Arms Reduction Research Articles

On the Brink: Reagan, Freeze, and the Nuclear Weapons Debate (1981-1984)

This article examines the nature of what motivated Reagan’s disarmament policy and what influence the Freeze movement had on it during his first term. It challenges the conventional view posited by scholars such as Lawrence S. Wittner and Angela Santese that early in his administration, Reagan was not interested in disarmament and that the Freeze movement, via public pressure and efforts in Congress, forced Reagan to soften his bellicose rhetoric and alter his approach to disarmament policy. By examining Freeze documents from the State Historical Society of Missouri (SHSMO), executive branch documents from the Reagan Library, and the State Department Office of the Historian, as well as pertinent memoirs, this article offers a more complex and nuanced analysis of what drove Reagan’s thinking during this crucial period in the Cold War. In contrast to Wittner and Santese, it asserts that Reagan genuinely sought nuclear arms reductions throughout his first term and that any tactical adaptation in his approach resulted from an evolution in his mindset toward the Soviets caused by the cumulative effect of the attempt on his life, relationship with Ambassador Dobrynin, the Pentecostalist case, and NATO’s Able Archer exercise, and was only tangentially related to the Freeze movement.

Digital Innovation to Grow Quality Care Through an Interprofessional Care Team (DIG IT) Among Underserved Patients With Hypertension.

The impact of digital health on medically underserved patients is unclear. This study aimed to determine the early impact of a digital innovation to grow quality care through an interprofessional care team (DIG IT) on the blood pressure (BP) and 10-year atherosclerotic cardiovascular disease (ASCVD) risk score of medically underserved patients. This was a 3-month, prospective intervention study that included patients aged 40 years or more with BP of 140/90 mmHg or higher who received care from DIG IT from August through December 2021. Sociodemographic and clinical outcomes of DIG IT were compared with historical controls (controls) whose data were randomly extracted by the University of California Data Warehouse and matched 1:1 based on age, ethnicity, and baseline BP of the DIG IT arm. Multiple linear regression was performed to adjust for potential confounding factors. A total of 140 patients (70 DIG IT, 70 controls) were included. Both arms were similar with an average age (SD) of 62.8 (9.7) years. The population was dominated by Latinx (79.3%) persons, with baseline mean BP of 163/81 mmHg, and mean ASCVD risk score of 23.9%. The mean (SD) reduction in systolic BP at 3 months in the DIG IT arm was twice that of the controls (30.8 [17.3] mmHg vs 15.2 [21.2] mmHg; P <.001). The mean (SD) ASCVD risk score reduction in the DIG IT arm was also twice that of the controls (6.4% [7.4%] vs 3.1% [5.1%]; P = .003). The DIG IT was more effective than controls (receiving usual care). Twofold improvement in the BP readings and ASCVD scores in medically underserved patients were achieved with DIG IT.

Internationalism, Isolationism, and Racism: What Woodrow Wilson Inherited from Thomas Jefferson in the 14 Points

Thomas Jefferson and Woodrow Wilson are influential American political figures who are famous for the succession and development of Jeffersonianism. Through Jeffersonian liberalism and textual analysis of the 14 Points by Woodrow Wilson, the paper finds that 14 Points expand American politics from domestic affairs to international political (covenants and open diplomacy), economic (freedom to navigate of all time), military (reduction of armaments), moral and cultural (national self-determinism all over the globe) issues, through the League of Nations as a way to isolate itself from European order and alliances. Besides, the colonies are excluded from independence despite some equal treatment. Expansionism, isolationism and racism are what Wilson inherited from Thomas Jefferson.

Switching to e-cigarettes as harm reduction among individuals with chronic disease who currently smoke: Results of a pilot randomized controlled trial.

