PMDedu: Assessing the educational needs of startups and academic investigators focused on pediatric medical device development.

Background: The pediatric medical device development (PMDD) process is highly complex, beset by a variety of financial, technical, medical, and regulatory barriers. Startup company innovators and academic investigators often struggle with accessing specialized knowledge relating to regulatory requirements, product development, research, and marketing strategies. Objectives: The West Coast Consortium for Technology & Innovation in Pediatrics (CTIP) conducted an educational needs assessment to understand knowledge gaps and inform our educational strategy. Methods: We surveyed a total of 49 medical device startups and 52 academic investigators. Electronic surveys were developed for each group on Qualtrics and focused on manufacturing, regulatory, research, commercialization, and funding. Descriptive statistics were used. Results: A larger proportion of academic investigator respondents had a clinical background compared to the startup respondents (45% vs. 22%). The biggest barriers for academic investigators were understanding regulatory and safety requirements testing (52%) and finding and obtaining non-dilutive funding was the most difficult (54%). Among startups, understanding clinical research methods and requirements was the biggest barrier (79%). Conclusion: Startup companies and academic investigators have similar, but not identical, educational needs to better understand the PMD development process. Investigators need more support in identifying funding sources, while startup companies identified an increased need for education on research regulatory topics. These findings can help guide curriculum development as well as opportunities for partnerships between academia and startups.

Improving Environmental Health in Schools.

School environmental conditions have immediate and long-term effects on student health and learning. Relying on disconnected, inconsistent, voluntary, or unenforced environmental standards has not resulted in sufficient protection of students from toxic insults. Furthermore, the United States public school system was not prepared to navigate a potentially deadly infectious disease like COVID-19. Although Department of Education agencies have policies to establish clean and safe learning spaces, deficiencies are evident. This article highlights common environmental challenges in schools and opportunities for improvement. Voluntary adoption of rigorous environmental policies by grassroots efforts alone is unlikely to occur in all school systems. In the absence of a legally enforced requirement, the dedication of sufficient resources to update infrastructure and build the environmental health workforce capacity is equally unlikely to occur. Environmental health standards in schools should not be voluntary. Science-based standards should be comprehensive, and part of an actionable, integrated strategy that includes preventive measures and addresses environmental health issues sustainably. Establishing an Integrated Environmental Management approach for schools will require a coordinated capacity-building effort, community-based implementation efforts, and enforcement of minimal standards. Schools will need ongoing technical support and training for staff, faculty, and teachers sufficient to enable them to assume greater oversight and responsibility for environmental management of their schools. Ideally, a holistic approach will include all environmental health components, including IAQ, IPM, green cleaning, pesticide and chemical safety, food safety, fire prevention, building legacy pollutant management, and drinking water quality. Thus, creating a comprehensive management system with continuous monitoring and maintenance. Clinicians who care for children can serve as advocates for children's health beyond their clinic walls by advising parents and guardians to be aware of school conditions and management practices. Medical professionals have always been valued and influential members of communities and school boards. In these roles they can greatly assist in identifying and providing solutions to reduce environmental hazards in schools.

Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study.

BACKGROUND: Conversion of 25-hydroxyvitamin D (25[OH]D) to the active form of vitamin D occurs primarily in the kidney. Observational studies suggest 25(OH)D clearance from the circulation differs by kidney function and race. However, these potential variations have not been tested using gold-standard methods. METHODS: We administered intravenous, deuterated 25(OH)D3 (d-25[OH]D3) in a pharmacokinetic study of 87 adults, including 43 with normal eGFR (≥60 ml/min per 1.73 m2), 24 with nondialysis CKD (eGFR <60 ml/min per 1.73 m2), and 20 with ESKD treated with hemodialysis. We measured concentrations of d-25(OH)D3 and deuterated 24,25-dihydroxyvitamin D3 at 5 minutes and 4 hours after administration, and at 1, 4, 7, 14, 21, 28, 42, and 56 days postadministration. We calculated 25(OH)D clearance using noncompartmental analysis of d-25(OH)D3 concentrations over time. We remeasured 25(OH)D clearance in a subset of 18 participants after extended oral vitamin-D3 supplementation. RESULTS: The mean age of the study cohort was 64 years; 41% were female, and 30% were Black. Mean 25(OH)D clearances were 360 ml/d, 313 ml/d, and 263 ml/d in participants with normal eGFR, CKD, and kidney failure, respectively (P=0.02). After adjustment for age, sex, race, and estimated blood volume, lower eGFR was associated with reduced 25(OH)D clearance (ß=-17 ml/d per 10 ml/min per 1.73 m2 lower eGFR; 95% CI, -21 to -12). Black race was associated with higher 25(OH)D clearance in participants with normal eGFR, but not in those with CKD or kidney failure (P for interaction=0.05). Clearance of 25(OH)D before versus after vitamin-D3 supplementation did not differ. CONCLUSIONS: Using direct pharmacokinetic measurements, we show that 25(OH)D clearance is reduced in CKD and may differ by race. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease (CLEAR), NCT02937350; Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation (CLEAR-PLUS), NCT03576716.

