 0.95, 95%CI: 0.58-1.57, p=0.85), thus suggesting a differential treatment effect according to p16 exp (pinteraction for PFS =0.12; pinteraction for OS =0.19). Among patients treated with FOLFIRI/bev in the TRIBE study (N=58) patients with p16 pos tumours reported longer PFS and OS than those with p16 neg. (HR for PFS: 0.45, 95%CI: 0.22-0.92, p=0.026; HR for OS: 0.41, 95%CI: 0.20-0.85, p=0.013). Conclusions: In mCRC, p16 pos exp seems associated with higher benefit from irinotecan. Prospective confirmation in independent randomized series is warranted.