Control Arm Research Articles

Exploring the effect of exercise training on breast cancer's pathologic response and tumor immune microenvironment after neoadjuvant chemotherapy.

Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) and the percentage of tumor-infiltrating lymphocytes (TILs) are established prognostic biomarkers in early breast cancer (BC). While exercise training is effective as supportive care throughout the BC journey, its impact on the efficacy of NAC is unknown. This study aims to investigate the influence of a supervised exercise training program (SETP) on pCR and TILs in BC women undergoing NAC. Retrospective exploratory analysis of the subgroup of BC patients treated with NAC included in a clinical trial randomizing to STEP and control arm. Endpoints were pCR, biopsy, and stromal TILs. Sixty-four participants were included, with a mean age of 50.3 ± 10.1years, predominantly stage II and III disease (n = 58, 90.6%), HER2 + (n = 23, 35.9%), or triple-negative (n = 19, 29.7%) tumors. pCR was achieved in 56.7% and 55.9% in the STEP and control arm (p = 0.950). In the STEP arm, median TILs were 5.0 (0.0-80.0) and 5.0 (5.0-30.0), while in the control arm, 5.0 (0.0-90.0) and 0.0 (0.0-30.0) for biopsy and tumor site, respectively. The difference in TILs between arms was 0.04 (confidence interval (CI 95%) - 13.6, 13.7; p = 0.995) and - 4.3 (CI 95% - 11.5, 2.9; (p = 0.233) for biopsy and tumor site, respectively. No statistically significant difference was discerned between the groups concerning TILs of the biopsy. However, a marginally higher TIL level at the tumor site was associated with the SETP arm. No differences were discerned within and between groups on both pCR and TILs, in possible relation to the exploratory nature of the analysis. Future adequately powered research is warranted.

Safety of single-dose bedaquiline combined with rifampicin for leprosy post-exposure prophylaxis: A Phase 2 randomized non-inferiority trial in the Comoros Islands.

To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. ClinicalTrials.gov NCT05406479.

Effectiveness of Home-Based Self-monitoring of Blood Pressure in a Primary Care set-up of India (EASE-BP): Protocol for an Open-Label Randomized Controlled Trial.

Rising hypertension from inadequate detection, noncompliance with treatment, and poor control presents a major public health challenge. Previously, adopting the strategy of self-monitoring of blood pressure (SMBP) showed better hypertension detection, control, and medication adherence. However, evidence from India is scarce. Here, we present the trial protocol for the effectiveness of SMBP intervention in hypertension detection, blood pressure (BP) control, and medication adherence in a primary care set-up. EASE-BP is an open-label randomized trial in two distinct adult populations - part-A self-reported non-hypertensive population (total sample size: 400) and part-B known hypertensive population (total sample size: 332). The two populations will be sampled from two separate villages under the Ballabgarh Health and Demographic Surveillance System. In both the populations, participants randomized in the intervention arm will receive a validated electronic BP device and will be advised to self-monitor BP for at least twice a month (or more). Those in the control arm will be advised to monitor BP for at least twice a month (or more) at the nearby health center. Participants in both arms will receive education on hypertension and atherosclerotic disease. In addition, adult family members in the households of randomized participants will be encouraged to monitor their BP. All participants and family members will be instructed to maintain a log of BP recordings in a diary that will be provided to them. Data will be collected at baseline and then every month for three-months. The primary outcome in part-A will be the incidence of new cases of hypertension during 3 months follow-up and in part-B will be the difference in SBP and rate of medication adherence at 3 months follow-up. Secondary outcomes will include (1) uptake of the intervention, (2) any stroke, myocardial infarction, or death, (3) additional yield of new cases of hypertension among the family members, and (4) integrating the intervention into the national programs for long-term noncommunicable disease goals. EASE-BP will help understand if SMBP improves hypertension detection, BP control, and medication adherence. Consequently, this will appraise policymakers on whether provision of BP instruments may be added to the national program for hypertension prevention and control. This trial was registered under Clinical Trial Registry - India with reference number CTRI/2023/02/049949.

