Pediatric Device Clinical Trials Activity: 1999-2022.

OBJECTIVES: This study assessed the state of pediatric medical device (PMD) development by comparing PMD clinical trials to pediatric trials evaluating drugs and biologics, from 1999 to 2022. METHODS: The site https://www.clinicaltrials.gov was used to identify and quantify both PMD clinical trials and pediatric trials for drugs and biologics. Clinical specialty was also assessed. The institutions included were the 7 children's hospitals primarily affiliated with the Food and Drug Administration (FDA) Pediatric Device Consortia (PDC) grant program between 2018 and 2023. For a national comparison, an additional search assessed PMD trials across all US medical institutions. RESULTS: A total of 243 PMD clinical trials were identified at the FDA-PDC institutions on the basis of the year of initiation; the average number of PMD trials initiated per year per institution was 1.5 from 1999 to 2022. However, PMD trials significantly increased during the period 2014 to 2022 compared with 1999 to 2013 (P < .001); the rate of initiation of drug and biologic pediatric trials demonstrated no significant differences between these time periods. A national survey of all institutions initiating PMD trials, and drugs and biologics trials, identified 1885 PMD trials out of a total 12 943. A comparable trend was noted in the national survey with initiation of PMD trials increasing significantly from 2014 to 2022 (P < .001), compared with 1999 to 2013, whereas the rate of initiation of drug and biologic trials during these periods did not demonstrate a significant change. CONCLUSIONS: Although pediatric clinical trial initiation for drugs and biologics remained stable from 1999 to 2022, the rate of new PMD trials significantly increased during the period 2014 to 2022 at FDA-PDC institutions and nationally.

Intensifying Salvage Therapy in Prostate-specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy with Apalutamide, Salvage Radiation, and Docetaxel: The Phase 2 STARTAR Trial.

BACKGROUND AND OBJECTIVE: Androgen deprivation therapy (ADT) with salvage radiation therapy (RT) improves survival for patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP) for prostate cancer (PC), but many patients suffer further relapse. This study aims to determine the benefit of the combination of ADT, apalutamide, salvage RT, and docetaxel for high-risk PSA recurrent PC. METHODS: STARTAR is a multicenter, investigator-initiated phase 2 trial of men with PSA recurrent PC after RP. The key inclusion criteria included M0 by computed tomography/bone scan, Gleason 7 with either T3/positive margin/N1 disease or Gleason 8-10 prostate adenocarcinoma, PSA relapse (0.2-4 ng/ml) <4 yr after RP, and fewer than four positive resected lymph nodes. Patients received ADT with apalutamide for 9 mo, RT starting week 8, and then six cycles of docetaxel. The primary endpoint was 36-mo progression-free survival (PFS) with testosterone recovery and compared against the prior STREAM trial. KEY FINDINGS AND LIMITATIONS: We enrolled 39 men, including those with Gleason 8-10 (46%), pN1 (23%); the median PSA was 0.58 ng/ml. The median follow-up was 37 mo. All patients achieved undetectable PSA nadir. At 24 and 36 mo, PFS rates were 84% and 71%, respectively, which improved significantly over 3-yr 47% historic PFS and 54% enzalutamide/ADT/RT (STREAM) PFS rates (p = 0.004 and p = 0.039, respectively). Common any-grade adverse events included 98% hot flashes, 88% fatigue, 77% alopecia, 53% rash (10% G3), and 5% febrile neutropenia. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this phase 2 trial of ADT, apalutamide, salvage RT, and six cycles of docetaxel for high-risk PSA recurrence, the 3-yr PFS rate improved to 71%, indicating feasible and efficacious treatment intensification, with durable remissions beyond historic data. PATIENT SUMMARY: Prostate cancer recurrence after surgical removal of the tumor occurs often, and current treatment options to limit recurrence after surgery are only partially effective. In this study, we found that the addition of an androgen receptor inhibitor and docetaxel chemotherapy to standard postsurgery radiation therapy and androgen deprivation therapy significantly improved progression-free survival at 3 yr after treatment. These results suggest that intensification of treatment after surgery can provide long-term benefit to a subset of patients with high-risk prostate cancer.

Immune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer.

Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (

Sustainable quality improvement: An essential ingredient for sustainability in modern medical curricula?

