Randomization-Based Confidence Intervals for Cluster Randomized Trials

In a cluster randomized trial (CRT), groups of people are randomly assigned to different interventions. Existing parametric and semiparametric methods for CRTs rely on distributional assumptions or a large number of clusters to maintain nominal confidence interval (CI) coverage. Randomization-based inference is an alternative approach that is distribution-free and does not require a large number of clusters to be valid. Although it is well-known that a CI can be obtained by inverting a randomization test, this requires randomization testing a non-zero null hypothesis, which is challenging with non-continuous and survival outcomes. In this paper, we propose a general method for randomization-based CIs using individual-level data from a CRT. This fast and flexible approach accommodates various outcome types, can account for design features such as matching or stratification, and employs a computationally efficient algorithm. We evaluate this method\u27s performance through simulations and apply it to the Botswana Combination Prevention Project, a large HIV prevention trial with an interval-censored time-to-event outcome

In Vivo rapid delivery of vasopressin from an implantable drug delivery micro-electro-mechanical device

A miniaturized implantable rapid drug delivery device based on micro-electro-mechanical-systems technology was recently developed and characterized. This device is intended to address acute conditions in high-risk subjects. This work provides an in vivo proof-of-concept for the device in a rabbit model, by releasing a physiologically active dose of vasopressin, a vasoconstrictor. The devices were implanted subcutaneously and activated to rapidly release vasopressin, with monitoring of mean arterial pressure and plasma levels.Device releases showed a rapid and measurable effect on mean arterial pressure as well as a continuous diffusion of vasopressin into the bloodstream, consistent with a depot effect. Plasma levels in rabbits receiving vasopressin with the device rose monotonically to 24.4 ± 2.9 ng/mL after one hour. Bioavailability after one hour was calculated to be 6.2 ± 2.8 % (mean ± s.d.).A new modality for rapid and controlled drug delivery has been developed. The device can be used as a new implantable device controlled by medical algorithms (based on heart rate or mean arterial pressure, for example) for autonomous operation in high-risk populations that require immediate ambulatory intervention.Keywords: Subcutaneous drug delivery; vasopressin; MEMS; rabbit; bioavailability

In Vivo rapid delivery of vasopressin from an implantable drug delivery micro-electro-mechanical device

A miniaturized implantable rapid drug delivery device based on micro-electro-mechanical-systems technology was recently developed and characterized. This device is intended to address acute conditions in high-risk subjects. This work provides an in vivo proof-of-concept for the device in a rabbit model, by releasing a physiologically active dose of vasopressin, a vasoconstrictor. The devices were implanted subcutaneously and activated to rapidly release vasopressin, with monitoring of mean arterial pressure and plasma levels.Device releases showed a rapid and measurable effect on mean arterial pressure as well as a continuous diffusion of vasopressin into the bloodstream, consistent with a depot effect. Plasma levels in rabbits receiving vasopressin with the device rose monotonically to 24.4 ± 2.9 ng/mL after one hour. Bioavailability after one hour was calculated to be 6.2 ± 2.8 % (mean ± s.d.).A new modality for rapid and controlled drug delivery has been developed. The device can be used as a new implantable device controlled by medical algorithms (based on heart rate or mean arterial pressure, for example) for autonomous operation in high-risk populations that require immediate ambulatory intervention.Keywords: Subcutaneous drug delivery; vasopressin; MEMS; rabbit; bioavailability

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

Background Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the eff ect of early detection by screening on ovarian cancer mortality. Methods In this randomised controlled trial, we recruited postmenopausal women aged 50–74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computergenerated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. Findings Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202 638 women: 50 640 (25·0%) to MMS, 50 639 (25·0%) to USS, and 101 359 (50·0%) to no screening. 202 546 (>99·9%) women were eligible for analysis: 50 624 (>99·9%) women in the MMS group, 50 623 (>99·9%) in the USS group, and 101 299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345 570 MMS and 327 775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0–12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0–14 of 15% (95% CI –3 to 30; p=0·10) with MMS and 11% (–7 to 27; p=0·21) with USS. The Royston-Parmar fl exible parametric model showed that in the MMS group, this mortality eff ect was made up of 8% (–20 to 31) in years 0–7 and 23% (1–46) in years 7–14, and in the USS group, of 2% (–27 to 26) in years 0–7 and 21% (–2 to 42) in years 7–14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly diff erent death rates (p=0·021), with an overall average mortality reduction of 20% (–2 to 40) and a reduction of 8% (–27 to 43) in years 0–7 and 28% (–3 to 49) in years 7–14 in favour of MMS. Interpretation Although the mortality reduction was not signifi cant in the primary analysis, we noted a signifi cant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7–14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-eff ectiveness of ovarian cancer screening

Impact of Medication Adherence on Virologic Failure in A5202: A Randomized, Partially Blinded, Phase 3B Study

Abstract In AIDS Clinical Trials Group A5202, participants who reported missing their medication within the past month or not providing adherence reports at both 8 and 24 weeks had 5 times the hazard of virological failure compared to more adherent participants. Adherence interventions should focus on such patients

Association of bridging therapy utilization with clinical outcomes in patients receiving chimeric antigen receptor (CAR) T-cell therapy