Natural history of otitis media with effusion without hearing loss in children under 12 years: a systematic review

ObjectiveThis study aimed to evaluate the natural history of otitis media with effusion (OME) without hearing loss in children under 12 years.MethodsWe performed a systematic search in Embase, CINAHL, MEDLINE,...

Effect of Probiotics Supplementation on Cortisol Levels: A Systematic Review and Meta-Analysis.

Background: Several randomized controlled trials (RCTs) have shown conflicting results on cortisol levels following probiotic administration in healthy and diseased populations. Previous analyses were inconclusive due to limited studies, and evidence is lacking on how these effects vary by health status; region; therapy duration; medications, and use of single or multiple strains. Methods: In this systematic review and meta-analysis (PROSPERO [CRD42024538539]), we searched PubMed, Cochrane Library, Embase, Scopus, Web of Science, CINAHL, ProQuest, and Web of Science Preprints until 13 August 2024, for RCTs on probiotic administration, either alone or combined, across all age groups and without specific medical condition requirements. We applied random-effects meta-analysis, assessed bias using the Cochrane RoB 2 tool, and evaluated evidence certainty with GRADE. Findings: We screened 1739 records and retrieved 46 RCTs (3516 participants). Probiotics supplementation decreased cortisol levels compared to the control arm [46 RCTs; SMD: -0.45; 95% CI: -0.83; -0.07; I2: 92.5%, low certainty]. Among various subgroups; probiotics supplementation decreased the cortisol levels in the subgroups without concomitant medications [37 RCTs; SMD: -0.30; 95% CI [-0.58; -0.03], I2: 88.7%] with a single probiotic strain [30 RCTs; SMD: -0.33; 95% CI: -0.63; -0.028; I2: 88.8%], in a healthy population [35 RCTs; SMD:-0.3; 95% CI: -0.58; -0.03; I2: 88.7] and in the Asia region [21 RCTs; SMD: -0.83; 95% CI: -1.58; -0.07; I2: 95%]. Interpretation: A low level of evidence suggests probiotics might reduce cortisol levels, but more targeted studies are needed to identify variables affecting the response in specific subgroups.

Australia’s bipolar approach to nuclear disarmament

ABSTRACT Australia is a strong supporter of global nuclear (and conventional) arms control and non-proliferation measures and has contributed significantly to their development; but it sees the world, strategically, through the eyes of a nuclear weapon state which, it believes, applies its nuclear deterrence doctrine also to the defence of Australia. It is thus effectively locked into what is essentially a nuclear weapon state’s view of the future that pays lip-service to nuclear disarmament as a distant ideal. Australian defence strategists routinely emphasise the importance of the US nuclear guarantee. Australia is though only likely to be attacked with nuclear weapons in the event of a nuclear war in which the United States is already engaged. The concept of extended nuclear deterrence thus assumes an essentially circular character by purporting to protect Australia from the nuclear threat that Australia’s alliance with its provider invites. Meanwhile, Australia is one of the few countries in its own region that have yet to sign the Treaty on the Prohibition of Nuclear Weapons (TPNW). This paper argues that—US hostility to the Treaty notwithstanding—Australian membership of the TPNW would be consistent with its generally positive disarmament record and compatible with its alliance commitments.

Reverse Selection Designs for Accommodating Multiple Control Arms.

Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual - yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.