BACKGROUND: Health care delivery contributes a significant carbon footprint in the United Kingdom, and paradoxically climate change is linked to poorer human health outcomes. New General Medical Council (GMC) requirements mandate medical graduates must be able to apply sustainable care to their practice. Implementation of sustainable health care (SHC) teaching is a new challenge for medical schools, and there are several identified barriers including an overcrowded curriculum, lack of expertise within faculties, lack of institutional support and inadequate assessment techniques. APPROACH: We established a new SHC curriculum spiralling throughout the overall medical curriculum, and as part of this introduced a sustainable quality improvement (susQI) project to our final year cohort. SusQI considers the environmental, social and financial impacts as well as patient and population outcomes. Our students undertook this in their final year GP assistantships. EVALUATION: We sought multi-sourced data through focus groups, formal end of placement feedback, informal feedback and external feedback. We applied thematic analysis to focus group transcriptions and triangulated with the other data sources. We identified some common themes: First, susQI was enjoyed and valuable; second, it allowed meaningful participation; third, it created a co-learning environment; and fourth, timing and curriculum placement are important when integrating susQI. IMPLICATIONS: SusQI can implement SHC into the overcrowded medical curriculum in a low cost, low resource manner without the need for experienced faculty. SusQI is empowering for students and grants them an active team role. Expansion into secondary and tertiary care is feasible, and we contend that susQI can be placed in other health care curricula.

Determinants of physical activity promotion in primary care from the patient perspective of people at risk of or living with chronic disease: a COM-B analysis.

BACKGROUND: Chronic disease (CD) accounts for more than half of the overall global disease burden and physical activity (PA) is an established evidence-based strategy for the prevention and management of CD. Global policy emphasises the value of embedding PA into primary healthcare, highlighting the positive effects on PA behaviour. However, there is limited implementation of PA protocols in primary care, and research is needed to guide its integration into routine practice. The voice of the patient is underrepresented in the literature, resulting in the absence of critical insights into determinants of PA promotion in primary care. The purpose of the research was to identify the perspectives of people at risk of or living with CD on the determinants of PA promotion in primary care and to map these determinants across the six COM-B constructs. METHODS: Semi-structured interviews (n = 22), guided by the COM-B model were conducted with people aged 35-60 years, at risk of or living with CD and not meeting the PA guidelines. A hybrid analytic approach of thematic inductive and deductive analysis was applied to the participant transcripts guided by a COM-B informed coding framework. RESULTS: In total, 37 determinants across constructs related to capability, opportunity and motivation were prominent, examples include; physical capability constraints, the conflation of exercise with weight management, credibility of the health services in PA advice, communication styles in PA promotion, expectations of tailored support for PA, social support, accessibility, and integration of PA into routine habits. CONCLUSION: Exploring the determinants of PA promotion through the lens of the COM-B model facilitated a systematic approach to understanding the primary care user perspective of the healthcare professional (HCP) broaching the topic of PA. Findings emphasise the value of HCPs being supported to broach the issue of PA in a therapeutic and patient-centred manner using diverse and flexible approaches, while highlighting the importance of tailored, accessible PA opportunities that build self-efficacy and foster social support. The research provides valuable learnings to support PA promotion and the development of strategies in primary care through encompassing the perspective of those living with or at risk of CD.

Foxp1 suppresses cortical angiogenesis and attenuates HIF-1alpha signaling to promote neural progenitor cell maintenance.

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.

Parameterization of nutrients and sediment build-up/wash-off processes for simulating stormwater quality from specific land uses.

Urbanization changes land cover through the expansion of impermeable surfaces, leading to a significant rise in runoff, sediment, and nutrient loading. The quality of stormwater is related to land use and is highly variable. Currently, stormwater is predominantly described through watershed models that rely minimally, if at all, on field monitoring data. The simple event mean concentration (EMC) wash-off approach by land use is a common method for estimating urban runoff loads. However, a major drawback of the EMC approach is it assumes concentration remains constant across events for a specific land use. Build-up/wash-off equations have been formulated to consider variations in concentration between events. However, several equation parameters are challenging to estimate, making them difficult to use. We conducted a monitoring and modeling study and investigated the impact of land use on stormwater quantity and quality and optimized and investigated the build-up/wash-off parameters for three homogenous urban land uses to estimate nutrients (nitrogen and phosphorus) and sediment loads. Stormwater from commercial, medium-density residential, and transportation land uses was sampled using automatic samplers during storm events, and water quality was characterized for a variety of them for 14 months. Analysis of stormwater samples included assessments for total nitrogen, total phosphorus, and total suspended solids. Results showed that medium-density residential land use had the highest median total nitrogen and total phosphorus event mean concentrations and commercial had the highest median total suspended solids EMCs. Water quality parameters (or build-up/wash-off parameters) exhibited significant variation between land uses, confirming that land use is a key determinant of stormwater quality. The median particle size for each land use was less than 150 µm, indicating that the most common particle size in stormwater was a very fine sand or smaller. This small size should be considered by stakeholders in the design of stormwater treatment systems.