E-cigarettes (ECs) may be an effective harm reduction strategy for individuals with conditions like chronic obstructive pulmonary disease (COPD), asthma, coronary artery disease (CAD), and peripheral arterial disease (PAD) who smoke combustible cigarettes (CCs). Our aim was to examine how individuals with chronic conditions transition from CCs to ECs and its impact on health outcomes. In a pilot randomized controlled trial (RCT), patients with COPD, asthma, CAD/PAD who currently smoke CCs and have not used nicotine replacement therapy (NRT) or ECs in the past 14 days were randomized to receive ECs or combination NRT with behavioral counselling. Disease symptoms, acceptability/satisfaction (TSQM-9) and feasibility, and cigarettes per day (CPD), and/or EC use were collected at baseline, 3-, and 6-months. Descriptive statistics and a linear regression were conducted to explore changes in CPD and chronic condition-specific assessments (CAT, SAQ-7, ACT) that assess COPD, asthma, and CAD/PAD symptom change. At 3-months, the EC group (n=63, mean CPD=9±11) reduced their CPD by 54% vs. 60% in the NRT group (n=58, mean CPD=7±6), p=0.56. At 6-months, 17.5% had switched completely to ECs while 23% quit smoking in the NRT arm. CAT scores showed a significant 6-point reduction in the EC arm (p=0.03). Participants scored an average of 69±27 for EC effectiveness, 87±23 for convenience, and 75±27 for overall satisfaction. This pilot study suggests that ECs may be a safer alternative for chronic condition patients using CCs and warrants further research on expected smoking cessation/reduction among individuals who use ECs. The findings from this pilot RCT hold significant implications with chronic conditions such as COPD, asthma, CAD and PAD who smoke CCs. The observed reduction in cigarettes per day and improvement in respiratory symptoms suggest that switching to ECs appears feasible and acceptable among those with chronic diseases. These results suggest that ECs may offer an alternative for individuals struggling to quit CC smoking through existing pharmacotherapies. This study supports further exploration of switching to ECs as a harm reduction strategy among CC users who have been unsuccessful at quitting by other means.

Development of a marker recyclable CRISPR/Cas9 system for scarless and multigene editing in Fusarium fujikuroi.

Iterative metabolic engineering of Fusarium fujikuroi has traditionally been hampered by its low homologous recombination efficiency and scarcity of genetic markers. Thus, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas9) system has emerged as a promising tool for precise genome editing in this organism. Some integrated CRISPR/Cas9 strategies have been used to engineer F. fujikuroi to improve GA3 production capabilities, but low editing efficiency and possible genomic instability became the major obstacle. Herein, we developed a marker recyclable CRISPR/Cas9 system for scarless and multigene editing in F. fujikuroi. This system, based on an autonomously replicating sequence, demonstrated the capability of a single plasmid harboring all editing components to achieve 100%, 75%, and 37.5% editing efficiency for single, double, and triple gene targets, respectively. Remarkably, even with a reduction in homologous arms to 50bp, we achieved a 12.5% gene editing efficiency. By employing this system, we successfully achieved multicopy integration of the truncated 3-hydroxy-3-methyl glutaryl coenzyme A reductase gene (tHMGR), leading to enhanced GA3 production. A key advantage of our plasmid-based gene editing approach was the ability to recycle selective markers through a simplified protoplast preparation and recovery process, which eliminated the need for additional genetic markers. These findings demonstrated that the single-plasmid CRISPR/Cas9 system enables rapid and precise multiple gene deletions/integrations, laying a solid foundation for future metabolic engineering efforts aimed at industrial GA3 production.

Enhancing poststroke hand movement recovery: Efficacy of RehabSwift, a personalized brain-computer interface system.

This study explores the efficacy of our novel and personalized brain-computer interface (BCI) therapy, in enhancing hand movement recovery among stroke survivors. Stroke often results in impaired motor function, posing significant challenges in daily activities and leading to considerable societal and economic burdens. Traditional physical and occupational therapies have shown limitations in facilitating satisfactory recovery for many patients. In response, our study investigates the potential of motor imagery-based BCIs (MI-BCIs) as an alternative intervention. In this study, MI-BCIs translate imagined hand movements into actions using a combination of scalp-recorded electrical brain activity and signal processing algorithms. Our prior research on MI-BCIs, which emphasizes the benefits of proprioceptive feedback over traditional visual feedback and the importance of customizing the delay between brain activation and passive hand movement, led to the development of RehabSwift therapy. In this study, we recruited 12 chronic-stage stroke survivors to assess the effectiveness of our solution. The primary outcome measure was the Fugl-Meyer upper extremity (FMA-UE) assessment, complemented by secondary measures including the action research arm test, reaction time, unilateral neglect, spasticity, grip and pinch strength, goal attainment scale, and FMA-UE sensation. Our findings indicate a remarkable improvement in hand movement and a clinically significant reduction in poststroke arm and hand impairment following 18 sessions of neurofeedback training. The effects persisted for at least 4 weeks posttreatment. These results underscore the potential of MI-BCIs, particularly our solution, as a prospective tool in stroke rehabilitation, offering a personalized and adaptable approach to neurofeedback training.