A constitutional perspective on EU arms controls: mediating trade, security, and humanitarian responsibility

Abstract This article examines how European Union (EU) arms control measures are tailored to its constitutional foundations. EU Member States subject shipments of arms and components to controls so as to screen them for risks and potentially block them. In this context different Member States may make different geopolitical and humanitarian risk assessments. Existing EU measures have achieved only limited security screening harmonisation, and have left room for Member States to shirk their obligations under international humanitarian law. But in case of joint arms production, which the EU subsidises to become more autonomous, one Member State’s arms controls may block another State’s exports and thereby jeopardise cooperation. This article posits that any reform of EU arms controls should start by re-evaluating their present legal basis. A constitutional competence analysis shows that controls on arms shipments to non-EU states should be regulated in part through the Common Commercial Policy (CCP), and not just through the Common Foreign and Security Policy (CFSP). This would be consistent with other EU regulatory regimes for trade security. While a joint CFSP-CCP approach cannot fully prevent conflict, since this would require further foreign policy harmonisation, it could help foster security convergence and strengthen humanitarian due diligence mechanisms.

A hand-washing community-based educational intervention to reduce abscess incidence among people who inject drugs: a cluster randomised controlled clinical trial protocol (the HAWA study protocol)

BackgroundBesides the high prevalence of HIV and HCV infections, people who inject drugs (PWID) have a cumulative risk of acquiring skin and soft tissue infections (SSTI) from, among other things, social precariousness, homelessness/unstable housing, and unhygienic injecting practices. We propose to evaluate whether a two-component educational hand hygiene intervention which combines training in hand-washing with the supply of a single-use alcohol-based hand rub, called MONO-RUB, is effective in reducing injection-related abscesses in the PWID population. Specifically, we shall implement a nationwide, two-arm, multi-centre, cluster randomised controlled trial to evaluate the effectiveness and cost-effectiveness of this intervention in PWID.MethodsHAWA is a community-based participatory research study to be conducted in 22 harm reduction centres (HR) in France (not yet recruiting); the latter will be randomised into two clusters: centres providing standard HR services and the intervention (i.e., intervention group) and those providing standard HR services only (i.e., control group). After randomization, each cluster will include 220 PWID, with an inclusion period of 12 months and an individual follow-up period of 6 months. For each participant, we will collect data at M0, M3 and M6 from photos of injection sites on the participant’s body, a face-to-face injection-related SSTI questionnaire, and a CATI questionnaire. The primary outcome is the reduction in abscess prevalence between M0 and M6, which will be compared between the control and intervention arms, and measured from observed (photographs) and self-declared (SSTI questionnaire) data. We will also assess the cost-effectiveness of the intervention.DiscussionThe HAWA trial will be the first cluster randomized controlled trial to improve hand hygiene among PWID with a view to reducing SSTI. If effective and cost-effective, the intervention combined with the distribution of MONO-RUBs (or a similar cleaning product) may prove to be an important HR tool, helping to reduce the enormous burden of infection-related deaths and diseases in PWID.Trial RegistrationNCT06131788, received on 2 January 2024.

A Remote Behaviorally Designed Intervention to Promote Physical Activity in Patients With Knee Osteoarthritis: Results of a Pilot Randomized Clinical Trial.

We evaluated a behaviorally designed intervention utilizing gamification and social support to improve physical activity and reduce symptoms in patients with osteoarthritis of the knee (KOA). Veterans with KOA, aged 40-80 years, were enrolled in this randomized controlled trial. Participants received a Fitbit and completed a 2- to 4-week baseline period. A Web-based platform administered biweekly surveys after randomization and tracked physical activity. Participants selected a daily step goal that was 33%, 40%, or 50% above their baseline. The intervention arm received game playing aspects and a social support partner to advance weekly step performance while the control arm only received weekly updates. The primary outcome was the change in steps per day averaged over 2-week intervals. We used mixed effects regression, adjusting for baseline step count. Secondary outcomes assessed the change in KOOS (Knee Injury and Osteoarthritis Outcome Score) over 32 weeks. Thirty-one participants were included in the final analysis. Most participants were male (90.3%), Black (70.96%), had a mean (SD) age of 60 (13) years, and body mass index of 33.7 (5.9) kg/m2. Participants that received the intervention walked a total of 1119 (95% confidence interval: -562, 2799) more steps per day (p = 0.19). The effect was greatest in the first 6 months (1491 [-272, 3254], p = 0.10). Compared with controls, those that received the intervention had improvement over time in total KOOS (mean 2-week change +0.62 [0.031, 1.20] vs -0.38 [-1.04, 0.28], p = 0.02) and several subscales. This intervention demonstrated promise for promoting greater physical activity and improving symptoms in patients with KOA.