Funding Learning Health System Research: Challenges and Strategies.

PURPOSE: A growing number of health systems are establishing learning health system (LHS) programs, where research focuses on rapidly improving the health system's internal operations and performance. The authors examine funding challenges facing such initiatives and identify strategies for managing tensions between reliance on external research funding and directly contributing to improvement and learning within the researchers' own system. METHOD: Qualitative case studies of LHS research programs in 5 health systems were performed via 38 semistructured interviews (October 2019-April 2021) with 35 diverse respondents. Inductive and deductive rapid qualitative analysis supported interview, system-level, and cross-system summaries and analysis. RESULTS: External funding awards to LHS researchers facilitated some internal improvement and learning, scientific advancements, and the reputation of researchers and their systems, but reliance on external funding also challenged researchers' responsiveness to concerns of system leaders, managers, practitioners, and system needs. Gaps between external funding requirements and internally focused projects arose in objectives, practical applicability, audiences, timetables, routines, skill sets, and researchers' careers. To contribute more directly to system improvement, LHS researchers needed to collaborate with clinicians and other nonresearchers and pivot between long research studies and shorter, dynamic improvement, evaluation, and data analysis projects. With support from system executives, LHS program leaders employed several strategies to enhance researchers' internal contributions. They aligned funded-research topics with long-term system needs, obtained internal funding for implementing and sustaining practice change, and diversified funding sources. CONCLUSIONS: To foster LHS research contributions to internal system learning and improvement, LHS program leaders need to manage tensions between concentrating on externally funded research and fulfilling their mission of providing research-based services to their own system. Health system executives can support LHS programs by setting clear goals for them; appropriately staffing, budgeting, and incentivizing LHS researchers; and developing supportive, system-wide teamwork, skill development programs, and data infrastructures.

Repair of complex esophageal atresia with tracheobronchial remnant using special magnets.

Esophageal atresia (EA) repair can be complicated by associated malformations such as a tracheobronchial remnant in the distal esophagus. We describe our experience with a patient found to have long-gap EA with a distal cartilaginous ring who was managed using a combination of esophageal lengthening and magnetic compression anastomosis. A 5-month-old girl was referred to us from an outside hospital with type C EA including a very high upper pouch. She had undergone a prior thoracotomy with fistula ligation during which a clip was placed on the lower esophagus, leaving a 2-cm diverticulum on the trachea and a short lower esophageal pouch. Upon endoscopic evaluation at our center, we found a tracheobronchial remnant in the lower esophagus between the clip and the carina. An open thoracotomy was performed to approximate the esophageal pouches and a magnet anchor (Connect EA, Myka Laboratories, San Francisco, California, United States) was placed retrograde through the distal esophageal cartilaginous ring into the lower pouch. On postoperative day 8, after adequate growth and decreased pouch tension, a second magnetic anchor was placed endoscopically to the upper pouch to mate with the previously placed lower pouch anchor. The anastomosis formed within 14 days. Due to the tracheobronchial remnant, the device did not pass distally and was removed endoscopically. On postoperative day 8, balloon dilation of the anastomosis and tracheobronchial remnant was performed. Subsequently, the patient required a total of 6 dilations in an 18-month follow-up. This case report illustrates the utility of using magnets to create an esophageal anastomosis in complex cases of EA with concomitant esophageal malformations. The parents of the patient gave their written consent to publish this technical report.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Centrifuge-Simulated Spaceflight After Aortic Valve Replacement and Atrial Septal Defect Repair.