Background Chimeric antigen receptor (CAR) T-cell therapy recipients may receive bridging therapy while awaiting product manufacturing to control disease. Yet, data are lacking regarding the impact of bridging therapy use on clinical outcomes.Methods We conducted a retrospective analysis of 235 patients who received CAR T-cell therapy at two tertiary care centers from February 2016 to December 2019. We abstracted clinical outcomes from review of the electronic health record including (1) overall response; (2) complete response (CR); (3) progression-free survival (PFS); (4) overall survival (OS); and (5) toxicity (cytokine release syndrome (CRS) and neurotoxicity). We assessed the association of bridging therapy use with overall response rate (ORR) and CR rate using multivariable logistic regression and with PFS and OS using multivariable Cox regression controlling for covariates. We analyzed the association of bridging therapy use with CRS and neurotoxicity using Fisher’s exact test.Results Patients’ median age was 63.1 years (range: 19–82), and the majority were men (144/235, 61.3%). Most patients received axicabtagene ciloleucel (192/235, 81.7%), and the most common lymphoma subtype was diffuse large B-cell lymphoma or grade 3B follicular lymphoma (107/235, 45.5%). Overall, 39.4% (93/236) received bridging therapy. Bridging therapy regimens included systemic chemotherapy (48/92, 52.2%), corticosteroids (25/92, 27.2%), radiation (9/92, 9.8%), and other systemic therapies (10/92, 10.9%). In multivariable Cox regression, bridging therapy use was associated with OS (HR: 1.97, p=0.004) but not PFS (HR: 1.18, p=0.449). In multivariable logistic regression, bridging therapy use was not associated with ORR (OR: 0.69, p=0.391) or CR rate (OR: 0.96, p=0.901). We did not identify an association of bridging therapy use with grade 3+ CRS (p=0.574) or grade 3+ neurotoxicity (p=0.748).Conclusions We identified that bridging therapy use is not associated with differences in ORR, CR rate, or PFS but is associated with worse OS. These data suggest bridging therapy may be a surrogate for additional poor prognostic factors leading to inferior OS and underscore the need for novel bridging therapy regimens to optimize outcomes in this patient population

Predictors of HIV infection: a prospective HIV screening study in a Ugandan refugee settlement

Background: The instability faced by refugees may place them at increased risk of exposure to HIV infection. Nakivale Refugee Settlement in southwestern Uganda hosts 68,000 refugees from 11 countries, many with high HIV prevalence. We implemented an HIV screening program in Nakivale and examined factors associated with new HIV diagnosis. Methods: From March 2013-November 2014, we offered free HIV screening to all clients in the Nakivale Health Center while they waited for their outpatient clinic visit. Clients included refugees and Ugandan nationals accessing services in the settlement. Prior to receiving the HIV test result, participants were surveyed to obtain demographic information including gender, marital status, travel time to reach clinic, refugee status, and history of prior HIV testing. We compared variables for HIV-infected and non-infected clients using Pearson’s chi-square test, and used multivariable binomial regression models to identify predictors of HIV infection. Results: During the HIV screening intervention period, 330 (4%) of 7766 individuals tested were identified as HIV-infected. Refugees were one quarter as likely as Ugandan nationals to be HIV-infected (aRR 0.27 [0.21, 0.34], p < 0.0001). Additionally, being female (aRR 1.43 [1.14, 1.80], p = 0.002) and traveling more than 1 h to the clinic (aRR 1.39 [1.11, 1.74], p = 0.003) increased the likelihood of being HIV-infected. Compared to individuals who were married or in a stable relationship, being divorced/separated/widowed increased the risk of being HIV-infected (aRR 2.41 [1.88, 3.08], p < 0.0001), while being single reduced the risk (aRR 0.60 [0.41, 0.86], p < 0.0001). Having been previously tested for HIV (aRR 0.59 [0.47, 0.74], p < 0.0001) also lowered the likelihood of being HIV-infected. Conclusions: In an HIV screening program in a refugee settlement in Uganda, Ugandan nationals are at higher risk of having HIV than refugees. The high HIV prevalence among clients seeking outpatient care, including Ugandan nationals and refugees, warrants enhanced HIV screening services in Nakivale and in the surrounding region. Findings from this research may be relevant for other refugee settlements in Sub-Saharan Africa hosting populations with similar demographics, including the 9 other refugee settlements in Uganda

Adolescent Linkage to Care After a Large-scale Transfer From a Hospital-based HIV Clinic to the Public Sector in South Africa

HIV clinics formerly supported by the President’s Emergency Plan for AIDS Relief are transferring patients to public-sector clinics. We evaluated adolescent linkage to care after a large-scale transfer from a President’s Emergency Plan for AIDS Relief-subsidized pediatric HIV clinic in Durban, South Africa. All adolescents (11–18 years) in care at a pediatric state-subsidized, hospital-based clinic (HBC) were transferred, from May to June 2012, to government sites [primary health care (PHC) clinic; community health center (CHC); and HBCs] or private clinics. Caregivers were surveyed 7–8 months after transfer to assess their adolescents’ linkage to care and their reports were validated by clinic record audits in a subset of randomly selected clinics. Of the 309 (91%) caregivers reached, only 5 (2%) reported that their adolescent did not link. Of the 304 adolescents who linked, 105 (35%) were referred to a PHC, 73 (24%) to a CHC and 106 (35%) to a HBC. A total of 146 (48%) linked adolescents attended a different clinic than that assigned. Thirty-five (20%) of the 178 who linked and were assigned to a PHC or CHC ultimately attended a HBC. Based on clinic validation, the estimated transfer success was 88% (95% confidence interval: 77%–97%). The large majority of adolescents successfully transferred to a new HIV clinic, although nearly half attended a clinic other than that assigned

Self-efficacy for exercise in adults with lifetime depression and low physical activity

People may be more likely to exercise if they have self-efficacy for exercise (SEE). We conducted an exploratory analysis of SEE using data from a clinical trial designed to increase physical activity (N = 340). We evaluated correlates of baseline SEE and the relationship between baseline SEE and physical activity. Low SEE at baseline was correlated with lower well-being, physical activity, and higher depression at baseline. Participants with high (vs. low) baseline SEE had higher physical activity (but no differential change in activity) over time. These data highlight the potential role of SEE in psychological health and physical activity