Post-exposure prophylaxis in leprosy (PEOPLE): a cluster randomised trial.

Post-exposure prophylaxis (PEP) using single-dose rifampicin reduces progression from infection with Mycobacterium leprae to leprosy disease. We compared effectiveness of different administration modalities, using a higher (20 mg/kg) dose of rifampicin-single double-dose rifampicin (SDDR)-PEP. We did a cluster randomised study in 16 villages in Madagascar and 48 villages in Comoros. Villages were randomly assigned to four study arms and inhabitants were screened once a year for leprosy, for 4 consecutive years. All permanent residents (no age restriction) were eligible to participate and all identified patients with leprosy were treated with multidrug therapy (SDDR-PEP was provided to asymptomatic contacts aged ≥2 years). Arm 1 was the comparator arm, in which no PEP was provided. In arm 2, SDDR-PEP was provided to household contacts of patients with leprosy, whereas arm 3 extended SDDR-PEP to anyone living within 100 m. In arm 4, SDDR-PEP was offered to household contacts and to anyone living within 100 m and testing positive to anti-phenolic glycolipid-I. The main outcome was the incidence rate ratio (IRR) of leprosy between the comparator arm and each of the intervention arms. We also assessed the individual protective effect of SDDR-PEP and explored spatial associations. This trial is registered with ClinicalTrials.gov, NCT03662022, and is completed. Between Jan 11, 2019, and Jan 16, 2023, we enrolled 109 436 individuals, of whom 95 762 had evaluable follow-up data. Our primary analysis showed a non-significant reduction in leprosy incidence in arm 2 (IRR 0·95), arm 3 (IRR 0·80), and arm 4 (IRR 0·58). After controlling for baseline prevalence, the reduction in arm 3 became stronger and significant (IRR 0·56, p=0·0030). At an individual level SDDR-PEP was also protective with an IRR of 0·55 (p=0·0050). Risk of leprosy was two to four times higher for those living within 75 m of an index patient at baseline. SDDR-PEP appears to protect against leprosy but less than anticipated. Strong spatial associations were observed within 75 m of index patients. Targeted door-to-door screening around index patients complemented by a blanket SDDR-PEP approach will probably have a substantial effect on transmission. European and Developing Countries Clinical Trials Partnership. For the French translation of the abstract see Supplementary Materials section.

ETHAN: A phase II study comparing different endocrine therapies for male breast cancer.

TPS632 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for male breast cancer. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across nine (9) sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy for the current breast cancer or any other malignancy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity component in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for three weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) versus tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) versus anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is four (4) months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha=10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: estradiol and testosterone levels at baseline, end of window, and during neoadjuvant phase; preoperative endocrine prognostic index (PEPI) score at surgery; adverse events; and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened to enrollment at Dana-Farber in October 2023, and additional sites will open in 2024. Clinical trial information: NCT05501704 .

Incidence of self-reported tuberculosis treatment with community-wide universal testing and treatment for HIV and tuberculosis screening in Zambia and South Africa: A planned analysis of the HPTN 071 (PopART) cluster-randomised trial.