INTRODUCTION: Human access to space is expanding rapidly in the commercial environment, with various private companies offering commercial flights to spaceflight participants (SFPs). SFPs are more likely than career astronauts to have medical conditions novel to spaceflight and may not have undergone as rigorous a medical screening process as that used for career astronauts, representing new and unstudied risks in the spaceflight environment. We report participation of a subject with recent median sternotomy for aortic valve replacement and atrial septal defect closure in centrifuge-simulated dynamic phases of orbital and suborbital spaceflight.CASE REPORT: A 40-yr-old man with a history of congenital bicuspid aortic valve and atrial septal defect with successful repair 8 mo prior participated in an ongoing human centrifuge research study. The subject had the opportunity to participate in up to five centrifuge runs in an 8-h period, with profiles simulating commercial spaceflight. Maximum exposures included +4.0 Gz, +4.5 Gx, 6.1 G resultant, and maximum onset rate < 0.5 Gz · s-1 and +1 Gx · s-1. Physiological data acquisition included hemodynamics, electrocardiogram, neurovestibular exams, and postrun questionnaires covering motion sickness, disorientation, and similar. The subject tolerated the physiological aspects of hypergravity well, noting progressive sternal pain with increasing +Gx, ultimately leading him to opt out of the final profile.DISCUSSION: Postcardiothoracic surgery risks to SFPs are largely unknown, especially within 12 mo of a significant surgical procedure. This case provides an approach for risk stratification, preparticipation evaluation, and medical management of a postsurgical patient with significant cardiac history in spaceflight and analog environments.Fernandez WL, Blue RS, Harrison MF, Powers W, Shah R, Auñón-Chancellor S. Centrifuge-simulated spaceflight after aortic valve replacement and atrial septal defect repair. Aerosp Med Hum Perform. 2024; 95(2):123-131.

A comparison of aerobic- and resistance-emphasised exercise on cardiometabolic health and quality of life in men receiving androgen deprivation therapy for prostate cancer: Protocol for a feasibility trial.

BACKGROUND: Those with intermediate and high-risk prostate cancer typically receive androgen deprivation therapy (ADT) as part of their treatment. ADT often results in extensive side effects including increased risk of cardiometabolic disease. Many ADT side effects can be influenced by exercise, both resistance and aerobic training. Exercise regimes typically combine aerobic and resistance exercise but the appropriate emphasis for achieving the broadest range of therapeutic benefits has yet to be determined. We propose to determine the feasibility of undertaking a larger trial comparing a resistance- vs an aerobic-emphasised exercise intervention in men with prostate cancer undergoing ADT. The trial will also investigate preliminary evidence of difference between arms for cardiometabolic health and quality of life outcomes. METHODS: This is a 6-month randomised two-armed feasibility trial. Prostate cancer patients undergoing ADT and radiotherapy will be recruited (n = 24) and randomised to either a resistance- or aerobic-emphasised group. Participants will attend twice-weekly supervised individual or small group sessions, with 75% of exercise time in the primary exercise modality. The primary outcome will be feasibility, determined via assessment of recruitment, retention, adherence, safety, and acceptability. Secondary outcomes will include quality of life, body composition, vascular indices, aerobic and muscular fitness and cardiometabolic health blood biomarkers. CONCLUSION: It is envisaged that the trial will provide valuable information and preliminary difference data that will aid in the design of an efficacious larger trial that will adopt a major and minor emphasis approach to the scheduling of resistance and aerobic exercise.

Spatial Relationships in the Tumor Microenvironment Demonstrate Association with Pathologic Response to Neoadjuvant Chemoimmunotherapy in Muscle-invasive Bladder Cancer.

BACKGROUND: Platinum-based neoadjuvant chemotherapy (NAC) is standard for patients with muscle-invasive bladder cancer (MIBC). Pathologic response (complete: ypT0N0 and partial:

Lessons Learned From the First-In-Human Compassionate Use of Connect-EA™ in Ten Patients With Esophageal Atresia.

INTRODUCTION: Delayed primary repair of esophageal atresia in patients with high-risk physiologic and anatomic comorbidities remains a daunting challenge with an increased risk for peri-operative morbidity and mortality via conventional repair. The Connect-EA device facilitates the endoscopic creation of a secure esophageal anastomosis. This follow-up study reports our long-term outcomes with the novel esophageal magnetic compression anastomosis (EMCA) Connect-EA device for EA repair, as well as lessons learned from the ten first-in-human cases. We propose an algorithm to maximize the advantages of the device for EA repair. METHODS: Under compassionate use approval, from June 2019 to December 2022, ten patients with prohibitive surgical or medical risk factors underwent attempted EMCA with this device. All patients underwent prior gastrostomy, tracheoesophageal fistula ligation (if necessary), and demonstrated pouch apposition prior to EMCA. RESULTS: Successful device deployment and EMCA formation were achieved in nine patients (90%). Mean time to anastomosis formation was 8 days (range 5-14) and the device was retrieved endoscopically in five (56%) cases. At median follow-up of 22 months (range 4-45), seven patients (78%) are tolerating oral nutrition. Balloon dilations (median 4, range 1-11) were performed either prophylactically for radiographic asymptomatic anastomotic narrowing (n = 7, 78%) or to treat clinically-significant anastomotic narrowing (n = 2, 22%) with no ongoing dilations at 3-month follow up post-repair. CONCLUSION: EMCA with the Connect-EA device is a safe and feasible minimally-invasive alterative for EA repair in high-risk surgical patients. Promising post-operative outcomes warrant further Phase I investigation. LEVEL OF EVIDENCE: IV, Case series of novel operative technique without comparison group.