Incidence of Skin and Respiratory Immune-Related Adverse Events Correlates With Specific Tumor Types in Patients Treated With Checkpoint Inhibitors.

Checkpoint inhibitors (CPIs) increase antitumor activity by unblocking regulators of the immune response. This action can provoke a wide range of immunologic and inflammatory side effects, some of which can be fatal. Recent studies suggest that CPI-induced immune-related adverse events (irAEs) may predict survival and response. However, little is known about the mechanisms of this association. This study was undertaken to evaluate the influence of tumor diagnosis and preexisting clinical factors on the types of irAEs experienced by cancer patients treated with CPIs. The correlation between irAEs and overall survival (OS) was also assessed. All cancer patients treated with atezolizumab (ATEZO), ipilimumab (IPI), nivolumab (NIVO), or pembrolizumab (PEMBRO) at Virginia Mason Medical Center between 2011 and 2019 were evaluated. irAEs were graded according to the Common Terminology Criteria for Adverse Events (Version 5) and verified independently. Statistical analyses were performed to assess associations between irAEs, pre-treatment factors, and OS. Of the 288 patients evaluated, 59% developed irAEs of any grade, and 19% developed irAEs of grade 3 or 4. A time-dependent survival analysis demonstrated a clear association between the occurrence of irAEs and OS (P < 0.001). A 6-week landmark analysis adjusted for body mass index confirmed an association between irAEs and OS in non-Small Cell Lung Cancer (NSCLC) (P < 0.03). An association between melanoma and skin irAEs (P < 0.01) and between NSCLC and respiratory irAEs (P = 0.03) was observed, independent of CPI administered. Patients with preexisting autoimmune disease experienced a higher incidence of severe irAEs (P = 0.01), but not a higher overall incidence of irAEs (P = 0.6). A significant association between irAEs and OS was observed in this diverse patient population. No correlation was observed between preexisting comorbid conditions and the type of irAE observed. However, a correlation between skin-related irAEs and melanoma and between respiratory irAEs and NSCLC was observed, suggesting that many irAEs are driven by a specific response to the primary tumor. In patients with NSCLC, the respiratory irAEs were associated with a survival benefit.

Multiple benign adnexal tumours: Anything but benign.

Muir Torre syndrome is an autosomal dominant disorder characterised by germline mutations in mismatch repair genes involved in DNA repair, leading to microsatellite instability and a propensity to tumour formation. We report a case of a 67-year-old gentleman who underwent biopsy of a smooth nodular lesion on the nasal tip, histopathologically consistent with sebaceous adenoma. Immunohistochemistry suggested a loss of MSH6. Subsequent colonoscopy identified a poorly differentiated adenocarcinoma, with loss of staining for MSH6 and a germline mutation identified on genetic analysis. These findings were consistent with a diagnosis of Muir Torre syndrome. Whilst there is controversy in the literature regarding universal screening for Muir Torre syndrome, the early detection of visceral neoplasms is crucial. The authors strongly support screening for Muir Torre syndrome (with patient consent) upon discovery of a cutaneous sebaceous neoplasm, even in the absence of a personal or family history of visceral malignancy.

Characterization and robust nature of newly isolated oleaginous marine yeast Rhodosporidium spp. from coastal water of Northern China.