A French-Language Web-Based Intervention Targeting Prolonged Grief Symptoms in People Who Are Bereaved and Separated: Randomized Controlled Trial.

Losing a loved one, through death or separation, counts among the most stressful life events and is detrimental to health and well-being. About 15% of people show clinically significant difficulties coping with such an event. Web-based interventions (WBIs) are effective for a variety of mental health disorders, including prolonged grief. However, no validated WBI is available in French for treating prolonged grief symptoms. This study aimed to compare the efficacy and adherence rates of 2 WBIs for prolonged grief symptoms following the loss of a loved one through death or romantic separation. LIVIA 2.0 was developed relying on theoretical and empirical findings on bereavement processes and WBIs, and is compared with LIVIA 1, which has already demonstrated its efficacy. We conducted a randomized controlled trial and provided on-demand guidance to participants. Outcomes were assessed through web-based questionnaires before the intervention, after the intervention (12 weeks later), and at follow-up (24 weeks later). Primary outcomes were grief symptoms, depressive symptoms, and well-being. Secondary outcomes were anxiety symptoms, grief coping strategies, aspects related to self-identity, and program satisfaction. In total, 62 participants were randomized (intent-to-treat [ITT] sample), 29 (47%) in LIVIA 2.0 (active arm) and 33 (53%) in LIVIA 1 (control arm). The dropout rate was 40% (37/62), and 10 participants were removed due to exclusion criteria, leading to a final per-protocol sample of 27 (44%) completers who differed from noncompleters only based on reporting fewer anxiety symptoms (t60=3.03; P=.004). Participants who are separated reported more grief symptoms (t60=2.22; P=.03) and attachment anxiety (t60=2.26; P=.03), compared to participants who are bereaved. There were pre-post within-group differences for both programs in the ITT sample, with significant reductions in grief (Cohen d=-0.90), depressive symptoms (Cohen d=-0.31), and centrality of the loss (Cohen d=-0.45). The same pattern was observed in the per-protocol sample, with the exception that anxiety symptoms also significantly diminished (Cohen d=-0.45). No difference was found in efficacy between the 2 programs (all P>.33). Participants (ITT sample) reported overall high levels of program satisfaction (mean 3.18, SD 0.54; over a maximum of 4). Effect stability was confirmed at the 6-month follow-up for all outcomes, with an improvement in self-concept clarity. The 2 grief-related WBIs were effective in reducing grief, depressive and anxiety symptoms for participants who are bereaved or separated. The analyses did not reveal any pre-post between-group differences, suggesting that the innovations brought to LIVIA 2.0 did not significantly affect the outcome. However, caution is warranted with the interpretation of the results given the limited power of the sample, which only allows the detection of medium effect sizes. ClinicalTrials.gov NCT05219760; https://clinicaltrials.gov/study/NCT05219760. RR2-10.2196/39026.

Pragmatic randomised trial assessing the impact of peer comparison and therapeutic recommendations, including repetition, on antibiotic prescribing patterns of family physicians across British Columbia for uncomplicated lower urinary tract infections

ObjectiveTo evaluate the impact of a personalised audit and feedback prescribing report (AF) and brief educational summary (ES) on empiric treatment of uncomplicated lower urinary tract infections (UTIs) by family...

Early Effects of the End-Stage Renal Disease Treatment Choices Model on Kidney Transplant Waitlist Additions.

