Injuries to the peripheral nervous system are major sources of disability and often result in painful neuropathies or the impairment of muscle movement and/or normal sensations. For gaps smaller than 10 mm in rodents, nearly normal functional recovery can be achieved; for longer gaps, however, there are challenges that have remained insurmountable. The current clinical gold standard used to bridge long, nonhealing nerve gaps, the autologous nerve graft (autograft), has several drawbacks. Despite best efforts, engineering an alternative "nerve bridge" for peripheral nerve repair remains elusive; hence, there is a compelling need to design new approaches that match or exceed the performance of autografts across critically sized nerve gaps. Here an immunomodulatory approach to stimulating nerve repair in a nerve-guidance scaffold was used to explore the regenerative effect of reparative monocyte recruitment. Early modulation of the immune environment at the injury site via fractalkine delivery resulted in a dramatic increase in regeneration as evident from histological and electrophysiological analyses. This study suggests that biasing the infiltrating inflammatory/immune cellular milieu after injury toward a proregenerative population creates a permissive environment for repair. This approach is a shift from the current modes of clinical and laboratory methods for nerve repair, which potentially opens an alternative paradigm to stimulate endogenous peripheral nerve repair.immunomodulation | nerve repair | monocyte | macrophage | fractalkine P eripheral nervous system (PNS) injuries lead to long-term disability and decreased function in ∼2.8% of all trauma patients (1), and are often followed by neuropathic pain that significantly affects the quality of life for individuals suffering from these injuries. Many of the current surgical techniques for repairing these nerve injuries were developed during World Wars I and II in the first half of the 20th century. With
Background Ensuring representative data accrual in clinical trials is important to safeguard the generalizability of results and to minimize disparities in care. This study's goal was to evaluate differences in gender representation in trials leading to US Food and Drug Administration (FDA) cancer drug approvals. Methods An observational study was conducted from January 2014 to April 2019 using PubMed and the National Institutes of Health trials registry for primary trial reports. The National Cancer Institute's Surveillance, Epidemiology, and End Results program and US Census were consulted for national cancer incidence. The outcome was an enrollment incidence disparity (EID), which was calculated as the difference between male and female trial enrollment and national incidence, with positive values representing male overrepresentation. Results There were 149 clinical trials with 59,988 participants—60.3% and 39.7% were male and female, respectively—leading to 127 oncology drug approvals. The US incidence rates were 55.4% for men versus 44.6% for women. Gender representation varied by specific tumor type. Most notably, women were underrepresented in thyroid cancer (EID, +27.4%), whereas men were underrepresented in soft tissue cancer (EID, –26.1%). Overall, women were underrepresented when compared with expected incidence (EID, +4.9%; 42% of trials). Conclusions For many specific tumor types, women are underrepresented in clinical trials leading to FDA oncology drug approvals. It is critical to better align clinical trial cohort demographics and the populations to which these data will be extrapolated. Lay Summary This study assesses whether gender disparities exist in clinical trials leading to US Food and Drug Administration (FDA) cancer drug approvals. From January 2014 to April 2019, 149 clinical trials leading to FDA oncology drug approvals showed 60.3% and 39.7% of the enrollees were male and female, respectively. Gender representation varied by specific tumor when compared with the expected incidence rate of cancer in the United States, although women were more often underrepresented. Increased efforts are needed with regard to ensuring equitable representation in oncology clinical trials.
Objective: To investigate seasonal variation of orofacial clefts (OC) and measure association between United States (U.S.) influenza incidences and OC development for the purpose of identifying a potential modifiable risk factor for pregnant women. Design: Retrospective population-based observational study from 2004 to 2013. Setting: National Inpatient Sample Database (NIS), Wide-ranging Online Data for Epidemiologic Research (WONDER) Database, and National Respiratory and Enteric Virus Surveillance System’s (NRVESS) FluView database. Patients: U.S.-born infants with OC from 2004 to 2013 and monthly influenza incidence from 2003 to 2013. Main outcome measures: Using logistic regression, monthly odds ratios (OR) of OC were derived using January as baseline. Mixed-effects logistic regression was utilized to test association between national influenza and OC incidences. Results: There were 58 270 U.S. babies born with OC from 2004 to 2013. September births had the highest OC association (OR = 1.094, 95% CI = 1.051-1.138, E-value = 1.41), followed by June. For each additional influenza case per 1000 people, odds of OC event occurring during the 2nd month of pregnancy, or 7 months before delivery, was increased by 2.7 (OR = 2.659, CI = 1.456-4.856, E-value = 4.76). Odds of OC event occurring was decreased at the 3rd month of pregnancy, or 6 months before delivery by 7.8 (OR = 0.129, 95% CI = 0.068-0.246, E-value = 14.99). Conclusion: September and June births have the highest OC association. There is increased risk for OC with influenza occurring at the 2nd pregnancy month. Conversely, there are protective effects against OC with influenza occurring at the 3rd pregnancy month. These findings demonstrate an association between influenza rate and OC, suggesting a connection between maternal immune activation (mIA) and OC. Although further research is needed to determine the definitive link between the use of flu vaccines and OC occurrence, as well as the mechanism behind mIA secondary to influenza infection impacting OC incidence, this study presents a modifiable risk factor that could decrease the potential for mIA causing OC.
Objective: Maternal immune activation secondary to influenza infection during critical periods of fetal development is a significant risk factor for neuropsychiatric and neurodevelopmental disorders. The association between influenza and craniosynostosis is not well documented. We investigate the association between the incidence of influenza infection and incidence of craniosynostosis in the United States. Materials and Methods: Retrospective population-based observational study spanning using the National Inpatient Sample Database, the United States Center for Disease Control and Prevention FluView databases, including infants born with craniosynostosis in the United States from 2004 to 2013 and monthly influenza incidence in the United States from 2003 to 2013. Mixed-effects logistic regression tested the association between 2 variables: national influenza incidences and rate of craniosynostosis. Odds ratios were calculated for the occurrence of craniosynostosis in relation to previous months’ flu incidence. E-values were calculated to evaluate unmeasured confounders. Results: Retrospective analysis performed on 45 356 newborns with craniosynostosis. Mixed-effects logistic regression revealed for each additional influenza case per 1000 people, the odds of craniosynostosis event occurring 6 months later increased by 3.4 (adjusted P = .009, OR = 3.444, CI = 1.756-6.754). For each additional influenza case per 1000 people, the odds of craniosynostosis event occurring 7 and 2 months later decreased by 3.8 and 6.1, respectively (OR = 0.262 and 0.165; adjusted P value = .007 and <.001). E-value for the association between influenza and craniosynostosis incidence 6 months later was 6.35. The E-values for the association between influenza and craniosynostosis incidences 7 months and 2 months later were 7.1 and 11.6. Conclusion: There is an increased risk for craniosynostosis with influenza occurring in third month of pregnancy. There are protective effects against craniosynostosis with influenza occurring in second and seventh months of pregnancy. To our knowledge, this is the first study demonstrating an association between the rate of influenza and craniosynostosis, suggesting a potentially important connection, though not necessarily causality, between maternal immune activation and craniosynostosis.
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