HIV is a potent risk factor for tuberculosis (TB). Therefore, community-wide universal testing and treatment for HIV (UTT) could contribute to TB control, but evidence for this is limited. Community-wide TB screening can decrease population-level TB prevalence. Combining UTT with TB screening could therefore significantly impact TB control in sub-Saharan Africa, but to our knowledge there is no evidence for this combined approach. HPTN 071 (PopART) was a community-randomised trial conducted between November 2013 to July 2018; 21 Zambian and South African communities (with a total population of approximately 1 million individuals) were randomised to arms A (community-wide UTT and TB screening), B (community-wide universal HIV testing with treatment following national guidelines and TB screening), or C (standard-of-care). In a cohort of randomly selected adults (18 to 44 years) enrolled between 2013 and 2015 from all 21 communities (total size 38,474; 27,139 [71%] female; 8,004 [21%] HIV positive) and followed-up annually for 36 months to measure the population-level impact of the interventions, data on self-reported TB treatment in the previous 12 months (self-reported TB) were collected by trained research assistants and recorded using a structured questionnaire at each study visit. In this prespecified analysis of the trial, self-reported TB incidence rates were measured by calendar year between 2014 and 2017/2018. A p-value ≤0.05 on hypothesis testing was defined as reaching statistical significance. Between January 2014 and July 2018, 38,287 individuals were followed-up: 494 self-reported TB during 104,877 person-years. Overall incidence rates were similar across all arms in 2014 and 2015 (0.33 to 0.46/100 person-years). In 2016 incidence rates were lower in arm A compared to C overall (adjusted rate ratio [aRR] 0.48 [95% confidence interval (95% CI) 0.28 to 0.81; p = 0.01]), with statistical significance reached. In 2017/2018, while incidence rates were lower in arm A compared to C, statistical significance was not reached (aRR 0.58 [95% CI 0.27 to 1.22; p = 0.13]). Among people living with HIV (PLHIV) incidence rates were lower in arm A compared to C in 2016 (RR 0.56 [95% CI 0.29 to 1.08; p = 0.08]) and 2017/2018 (RR 0.50 [95% CI 0.26 to 0.95; p = 0.04]); statistical significance was only reached in 2017/2018. Incidence rates in arms B and C were similar, overall and among PLHIV. Among HIV-negative individuals, there were too few events for cross-arm comparisons. Study limitations include the use of self-report which may have been subject to under-reporting, limited covariate adjustment due to the small number of events, and high losses to follow-up over time. In this study, community-wide UTT and TB screening resulted in substantially lower TB incidence among PLHIV at population-level, compared to standard-of-care, with statistical significance reached in the final study year. There was also some evidence this translated to a decrease in self-reported TB incidence overall in the population. Reduction in arm A but not B suggests UTT drove the observed effect. Our data support the role of UTT in TB control, in addition to HIV control, in high TB/HIV burden settings. ClinicalTrials.gov: NCT01900977.

Clinical study of a micro-implantable pulse generator for the treatment of peripheral neuropathic pain: 3-month and 6-month results from the COMFORT-randomised controlled trial

BackgroundWe report the results from the first large, postmarket, multicentre, randomised controlled trial (RCT) evaluating peripheral nerve stimulation (PNS) for the treatment of chronic peripheral pain with a micro-implantable pulse...

Results of a study examining the use of onabotulinumtoxinA in pediatric patients with overactive bladder

There is a lack of approved treatments for pediatric patients with overactive bladder (OAB) with inadequate response to anticholinergic therapy. OnabotulinumtoxinA 100U is approved to treat OAB in adults based on data from randomized, pivotal trials. To investigate the efficacy and safety of onabotulinumtoxinA treatment of OAB in children aged 12-17 years who were not adequately managed with anticholinergics. In this multinational, multicenter, randomized, double-blind, parallel-group, multiple-dose study (NCT02097121), pediatric patients with OAB were randomized 1:1:1 to receive onabotulinumtoxinA 25U, 50U, or 100U (≤6U/kg). Patients could request retreatment starting at week 12. The primary endpoint was change from baseline to week 12 after treatment 1 in daily frequency of daytime urinary incontinence (UI) episodes. Safety assessments evaluated treatment-emergent adverse events (TEAEs). Of 68 screened patients, 55 received ≥1 treatment. Mean age was 14 years; 85.5% of patients were female. At week 12 after treatment 1, least squares mean change from baseline in daily frequency of daytime UI episodes showed a numerically greater reduction in the 100U arm (-2.4) versus the 25U arm (-1.4; P=0.38), with a significant within-group change from baseline in the 100U arm (P=0.0027). Achievement of treatment response was significantly greater with onabotulinumtoxinA 100U vs 25U (Figure). Median time to request retreatment was ≥16 weeks in all groups. The most frequently reported TEAEs were nasopharyngitis (10.9%) and urinary tract infection (UTI; 10.9%). Urinary retention was observed in 1 patient during treatment cycle 2; there were no serious TEAEs of UTI or urinary retention. Throughout 2 additional treatment cycles continued efficacy for the 100U dose arm was observed along with a consistent safety profile. Change in daily frequency of UI episodes at week 12 in treatment cycle 1 was not significantly different between arms. However, ≥50% response rate was significantly higher with onabotulinumtoxinA 100U versus 25U. Enrollment challenges that lowered the sample size could have reduced statistical power. Also, the lack of a placebo arm and the observed benefit with the 25U comparator limited interpretation. OnabotulinumtoxinA injections were well tolerated in children with OAB at all doses studied. Although the primary endpoint was not met, the significantly greater treatment response rate observed with onabotulinumtoxinA 100U versus 25U suggests additional benefit of the higher dose, without additional safety concerns.