Despite the mortality benefit of kidney transplantation over dialysis, only 13% of patients with end-stage kidney disease are on the transplant waitlist. Given the low rates of transplant waitlisting in the US, Medicare launched the End-Stage Renal Disease Treatment Choices (ETC) Model in 2021, the largest mandatory trial of payment incentives in kidney disease, which randomized 30% of healthcare markets to financial bonuses/penalties to improve kidney transplantation and home dialysis use. This study examines the effect of ETC payment adjustments on US kidney transplant waitlist additions. Using data from the Organ Procurement and Transplantation Network registry, we examined kidney transplant waitlisting trends between 01/01/2017 and 06/30/2022. Participants were divided into intervention and control arms of the ETC Model. Using an interrupted time series design, we compared slope changes in waitlist additions post-ETC Model implementation (implementation date: 01/01/2021) between the two arms, while accounting for differential changes during the COVID-19 pandemic. Results were stratified by race and ethnicity (White, Black, Hispanic, and other). To examine balance between the two ETC arms, we conducted supplementary analyses using United States Renal Data System and Medicare data. Following implementation of the ETC Model, there were 5,550 waitlist additions in the intervention and 11,332 additions in the control arm (versus 14,023 and 30,610 additions before the ETC Model). Post-ETC, there were no significant differences in kidney transplant waitlist additions between the two arms for the overall cohort (slope difference 6.9 new listings/month, 95% CI: -7.4 to 21.1) or among either White (slope difference 2.6/month, 95% CI -3.0 to 8.1), Black (slope difference 2.2/month, 95% CI: -4.3 to 8.7), or Hispanic (slope difference 0.2/month, 95% CI: -4.5 to 4.9) patients. In the 18 months following implementation, the ETC Model was not associated with significant changes in new kidney transplant waitlist additions.

Quantifying the Impact of C7 Spinal Nerve Harvest on Spontaneous, Patient-Initiated Movement of the Donor Upper Extremity.

Transfer of a healthy C7 spinal nerve is a tool for upper extremity reanimation in patients with severe brachial plexus injury (BPI). Its use remains controversial owing to concern for neurological injury to the donor arm. Utilizing wearable motion-sensor technology, we aimed to quantify donor arm morbidity after C7 spinal nerve harvest in patients with pan-BPI, reporting both the time and magnitude of donor arm movement in a real-world setting compared to healthy controls. Seventeen patients who underwent contralateral C7 (CC7) transfer for traumatic pan-BPI at least 2 years prior were compared to 14 healthy controls. Each participant wore an accelerometer on both arms for 7 consecutive days. The vector time (VT), or time of movement measured in hours/day, and the vector magnitude (VM), or magnitude of arm movement measured as a single vector magnitude per second, were collected and compared between groups. The correlation between VT and VM and time from C7 spinal nerve harvest was also calculated. At mean 7.7 years after C7 spinal nerve harvest, there was no difference between donor and control arms for VT (5.76±1.55] vs 5.45±1.22 hours, P = 0.56) or VM (2242236±753853 vs 1919223±579723 activity counts, P = 0.20), regardless of donor arm dominance. The C7 harvest cohort used the injured arm 53% of the time and with 27% of the power of the donor arm. There was no significant difference in time or magnitude of arm movement between donor arms and the arms of healthy controls.

A personalised and systematically designed adherence intervention improves photoprotection in adults with Xeroderma Pigmentosum (XP): Results of the XPAND randomised controlled trial.