Evaluation of a Magnetic Compression Anastomosis for Jejunoileal Partial Diversion in Rhesus Macaques.

PURPOSE: Metabolic surgery remains underutilized for treating type 2 diabetes, as less invasive alternative interventions with improved risk profiles are needed. We conducted a pilot study to evaluate the feasibility of a novel magnetic compression device to create a patent limited caliber side-to-side jejunoileal partial diversion in a nonhuman primate model. MATERIALS AND METHODS: Using an established nonhuman primate model of diet-induced insulin resistance, a magnetic compression device was used to create a side-to-side jejunoileal anastomosis. Primary outcomes evaluated feasibility (e.g., device mating and anastomosis patency) and safety (e.g., device-related complications). Secondary outcomes evaluated the device's ability to produce metabolic changes associated with jejunoileal partial diversion (e.g., homeostatic model assessment of insulin resistance [HOMA-IR] and body weight). RESULTS: Device mating, spontaneous detachment, and excretion occurred in all animals (n = 5). There were no device-related adverse events. Upon completion of the study, ex vivo anastomoses were widely patent with healthy mucosa and no evidence of stricture. At 6 weeks post-device placement, HOMA-IR improved to below baseline values (p < 0.05). Total weight also decreased in a linear fashion (R2 = 0.97) with total weight loss at 6 weeks post-device placement of 14.4% (p < 0.05). CONCLUSION: The use of this novel magnetic compression device to create a limited caliber side-to-side jejunoileal anastomosis is safe and likely feasible in a nonhuman primate model. The observed glucoregulatory and metabolic effects of a partial jejunoileal bypass with this device warrant further investigation to validate the long-term glucometabolic impact of this approach.

Beyond the gut: spectrum of magnetic surgery devices.

Since the 1970s, magnetic force has been used to augment modern surgical techniques with the aims of minimizing surgical trauma and optimizing minimally-invasive systems. The majority of current clinical applications for magnetic surgery are largely centered around gastrointestinal uses-such as gastrointestinal or bilioenteric anastomosis creation, stricturoplasty, sphincter augmentation, and the guidance of nasoenteric feeding tubes. However, as the field of magnetic surgery continues to advance, the development and clinical implementation of magnetic devices has expanded to treat a variety of non-gastrointestinal disorders including musculoskeletal (pectus excavatum, scoliosis), respiratory (obstructive sleep apnea), cardiovascular (coronary artery stenosis, end-stage renal disease), and genitourinary (stricture, nephrolithiasis) conditions. The purpose of this review is to discuss the current state of innovative magnetic surgical devices under clinical investigation or commercially available for the treatment of non-gastrointestinal disorders.

Designing effective exercise intervention trials for prostate cancer cohorts: a qualitative study on experiences and views of exercise oncology researchers.

BACKGROUND: Exercise intervention research has shown promising results in preventing and reversing the side effects caused by prostate cancer and its' treatment. However, there are still unanswered questions and the need for additional research. As the field of exercise oncology in the context of prostate cancer presents unique challenges and complexities, seeking the advice of experienced exercise oncology researchers before initiating a similar trial could help to design more effective and efficient studies and help avoid pitfalls. METHODS: A qualitative descriptive study design and a nonprobability, purposive sampling method was employed. An interview guide was developed and included topics such as recruitment, retention, programme goals, research design, health considerations, treatment considerations, adverse events, exercise prescription and outcome tools. Individual semi-structured interviews were conducted and interviews were transcribed and analysed using thematic analysis. RESULTS: Eight individuals with extensive experience working with prostate cancer patients in exercise oncology research settings were interviewed. Four main themes and seven subthemes were generated and supported by the data. Theme 1 highlighted the critical role of recruitment, with associated subthemes on recruitment barriers and recruitment methods. Theme 2 explored the positives and negatives of home-based programmes. Theme 3 focused on specific health characteristics, exercise prescription and outcome measure factors that must be considered when working with prostate cancer cohorts. Finally, theme 4 centered around the emotional dimensions present in exercise oncology trials, relating to both researchers and study participants. CONCLUSION: Exercise oncology remains a challenging area in which to conduct research. Learning from experienced personnel in the field offers valuable information and guidance that could impact the success of future trials.