A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone.

BACKGROUND: Checkpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response. METHODS: We evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens. RESULTS: Five (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression. CONCLUSIONS: Pembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects. TRIAL REGISTRATION NUMBER: clinicaltrials.gov (NCT02312557)

Multicentre pilot randomised clinical trial of early in-bed cycle ergometry with ventilated patients.

Introduction: Acute rehabilitation in critically ill patients can improve post-intensive care unit (post-ICU) physical function. In-bed cycling early in a patient\u27s ICU stay is a promising intervention. The objective of this study was to determine the feasibility of recruitment, intervention delivery and retention in a multi centre randomised clinical trial (RCT) of early in-bed cycling with mechanically ventilated (MV) patients. Methods: We conducted a pilot RCT conducted in seven Canadian medical-surgical ICUs. We enrolled adults who could ambulate independently before ICU admission, within the first 4 days of invasive MV and first 7 days of ICU admission. Following informed consent, patients underwent concealed randomisation to either 30 min/day of in-bed cycling and routine physiotherapy (Cycling) or routine physiotherapy alone (Routine) for 5 days/week, until ICU discharge. Our feasibility outcome targets included: accrual of 1-2 patients/month/site; \u3e80% cycling protocol delivery; \u3e80% outcomes measured and \u3e80% blinded outcome measures at hospital discharge. We report ascertainment rates for our primary outcome for the main trial (Physical Function ICU Test-scored (PFIT-s) at hospital discharge). Results: Between 3/2015 and 6/2016, we randomised 66 patients (36 Cycling, 30 Routine). Our consent rate was 84.6 % (66/78). Patient accrual was (mean (SD)) 1.1 (0.3) patients/month/site. Cycling occurred in 79.3% (146/184) of eligible sessions, with a median (IQR) session duration of 30.5 (30.0, 30.7) min. We recorded 43 (97.7%) PFIT-s scores at hospital discharge and 37 (86.0%) of these assessments were blinded. Discussion: Our pilot RCT suggests that a future multicentre RCT of early in-bed cycling for MV patients in the ICU is feasible. Trial registration number: NCT02377830

Energy compensation following consumption of sugar-reduced products: a randomized controlled trial

PURPOSE: Consumption of sugar-reformulated products (commercially available foods and beverages that have been reduced in sugar content through reformulation) is a potential strategy for lowering sugar intake at a population level. The impact of sugar-reformulated products on body weight, energy balance (EB) dynamics and cardiovascular disease risk indicators has yet to be established. The REFORMulated foods (REFORM) study examined the impact of an 8-week sugar-reformulated product exchange on body weight, EB dynamics, blood pressure, arterial stiffness, glycemia and lipemia. METHODS: A randomized, controlled, double-blind, crossover dietary intervention study was performed with fifty healthy normal to overweight men and women (age 32.0 ± 9.8 year, BMI 23.5 ± 3.0 kg/m2) who were randomly assigned to consume either regular sugar or sugar-reduced foods and beverages for 8 weeks, separated by 4-week washout period. Body weight, energy intake (EI), energy expenditure and vascular markers were assessed at baseline and after both interventions. RESULTS: We found that carbohydrate (P < 0.001), total sugars (P < 0.001) and non-milk extrinsic sugars (P < 0.001) (% EI) were lower, whereas fat (P = 0.001) and protein (P = 0.038) intakes (% EI) were higher on the sugar-reduced than the regular diet. No effects on body weight, blood pressure, arterial stiffness, fasting glycemia or lipemia were observed. CONCLUSIONS: Consumption of sugar-reduced products, as part of a blinded dietary exchange for an 8-week period, resulted in a significant reduction in sugar intake. Body weight did not change significantly, which we propose was due to energy compensation

Anticipating and Adapting to the Future Impacts of Climate Change on the Health, Security and Welfare of Low Elevation Coastal Zone (LECZ) Communities in Southeastern USA

Low elevation coastal zones (LECZ) are extensive throughout the southeastern United States. LECZ communities are threatened by inundation from sea level rise, storm surge, wetland degradation, land subsidence, and hydrological flooding. Communication among scientists, stakeholders, policy makers and minority and poor residents must improve. We must predict processes spanning the ecological, physical, social, and health sciences. Communities need to address linkages of (1) human and socioeconomic vulnerabilities; (2) public health and safety; (3) economic concerns; (4) land loss; (5) wetland threats; and (6) coastal inundation. Essential capabilities must include a network to assemble and distribute data and model code to assess risk and its causes, support adaptive management, and improve the resiliency of communities. Better communication of information and understanding among residents and officials is essential. Here we review recent background literature on these matters and offer recommendations for integrating natural and social sciences. We advocate for a cyber-network of scientists, modelers, engineers, educators, and stakeholders from academia, federal state and local agencies, non-governmental organizations, residents, and the private sector. Our vision is to enhance future resilience of LECZ communities by offering approaches to mitigate hazards to human health, safety and welfare and reduce impacts to coastal residents and industries