Poor adherence to photoprotection in Xeroderma Pigmentosum (XP) increases morbidity and shortens lifespan due to skin cancers. To test a highly personalised intervention (XPAND) to reduce the dose of ultraviolet radiation (UVR) reaching the face in adults with XP, designed using known psychosocial determinants of poor photoprotection. A two-arm parallel group randomised controlled trial, including patients with sub-optimal photoprotection to receive XPAND or a delayed intervention control arm that received XPAND the following year. XPAND comprises seven one-to-one sessions targeting photoprotection barriers (e.g., misconceptions about UVR) supported by personalised text messages, activity sheets, and educational materials incorporating behaviour change techniques. The primary outcome, mean daily UVR dose-to-face across 21 days in June-July 2018, was calculated by combining UVR exposure at the wrist with a face photoprotection activity diary. Secondary outcomes were UVR dose-to-face across 21 days in August 2018, time spent outside, photoprotective measures used outside, mood, automaticity, confidence-to-photoprotect. Financial costs and quality-adjusted life years (QALYs) were calculated. 16 patients were randomised, 13 provided sufficient data for primary outcome analysis. The XPAND group (n=8) had lower mean daily UVR dose-to-face [0.03 SED (SD 0.02] compared to control (n=7) [0.36 SED (SD 0.16)] (adjusted difference=-0.25, p<0.001, Hedge's g=2.2). No significant between-group differences were observed in time spent outside, photoprotection outside, mood, or confidence. The delayed intervention control showed improvements in UVR dose-to-face (adjusted difference=-0.05, Hedge's g=-0.1) , time outside (adjusted difference=-69.9, Hedge's g=-0.28), and photoprotection (adjusted difference=-0.23, Hedge's g=0.45), after receiving XPAND. XPAND was associated with lower treatment costs (£-2642; 95% CI: -£8715 to £3873) and fewer QALYs (-0.0141; 95% CI: -0.0369 to 0.0028). XPAND was associated with a lower UVR dose-to-face in XP patients and was cost-effective.

Accuracy of the LaserSAFE technique for detecting positive surgical margins during robot-assisted radical prostatectomy: blind assessment and inter-rater agreement analysis.

Fluorescence confocal microscopy (FCM) is a new imaging modality capable of generating digital microscopic resolution scans of fresh surgical specimens, and holds potential as an alternative to frozen section (FS) analysis for intra-operative assessment of surgical margins. Previously, we described the LaserSAFE technique as an application of FCM for margin assessment in robot-assisted radical prostatectomy (RARP) using the Histolog® scanner. This study describes the accuracy and inter-rater agreement of FCM imaging compared to corresponding paraffin-embedded analysis (PA) among four blinded pathologists for the presence of positive surgical margins (PSM). RARP specimens from patients enrolled in the control arm of the NeuroSAFE PROOF study (NCT03317990) were analysed from April 2022 to February 2023. Prostate specimens were imaged using the Histolog® scanner before formalin fixation and PA. Four trained assessors, blinded to PA, reviewed and analysed FCM images of the posterolateral prostatic surface. A total of 31 prostate specimens were included in the study. PA per lateral side of the prostate identified 11 instances of positive margins. Among the four histopathologists included in our study, FCM achieved a sensitivity of 73-91 and specificity of 94-100% for the presence of PSM. Fleiss' Kappa for inter-rater agreement on PSM was 0.78 (95% confidence interval = 0.64-0.92), indicating substantial agreement. This blinded analysis of FCM versus PA among histopathologists with different experience levels demonstrated high accuracy and substantial inter-rater agreement for diagnosing PSM. This supports the role of the FCM as an alternative to FS.

More Efficient Smaller Multi-Cancer Screening Trials.

The NHS-Galleri trial has demonstrated feasibility for multi-cancer screening trial design where all participants provide a 'sample' for screening, but only samples from the intervention arm are tested and acted upon during the trial. We assess efficiency of analysis methods when the control arm may be retrospectively tested at time of analysis. Analyses considered are: (1, traditional) by randomised allocation with all events included; (2, 'intended-effect') nested in those who tested positive in both arms and all events therein; and (3, targeted) by randomised allocation but with endpoint 'test-positive event'. They are compared using approximate statistical methods and scenario analysis. Provided the number who die from cancer after a test-positive sample is a small fraction of the total number who die from cancer, intended-effect and targeted analyses require a much smaller sample size to evaluate cancer-specific mortality than the traditional approach. Intended-effect analysis has a smaller sample size requirement than targeted analysis. This gain is only substantial when the risk of cancer death in test positives is high. Intended-effect or targeted analysis will substantially reduce the sample size needed to evaluate cancer-specific mortality in blood-based screening trials. Targeted analysis requires many fewer retrospective tests and avoids potential effects of needing to inform those whose stored samples test positive. Trialists should consider the trade-off of costs between sample size and retrospective testing requirements when choosing the analysis.