Left Atrial Improvement in Patients With Secondary Mitral Regurgitation and Heart Failure: The COAPT Trial

BackgroundFunctional mitral regurgitation induces adverse effects on the left ventricle and the left atrium. Left atrial (LA) dilatation and reduced LA strain are associated with poor outcomes in heart failure (HF). Transcatheter edge-to-edge repair (TEER) of the mitral valve reduces heart failure hospitalization (HFH) and all-cause death in selected HF patients. ObjectivesThe aim of this study was to evaluate the impact of LA strain improvement 6 months after TEER on the outcomes of patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. MethodsThe difference in LA strain between baseline and the 6-month follow-up was calculated. Patients with at least a 15% improvement in LA strain were labeled as “LA strain improvers.” All-cause death and HFH were assessed between the 6- and 24-month follow-up. ResultsAmong 347 patients (mean age 71 ± 12 years, 63% male), 106 (30.5%) showed improvement of LA strain at the 6-month follow-up (64 [60.4%] from the TEER + guideline-directed medical therapy [GDMT] group and 42 [39.6%] from the GDMT alone group). An improvement in LA strain was significantly associated with a reduction in the composite of death or HFH between the 6-month and 24-month follow-up, with a similar risk reduction in both treatment arms (Pinteraction = 0.27). In multivariable analyses, LA strain improvement remained independently associated with a lower risk of the primary composite endpoint both as a continuous variable (adjusted HR: 0.94 [95% CI: 0.89-1.00]; P = 0.03) and as a dichotomous variable (adjusted HR: 0.49 [95% CI: 0.27-0.89]; P = 0.02). The best outcomes were observed in patients treated with TEER in whom LA strain improved. ConclusionsIn symptomatic HF patients with severe mitral regurgitation, improved LA strain at the 6-month follow-up is associated with subsequently lower rates of the composite endpoint of all-cause mortality or HFH, both after TEER and GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079)

P505 Accelerating Crohn's Disease clinical trials using generative artificial intelligence

Abstract Background At Unlearn.AI, we expedite decision making and address challenges of lengthy and costly Crohn’s Disease (CD) trial enrollment by introducing deep learning models that create digital twins of trial participants, which are comprehensive forecasts of health outcomes. These generative predictions are incorporated into standard linear and logistic regression analyses, in addition to more advanced methods, in clinical trials. Our TwinRCT technology, which aligns with regulatory guidance, augments standard RCTs for easy integration into clinical programs. We demonstrate the expected benefit of these solutions in a subset of IBD Plexus data that were not previously involved in the training of the generative model, showcasing its potential to transform future CD trials. Methods We developed a generative deep learning model using data from approximately 4,500 Inflammatory Bowel Disorder (IBD) participants in observational studies and randomized controlled trial (RCT) control arms from the IBD Plexus program of the Crohn’s &amp; Colitis Foundation. The trained model was used to forecast, entirely from each participant’s baseline data, the control outcomes of participants in a held out set of 300 participants. The resultant forecasts, or digital twins, represent comprehensive longitudinal trajectories across a range of outcomes, laboratory measures, and vital signs. We evaluated the expected benefits of incorporating the digital twins in linear and logistic regression models, analyzing the change from baseline to follow-up (Weeks 12 through 52) on sCDAI total score, change in daily bowel movement count, change in abdominal pain score and proportion of patients achieving clinical remission (sCDAI &amp;lt; 150; sCDAI is very closely related to CDAI). Results Digital twins provided substantial attainable benefit across outcomes and time points, enabling up to 21% overall sample size reduction or 34% reduction in the control arm only. Conclusion TwinRCTs offer a strategic enhancement to traditional RCTs by minimizing the required sample size needed to identify significant treatment effects. Aligning with existing FDA and EMA guidelines, TwinRCTs can be effectively utilized in Phase 2 and Phase 3 CD studies for faster decision making, as well as reduced timelines and costs, without increasing regulatory risk over standard approaches.