Clinician-rated quality of video otoscopy recordings and still images for the asynchronous assessment of middle-ear disease

INTRODUCTION : Video otoscopy plays an important role in improving access to ear health services. This study investigated the clinician-rated quality of video otoscopy recordings and still images, and compared their suitability for asynchronous diagnosis of middle-ear disease. METHODS : Two hundred and eighty video otoscopy image–recording pairs were collected from 150 children (aged six months to 15 years) by an ear, nose, and throat (ENT) specialist, audiologists, and trained research assistants, and independently rated by an audiologist and ENT surgeon. On a five-point scale, clinicians rated the cerumen amount, field of view, quality, focus, light, and gave an overall rating, and asked whether they could make an accurate diagnosis for both still images and recordings. RESULTS : More video otoscopy recordings were rated as ‘good’ or ‘excellent’ compared to still images across all domains. The mean difference between the two otoscopic procedures ratings was significant across almost all domains (p < 0.05), except ‘cerumen amount’. The suitability to make a diagnosis significantly improved when using recordings (p<0.05). Younger participant age was found to have a significant, negative impact on the ratings across all domains (p < 0.03). The role of the tester conducting video otoscopy did not have a significant impact on the ratings. DISCUSSION : Video otoscopy recordings were found to provide clearer views of the tympanic membrane and increase the ability to make diagnoses, compared to still images, for both audiologists and ENT surgeons. Research assistants with limited practice were able to obtain video otoscopy images and recordings that were comparable to the ones obtained by clinicians.The Telethon Kids Institutehttps://journals.sagepub.com/home/jtthj2022Speech-Language Pathology and Audiolog

Clinician-rated quality of video otoscopy recordings and still images for the asynchronous assessment of middle-ear disease

INTRODUCTION : Video otoscopy plays an important role in improving access to ear health services. This study investigated the clinician-rated quality of video otoscopy recordings and still images, and compared their suitability for asynchronous diagnosis of middle-ear disease. METHODS : Two hundred and eighty video otoscopy image–recording pairs were collected from 150 children (aged six months to 15 years) by an ear, nose, and throat (ENT) specialist, audiologists, and trained research assistants, and independently rated by an audiologist and ENT surgeon. On a five-point scale, clinicians rated the cerumen amount, field of view, quality, focus, light, and gave an overall rating, and asked whether they could make an accurate diagnosis for both still images and recordings. RESULTS : More video otoscopy recordings were rated as ‘good’ or ‘excellent’ compared to still images across all domains. The mean difference between the two otoscopic procedures ratings was significant across almost all domains (p < 0.05), except ‘cerumen amount’. The suitability to make a diagnosis significantly improved when using recordings (p<0.05). Younger participant age was found to have a significant, negative impact on the ratings across all domains (p < 0.03). The role of the tester conducting video otoscopy did not have a significant impact on the ratings. DISCUSSION : Video otoscopy recordings were found to provide clearer views of the tympanic membrane and increase the ability to make diagnoses, compared to still images, for both audiologists and ENT surgeons. Research assistants with limited practice were able to obtain video otoscopy images and recordings that were comparable to the ones obtained by clinicians.The Telethon Kids Institutehttps://journals.sagepub.com/home/jtthj2022Speech-Language Pathology and Audiolog

Handler beliefs affect scent detection dog outcomes

Our aim was to evaluate how human beliefs affect working dog outcomes in an applied environment. We asked whether beliefs of scent detection dog handlers affect team performance and evaluated relative importance of human versus dog influences on handlers’ beliefs. Eighteen drug and/or explosive detection dog/handler teams each completed two sets of four brief search scenarios (conditions). Handlers were falsely told that two conditions contained a paper marking scent location (human influence). Two conditions contained decoy scents (food/toy) to encourage dog interest in a false location (dog influence). Conditions were (1) control; (2) paper marker; (3) decoy scent; and (4) paper marker at decoy scent. No conditions contained drug or explosive scent; any alerting response was incorrect. A repeated measures analysis of variance was used with search condition as the independent variable and number of alerts as the dependent variable. Additional nonparametric tests compared human and dog influence. There were 225 incorrect responses, with no differences in mean responses across conditions. Response patterns differed by condition. There were more correct (no alert responses) searches in conditions without markers. Within marked conditions, handlers reported that dogs alerted more at marked locations than other locations. Handlers’ beliefs that scent was present potentiated handler identification of detection dog alerts. Human more than dog influences affected alert locations. This confirms that handler beliefs affect outcomes of scent detection dog deployments