A seamless Phase I/II platform design with a time-to-event efficacy endpoint for potential COVID-19 therapies.

In the search for effective treatments for COVID-19, the initial emphasis has been on re-purposed treatments. To maximize the chances of finding successful treatments, novel treatments that have been developed for this disease in particular, are needed. In this article, we describe and evaluate the statistical design of the AGILE platform, an adaptive randomized seamless Phase I/II trial platform that seeks to quickly establish a safe range of doses and investigates treatments for potential efficacy. The bespoke Bayesian design (i) utilizes randomization during dose-finding, (ii) shares control arm information across the platform, and (iii) uses a time-to-event endpoint with a formal testing structure and error control for evaluation of potential efficacy. Both single-agent and combination treatments are considered. We find that the design can identify potential treatments that are safe and efficacious reliably with small to moderate sample sizes.

Non-invasive brain-machine interface control with artificial intelligence copilots.

Motor brain-machine interfaces (BMIs) decode neural signals to help people with paralysis move and communicate. Even with important advances in the last two decades, BMIs face key obstacles to clinical viability. Invasive BMIs achieve proficient cursor and robotic arm control but require neurosurgery, posing significant risk to patients. Non-invasive BMIs do not have neurosurgical risk, but achieve lower performance, sometimes being prohibitively frustrating to use and preventing widespread adoption. We take a step toward breaking this performance-risk tradeoff by building performant non-invasive BMIs. The critical limitation that bounds decoder performance in non-invasive BMIs is their poor neural signal-to-noise ratio. To overcome this, we contribute (1) a novel EEG decoding approach and (2) artificial intelligence (AI) copilots that infer task goals and aid action completion. We demonstrate that with this "AI-BMI," in tandem with a new adaptive decoding approach using a convolutional neural network (CNN) and ReFIT-like Kalman filter (KF), healthy users and a paralyzed participant can autonomously and proficiently control computer cursors and robotic arms. Using an AI copilot improves goal acquisition speed by up to 4.3 × in the standard center-out 8 cursor control task and enables users to control a robotic arm to perform the sequential pick-and-place task, moving 4 randomly placed blocks to 4 randomly chosen locations. As AI copilots improve, this approach may result in clinically viable non-invasive AI-BMIs.

Online Mental Health Assessment in a psychiatry emergency department in adults using touchscreen mobile devices: A randomised controlled trial.

To determine whether completion of an online mental health self-assessment by patients who are waiting in the emergency department can save clinician time taken to complete clinical assessment and documentation. Patients presenting to a psychiatric emergency department for a period of 6 months were allocated by week of presentation to either the intervention arm (online mental health self-assessment, followed by a clinical interview) or the control arm (usual assessment) arm on a random basis. Time at the beginning and end of the interview was recorded and used to derive interview time. Similarly, time at the beginning and end of the clinical documentation was recorded and used to derive the time to complete clinical documentation. Of 168 patients who presented during the study period, 69 (38.55%) agreed to participate, 33 completed the usual assessment and 30 completed the online mental health self-assessment followed by a clinical interview. Patients receiving usual care had a statistically significant, t(61) = 2.15, p = 0.035, longer interview duration (M = 48.7 minutes, SD = 19.8) compared with those in the online mental health self-assessment arm (M = 38.9 minutes, SD = 15.9). There was no statistically significant difference between groups for documentation time, t(61) = -0.64, p = 0.52. Online mental health self-assessment was associated with a statistically significant reduction in interview time by approximately 10 minutes without increasing documentation time. While online mental health self-assessment is not appropriate for all patients in the emergency department setting, it is likely to yield greater benefits in less acute settings.