Thoracic radiation in combination with erlotinib-results from a phase 2 randomized trial.

Radiotherapy (RT) can be used to reduce symptoms and maintain open airways for patients with non-small cell lung cancer when systemic treatment is not sufficient. For some patients, tumor control is not achieved due to radioresistance. Concurrent inhibition of epidermal growth factor receptors has been proposed as a strategy to overcome radioresistance but may increase toxicity. We performed a randomized trial to assess the efficacy, tolerance, and quality of life of concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer. Patients were randomized 1:1 to RT alone (arm A) or in combination with erlotinib (arm B). A computed tomography (CT) scan at baseline and one at 4-12 weeks after inclusion was used to evaluate treatment response. Adverse events were registered during treatment and the subsequent 30 days. Health-related quality-of-life questionnaires were completed by the patients at baseline, weeks 2, 6, and 20. A total of 114 patients were included. Of the 74 patients with CT scans available for evaluation of treatment effect, there were no significant differences in tumor size reduction between the two groups: median 14.5% reduction in the control arm A and 17.0% in the erlotinib arm B (p = 0.68). Overall survival was not significantly different between the two treatment arms: 7.0 and 7.8 months in arm A and arm B, respectively (log-rank p = 0.32). There was no significant increase in adverse events in the experimental arm, other than what is expected from erlotinib treatment alone. Overall, patients reported similar quality of life in both treatment arms. Concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer was well tolerated but did not improve the efficacy of the RT. ClinicalTrials.gov, identifier NCT02714530.

A Meta-Analysis of the Antidepressant Responses in Pivotal Trials on Esketamine Nasal Spray and Atypical Antipsychotics.

This meta-analysis assessed whether atypical antipsychotics (AAPs) and esketamine nasal spray (ESK-NS), which are mechanistically distinct, differ in antidepressant outcomes. Data were extracted from 12 trials of ESK-NS or AAPs in depressed patients (4276) with inadequate response or resistance to conventional antidepressants. Montgomery-Åsberg Depression Rating Scale (MADRS) score reductions from baseline and response rates (≥50% reduction) were analyzed. At endpoint, the estimated MADRS score reduction of pooled ESK-NS arms was greater than pooled AAP arms (+9.16 points, p < 0.0001). The reduction also was greater in the pooled control arms of the ESK-NS trials than the pooled control arms of the AAP trials (+7.57 points, p < 0.0001). The mean difference in the reductions between pooled ESK-NS and control arms was 1.87 points greater than that between pooled AAP and control arms, but this difference was not significant (95% CI: -4.49, 0.74, p = 0.16). Relative to their respective control arms, the mean difference in response rates was 25% for the pooled ESK-NS and 9% for the pooled AAP arms; the mean response rate was 16% greater in the pooled ESK-NS studies than the pooled AAP studies (p = 0.0004). Comparisons against specific AAPs showed mean differences in the MADRS score reductions at 1 week between the experimental and control arms that were numerically larger in the ESK-NS trials than in the aripiprazole trials (mean difference of 1.71 points, p = 0.06) and the brexpiprazole trials (mean difference of 2.05 points, p = 0.02). The ESK-NS arms showed numerically larger MADRS score reductions at week-1 and endpoint, and a significantly larger response rate compared with AAP arms. Prospective studies involving direct comparisons are warranted to compare the relative efficacy between these treatment regimens.