A total of ten marine yeast strains isolated from Bohai Sea, Northern China were identified to be members of three genera Rhodosporidium, Rhodotorula, and Cryptococcus. Two representative strains Rhodosporidium TJUWZ4 and Cryptococcus TJUWZA11 with high lipid content based on Nile red staining method were further characterized. A wide range of culture conditions (C and N sources, pH, temperature, salinity and C/N ratio) were tested to characterize the biomass and lipid production (yield and productivity) of these strains. Results indicated that Rhodosporidium TJUWZ4 was capable of achieving lipid yield up to 44% and 0.09 g/l-h productivity on glucose and peptone medium at pH 4, 20 °C, 30% salinity, and C/N 80. Three fatty acids, namely oleic acid (18:1), palmitic acid (C16:0) and linoleic acid (18:2) were the major intracellular fatty acids, which accounted for 90% of total lipids. With promising features for intracellular lipid accumulation, Rhodosporidium TJUWZ4 is a robust strain with great potentials for application in biodiesel production from renewable feedstocks.

Collaborative academic medical product development: An 8-year review of commercialization outcomes at the Institute of Translational Health Sciences.

INTRODUCTION: The Institute of Translational Health Sciences (ITHS), a Clinical and Translational Science Award (CTSA)-funded program at the University of Washington (UW), established the Drug and Device Advisory Committee (DDAC) to provide product-specific scientific and regulatory mentoring to investigators seeking to translate their discoveries into medical products. An 8-year retrospective analysis was undertaken to evaluate the impact of the DDAC programs on commercialization metrics. METHODS: Tracked metrics included the number of teams who consulted with the DDAC, initiated a clinical trial, formed a startup, or were successful obtaining federal small business innovation awards or venture capital. The review includes historical comparisons of the startup rates for the UW School of Medicine and the Fred Hutchinson Cancer Research Center, two ITHS-affiliated institutions that have had different DDAC utilization rates. RESULTS: Between 2008 and 2016, the DDAC supported 161 unique project teams, 28% of which went on to form a startup. The commercialization rates for the UW School of Medicine increased significantly following integration of the DDAC into the commercialization programs offered by the UW technology transfer office. CONCLUSIONS: A formalized partnership between preclinical consulting and the technology transfer programs provides an efficient use of limited development funds and a more in-depth vetting of the business opportunity and regulatory path to development.

Use of ibuprofen to assess inflammatory biomarkers in induced sputum: Implications for clinical trials in cystic fibrosis.

BACKGROUND: High-dose ibuprofen (HDI) is a clinically beneficial anti-inflammatory regimen that may be a useful reagent to study induced sputum inflammatory marker changes over short study periods appropriate for early-phase CF clinical trials. METHODS: We conducted a 28-day, open-label, randomized, controlled trial among 72 clinically stable CF subjects (FEV1≥40% predicted) randomized to HDI or routine care that assessed IL-6, IL-8, TNF-α, IL-1-ß, free neutrophil elastase, and white cell counts with differentials change from baseline in induced sputum. RESULTS: IL-6 was the only biomarker with significant within-group change: 0.13 log10 pg/mL mean reduction among ibuprofen-treated subjects (p=0.04); and no change in the control group. IL-6 change between groups was statistically significant (p=0.024). No other inflammatory biomarker differences were observed between groups after 28 days. CONCLUSION: Although we studied only one agent, HDI, these results suggest that one month may be inadequate to assess anti-inflammatory candidates using markers from induced sputum.

Academic medical product development: an emerging alliance of technology transfer organizations and the CTSA.

To bring the benefits of science more quickly to patient care, the NIH National Center Advancing Translational Sciences (NCATS) supports programs that enhance the development, testing, and implementation of new medical products and procedures. The NCATS clinical and translational science award (CTSA) program is central to that mission; creating an academic home for clinical and translational science and supporting those involved in the discovery and development of new health-related inventions. The technology transfer Offices (TTO) of CTSA-funded universities can be important partners in the development process; facilitating the transfer of medical research to the commercial sector for further development and ultimately, distribution to patients. The Aggregating Intellectual Property (IP) Working Group (AWG) of the CTSA public private partnerships key function committee (PPP-KFC) developed a survey to explore how CTSA-funded institutions currently interface with their respective TTOs to support medical product development. The results suggest a range of relationships across institutions; approximately half have formal collaborative programs, but only a few have well-connected programs. Models of collaborations are described and provided as examples of successful CTSA/TTO partnerships that have increased the value of health-related inventions as measured by follow-on funding and industry involvement; either as a consulting partner or licensee.

Pulmonary exacerbations in CF patients with early lung disease.