Lost in Broadcasting: League of Nations, International Broadcasting and Swiss Neutrality

The article delves into the historical context of cross-border radio broadcasting during the 1930s by the League of Nations (LN) and the significant impact of Switzerland's neutrality as the host country on this international organization. Drawing from the recently digitized and accessible LN archive in Geneva, this narrative unveils a minor conflict of interest that evolved into a notable political crisis, marking an international legal precedent by showcasing the influence wielded by a smaller host nation upon a global organization. The architects of the League of Nations envisioned Geneva as an ideal hub for the organization's activities, complete with modern communication technologies for global outreach. However, Switzerland's neutral stance posed an obstacle to the establishment of the League's radio broadcasting infrastructure. Recognizing the absence of robust emergency communications, transport links, and the absence of a dedicated radio station in Geneva during the mid-1920s, the LN sought an agreement with the Radio-Swiss station. Consequently, the LN's own radio station, Radio-Nations, commenced broadcasting on February 2, 1932, coinciding with the start of the Conference on the Reduction and Limitation of Arms. By May 1938, amidst mounting tensions in Europe, Switzerland chose to assert complete neutrality within the League. Discussions within the Federal Council revolved around the possibility of suspending the agreement made on May 21, 1930, along with the support for Radio-Nations. Unexpectedly, on November 3, 1938, the LN leadership in Geneva expressed a desire to re-evaluate the 1930 convention. The outbreak of World War II drastically reshaped the relationship between the LN and Radio-Nations. Switzerland decided against entering into a new agreement with the LN, leading to the closure of Radio-Nations on February 2, 1942. Maintaining the nation's neutrality, the Swiss government vigilantly observed the unfolding events during the war. During the peak of Nazi Germany's advances, Bern adopted stringent measures against the LN, upholding a resolute diplomatic stance. However, the Swiss stance toward the LN and the division of Radio-Nations’ ownership gradually shifted from 1943, culminating in the resolution of several financial matters. Ultimately, in 1947, the LN's liquidation commission transferred the remaining assets of Radio-Nations and its radio waves to the United Nations.

Health-related quality of life trajectories in critical illness: Protocol for a Monte Carlo simulation study.

Health-related quality of life (HRQoL) is a patient-centred outcome increasingly used as a secondary outcome in critical care research. It may cover several important dimensions of clinical status in intensive care unit (ICU) patients that arguably elude other more easily quantified outcomes such as mortality. Poor associations with harder outcomes, conflicting data on HRQoL in critically ill compared to the background population, and paradoxical effects on HRQoL and mortality complicate the current operationalisation in critical care trials. This protocol outlines a simulation study that will gauge if the areas under the HRQoL trajectories could be a viable alternative. We will gauge the behaviour of the proposed HRQoL operationalisation through Monte Carlo simulations, under clinical scenarios that reflect a broad critical care population eligible for inclusion in a large pragmatic trial. We will simulate 15,360 clinical scenarios based on a full factorial design with the following seven simulation parameters: number of patients per arm, relative mortality reduction in the interventional arm, acceleration of HRQoL improvement in the interventional arm, the relative improvement in final HRQoL in the interventional arm, dampening effect of mortality on HRQoL values at discharge from the ICU, proportion of so-called mortality benefiters in the interventional arm and mortality trajectory shape. For each clinical scenario, we will simulate 100,000 two-arm trials with 1:1 randomisation. HRQoL will be sampled fortnightly after ICU discharge. Outcomes will include HRQoL in survivors and all patients at the end of follow-up; mean areas under the HRQoL trajectories in both arms; and mean difference between areas under the HRQoL trajectories and single-sampled HRQoLs at the end of follow-up. In the outlined simulation study, we aim to assess whether the area under the HRQoL trajectory curve could be a candidate for reconciling the seemingly paradoxical effects on improved mortality and reduced HRQoL while remaining sensitive to early or accelerated improvement in patient outcomes. The resultant insights will inform subsequent methodological work on prudent collection and statistical analysis of such data from real critically ill patients.

Changes in Left Ventricular Global Longitudinal Strain in Patients With Heart Failure and Secondary Mitral Regurgitation: The COAPT Trial.