BACKGROUND: Current definitions of pulmonary exacerbation (PE) in cystic fibrosis are based on studies in participants with significant lung disease and may not reflect the spectrum of findings observed in younger patients with early lung disease. METHODS: We used data from a recent trial assessing the efficacy of azithromycin in children to study signs and symptoms associated with PEs and related changes in lung function and weight. RESULTS: While increased cough was present in all PEs, acute weight loss and reduction in oxygen saturation were not observed. Changes in lung function did not differ between subjects who did experience a PE and those who were exacerbation-free. CONCLUSIONS: Cough was the predominant symptom in CF patients with early lung disease experiencing a PE. There was no significant difference in mean 6-month change in lung function or weight among subjects with one or more exacerbations and those without an exacerbation.

Study design considerations for evaluating the efficacy and safety of pancreatic enzyme replacement therapy in patients with cystic fibrosis.

In 2006, the US FDA issued a 'Guidance for Industry' regarding submission of New Drug Applications for pancreatic enzyme replacement therapy (PERT) products. Five oral delayed-release PERT products have been approved by the FDA, and several others are under development and/ or evaluation for New Drug Application submission. We present in this paper recommendations of the Cystic Fibrosis Foundation's Cystic Fibrosis (CF) Therapeutics Development Network and Data Safety Monitoring Board regarding study design considerations for evaluating PERT products in patients with CF. Careful attention to study design and accuracy of the outcome measures has confirmed our understanding of the efficacy and safety of PERT for the treatment of exocrine pancreatic insufficiency of CF.

Open-label, follow-on study of azithromycin in pediatric patients with CF uninfected with Pseudomonas aeruginosa.

BACKGROUND: We previously performed a randomized placebo-controlled trial to examine the effects of azithromycin in children and adolescents 6-18 years of age with cystic fibrosis uninfected with Pseudomononas aeruginosa and demonstrated that while azithromycin did not acutely improve pulmonary function, azithromycin-reduced pulmonary exacerbations, decreased the initiation of new oral antibiotics, and improved weight gain. We now report the results of the open-label, follow-on study to assess durability of response to azithromycin and continued safety and tolerability. METHODS: Eligible participants were enrolled in a 24-week open-label study of azithromycin to compare efficacy and safety endpoints during the placebo-controlled trial versus open-label study in two groups: participants initially on azithromycin continued azithromycin (azithromycin-azithromycin) and participants initially on placebo who then received azithromycin (placebo-azithromycin). As in the placebo-controlled trial, the azithromycin dose in the open-label study was 250 mg Monday-Wednesday-Friday for participants weighing 18-35.9 kg and 500 mg Monday-Wednesday-Friday for participants weighing 36 kg or greater. RESULTS: Of 174 eligible participants, 146 (83.9%) enrolled in the open-label study. No significant improvements in lung function were observed within either group. There were no differences in outcomes in the placebo-azithromycin group during the placebo-controlled versus open-label phase. The azithromycin-azithromycin group had comparable odds of experiencing an exacerbation during the two phases (OR 1.6, CI(95) 0.8, 3.0) and stable weight gain, but new oral antibiotics were initiated more frequently during the open-label study (OR 1.9, CI(95) 1.0, 3.5). In both groups, adverse event rates were comparable during the placebo-controlled and open-label study and treatment-emergent pathogens were rare. CONCLUSIONS: During the open-label study, we observed continued durability of treatment response to azithromycin, as measured by pulmonary exacerbations and continued weight gain, although use of oral antibiotics increased. There were no new safety concerns. Currently available data suggest that azithromycin reduces exacerbations and improves weight gain for 6-12 months among children and adolescents with CF uninfected with P. aeruginosa.

Biology and data-intensive scientific discovery in the beginning of the 21st century.

The life sciences are poised at the beginning of a paradigm-changing evolution in the way scientific questions are answered. Data-Intensive Science (DIS) promise to provide new ways of approaching scientific challenges and answering questions. This article is a summary of the life sciences issues and challenges as discussed in the DIS workshop in Seattle, September 19-20, 2010.

The CTSA Pharmaceutical Assets Portal - a public-private partnership model for drug repositioning.

The Pharmaceutical Assets Portal aims to facilitate industry-academic collaborations for discovery of new indications for compounds no longer being developed by pharmaceutical companies, through eliminating barriers to access such compounds. The Portal's enabling infrastructure includes a national investigator database; a Foci-of-Expertise browser; a material transfer agreement template; and a funding partner. Whereas the goal of creating a shared compound repository remains to be achieved, the Portal has established a mechanism to facilitate future drug repositioning opportunities.

Development of the first inhaled antibiotic for the treatment of cystic fibrosis.

Tobramycin Inhalation Solution USP (TOBI), a therapy developed to treat lung infections associated with cystic fibrosis (CF), was presented as a demonstration case for collaborative pharmaceutical development at a Clinical and Translational Science Awards Industry Forum on "Promoting Efficient and Effective Collaborations Among Academia, Government, and Industry" held in February 2010. TOBI was developed by PathoGenesis Corporation (Seattle, WA) in collaboration with the academic inventors, the National Institutes of Health, the U.S. Food and Drug Administration, and the CF Foundation. The presenters, representing the academic, industry, and foundation partners, each reviewed the program from their perspectives and identified challenges that existed during the discovery, development, and commercialization of TOBI. The attendees were asked to consider other collaborative opportunities that might have further improved TOBI development, including the optimal roles of the academic researchers, foundations, and other agencies when industry drives development and commercialization decisions.

Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.

BACKGROUND: A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro. METHODS: We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). RESULTS: At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P=0.008 for the within-subject comparison, P=0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770. CONCLUSIONS: This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.).

Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial.

CONTEXT: Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF. OBJECTIVE: To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada. Of the 324 participants screened, 260 were randomized and received study drug. Eligibility criteria included age of 6 to 18 years, a forced expiratory volume in the first second of expiration (FEV(1)) of at least 50% predicted, and negative respiratory tract cultures for P. aeruginosa for at least 1 year. Randomization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center. INTERVENTION: The active group (n = 131) received 250 mg (weight 18-35.9 kg) or 500 mg (weight > or = 36 kg) of azithromycin 3 days per week (Monday, Wednesday, and Friday) for 168 days. The placebo group (n = 129) received identically packaged placebo tablets on the same schedule. MAIN OUTCOME MEASURES: The primary outcome was change in FEV(1). Exploratory outcomes included additional pulmonary function end points, pulmonary exacerbations, changes in weight and height, new use of antibiotics, and hospitalizations. Changes in microbiology and adverse events were monitored. RESULTS: The mean (SD) age of participants was 10.7 (3.17) years. The mean (SD) FEV(1) at baseline and 168 days were 2.13 (0.85) L and 2.22 (0.86) L for the azithromycin group and 2.12 (0.85) L and 2.20 (0.88) L for the placebo group. The difference in the change in FEV(1) between the azithromycin and placebo groups was 0.02 L (95% confidence interval [CI], -0.05 to 0.08; P = .61). None of the exploratory pulmonary function end points were statistically significant. Pulmonary exacerbations occurred in 21% of the azithromycin group and 39% of the placebo group. Participants in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Participants in the azithromycin group had no increased risk of adverse events, but had less cough (-23% treatment difference; 95% CI, -33% to -11%) and less productive cough (-11% treatment difference; 95% CI, -19% to -3%) compared with placebo participants. CONCLUSION: In children and adolescents with CF uninfected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00431964.

The construct of problem solving in higher level neuropsychological assessment and rehabilitation.

Three inter-related studies examine the construct of problem solving as it relates to the assessment of deficits in higher level outpatients with traumatic brain injury (TBI). Sixty-one persons with TBI and 58 uninjured participants completed measures of problem solving and conceptually related constructs, which included neuropsychological tests, self-report inventories, and roleplayed scenarios. In Study I, TBI and control groups performed with no significant differences on measures of memory, reasoning, and executive function, but medium to large between-group differences were found on timed attention tasks. The largest between-group differences were found on psychosocial and problem-solving self-report inventories. In Study II, significant-other (SO) ratings of patient functioning were consistent with patient self-report, and for both self-report and SO ratings of patient problem solving, there was a theoretically meaningful pattern of correlations with timed attention tasks. In Study III, a combination of self-report inventories that accurately distinguished between participants with and without TBI, even when cognitive tests scores were in the normal range, was determined. The findings reflect intrinsic differences in measurement approaches to the construct of problem solving and suggest the importance of using a multidimensional approach to assessment.