Background Left ventricular (LV) global longitudinal strain (GLS) provides incremental prognostic information over LV ejection fraction in patients with heart failure (HF) and secondary mitral regurgitation. We examined the prognostic impact of LV GLS improvement in this population. Methods and Results The COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial randomized symptomatic patients with HF with severe (3+/4+) mitral regurgitation to transcatheter edge-to-edge repair with the MitraClip device plus maximally tolerated guideline-directed medical therapy (GDMT) versus GDMT alone. LV GLS was measured at baseline and 6-month follow-up. The relationship between the improvement in LV GLS from baseline to 6 months and the composite of all-cause death or HF hospitalization between 6- and 24-month follow-up were assessed. Among 383 patients, 174 (45.4%) had improved LV GLS at 6-month follow-up (83/195 [42.6%] with transcatheter edge-to-edge repair+GDMT and 91/188 [48.4%] with GDMT alone; P=0.25). Improvement in LV GLS was strongly associated with reduced death or HF hospitalization between 6 and 24 months (P<0.009), with similar risk reduction in both treatment arms (Pinteraction=0.40). By multivariable analysis, LV GLS improvement at 6 months was independently associated with a lower risk of death or HF hospitalization (hazard ratio [HR], 0.55 [95% CI, 0.36-0.83]; P=0.009), death (HR, 0.48 [95% CI, 0.29-0.81]; P=0.006), and HF hospitalization (HR, 0.50 [95% CI, 0.31-0.81]; P=0.005) between 6 and 24 months. Conclusions Among patients with HF and severe mitral regurgitation in the COAPT trial, improvement in LV GLS at 6-month follow-up was associated with improved outcomes after both transcatheter edge-to-edge repair and GDMT alone between 6 and 24 months. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01626079.

The influence of professional identity on perceptions of substance use harm reduction among professional counselors

AbstractHarm reduction (HR) approaches to substance use show promising efficacy, but limited research exists exploring professional counselors’ perceptions of HR. An online survey gathered data from 395 substance use providers, including 128 professional counselors. In measuring HR acceptance, t‐tests compared this sample to prior samples, an analysis of variance compared counselors to other providers, and multiple regression explored the influence of counselor identity factors. Empathic responsiveness and positive social justice attitudes were predictors of HR acceptance. Counselors’ perceptions of HR were similar to other providers. Results indicated that counselor identity influences HR perceptions, with implications for practice and training considered.

Metformin Immediate and Extended-Release Adverse Events and Effects on Metabolic Parameters: A Meta-Analysis

Metformin is the first-line antidiabetic medication, and face-to-face comparisons between immediate-release and extended-release are scarce. The current meta-analysis aimed to compare metformin's immediate and extended-release effects on glycemic control, adverse events, and lipid profile. We searched PubMed, Cochrane Library, and the first 100 articles in Google Scholar from inception until September 2022. Studies were eligible if they were randomized controlled trials and compared metformin's immediate and extended-release effects on glycemic control, adverse events, and lipid profile. The keywords used were metformin immediate-release, extended-release, glycated hemoglobin, HbA1c, high-density lipoproteins, low-density lipoproteins triglycerides, total cholesterol, adverse effects, and side effects. The retrieved data were exported to an Excel sheet detailing the authors' names, the country of origin of the study, the number of patients and control subjects, and the total number of events in the interventional and control groups. No significant statistical difference was found between metformin immediate-release and metformin extended-release regarding the reduction of HbA1c, overall adverse effects, low-density lipoproteins, and high-density lipoproteins; odd ratio, 0.08, 95% CI, -0.14-0.29; 1.34, 95% CI, 0.86-2.08; -0.03, 95% CI, -0.22-0.17; and -0.26, 95% CI, -1.32-0.80 respectively. Metformin immediate-released reduced total cholesterol better than the extended-release; odd ratio, -2.35, 95% CI, -2.57-2.12. However, a paradox was observed regarding triglycerides (increment on extended-release and reduction with extended-release); odd ratio, -0.36, 95% CI, -0.44-0.28. No significant differences were found between the two formulations except for a better triglyceride reduction and total cholesterol in the immediate-release arm. Keywords: , , , ,