Efficient electrospray deposition of surfaces smaller than the spray plume.

Electrospray deposition (ESD) is a promising technique for depositing micro-/nano-scale droplets and particles with high quality and repeatability. It is particularly attractive for surface coating of costly and delicate biomaterials and bioactive compounds. While high efficiency of ESD has only been successfully demonstrated for spraying surfaces larger than the spray plume, this work extends its utility to smaller surfaces. It is shown that by architecting the local "charge landscape", ESD coatings of surfaces smaller than plume size can be achieved. Efficiency approaching 100% is demonstrated with multiple model materials, including biocompatible polymers, proteins, and bioactive small molecules, on both flat and microneedle array targets. UV-visible spectroscopy and high-performance liquid chromatography measurements validate the high efficiency and quality of the sprayed material. Here, we show how this process is an efficient and more competitive alternative to other conformal coating mechanisms, such as dip coating or inkjet printing, for micro-engineered applications.

Novel suction-based in vivo cutaneous DNA transfection platform.

This work reports a suction-based cutaneous delivery method for in vivo DNA transfection. Following intradermal Mantoux injection of plasmid DNA in a rat model, a moderate negative pressure is applied to the injection site, a technique similar to Chinese báguàn and Middle Eastern hijama cupping therapies. Strong GFP expression was demonstrated with pEGFP-N1 plasmids where fluorescence was observed as early as 1 hour after dosing. Modeling indicates a strong correlation between focal strain/stress and expression patterns. The absence of visible and/or histological tissue injury contrasts with current in vivo transfection systems such as electroporation. Specific utility was demonstrated with a synthetic SARS-CoV-2 DNA vaccine, which generated host humoral immune response in rats with notable antibody production. This method enables an easy-to-use, cost-effective, and highly scalable platform for both laboratorial transfection needs and clinical applications for nucleic acid­based therapeutics and vaccines.

An early endothelial cell-specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice.

Paucity of the glucose transporter-1 (Glut1) protein resulting from haploinsufficiency of the SLC2A1 gene arrests cerebral angiogenesis and disrupts brain function to cause Glut1 deficiency syndrome (Glut1 DS). Restoring Glut1 to Glut1 DS model mice prevents disease, but the precise cellular sites of action of the transporter, its temporal requirements, and the mechanisms linking scarcity of the protein to brain cell dysfunction remain poorly understood. Here, we show that Glut1 functions in a cell-autonomous manner in the cerebral microvasculature to affect endothelial tip cells and, thus, brain angiogenesis. Moreover, brain endothelial cell-specific Glut1 depletion not only triggers a severe neuroinflammatory response in the Glut1 DS brain, but also reduces levels of brain-derived neurotrophic factor (BDNF) and causes overt disease. Reduced BDNF correlated with fewer neurons in the Glut1 DS brain. Controlled depletion of the protein demonstrated that brain pathology and disease severity was greatest when Glut1 scarcity was induced neonatally, during brain angiogenesis. Reducing Glut1 at later stages had mild or little effect. Our results suggest that targeting brain endothelial cells during early development is important to ensure proper brain angiogenesis, prevent neuroinflammation, maintain BDNF levels, and preserve neuron numbers. This requirement will be essential for any disease-modifying therapeutic strategy for Glut1 DS.

Therapeutic strategies for glucose transporter 1 deficiency syndrome.

Proper development and function of the mammalian brain is critically dependent on a steady supply of its chief energy source, glucose. Such supply is mediated by the glucose transporter 1 (Glut1) protein. Paucity of the protein stemming from mutations in the associated SLC2A1 gene deprives the brain of glucose and triggers the infantile-onset neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). Considering the monogenic nature of Glut1 DS, the disease is relatively straightforward to model and thus study. Accordingly, Glut1 DS serves as a convenient paradigm to investigate the more general cellular and molecular consequences of brain energy failure. Here, we review how Glut1 DS models have informed the biology of a prototypical brain energy failure syndrome, how these models are facilitating the development of promising new treatments for the human disease, and how important insights might emerge from the study of Glut1 DS to illuminate the myriad conditions involving the Glut1 protein.

Evaluation of 4 Outcomes Measures in Microtia Treatment: Exposures, Infections, Aesthetics, and Psychosocial Ramifications.

BACKGROUND: In craniofacial microsomia, microtia and canal atresia pose formidable reconstructive challenges. We review our institutional experience in treating microtia and atresia to identify variables associated with 4 outcomes measures: complications, surgical revisions, aesthetic outcomes, and psychosocial function. METHODS: Craniofacial microsomia patients treated at the University of California Los Angeles Craniofacial Clinic between 2008 and 2014 greater than 13 years of age (n = 68) were reviewed for microtia and atresia treatment and outcomes. RESULTS: In total, 91.2% of patients diagnosed with craniofacial microsomia presented with microtia, affecting 75 ears. Both a male and right-sided predominance were observed. Fifty-six patients (90.3%) underwent autologous external ear reconstruction at an average age of 8.5 years. Age, type of incision, and size of cartilage framework did not predict total number of surgeries or complications. Severity of ear anomalies correlated with increased number of surgeries (P < 0.001) and decreased aesthetic outcomes (P < 0.001) but not complications. In total, 87.1% of patients with microtia had documented hearing loss, of which the majority were conductive and 18.5% were mixed sensorineural and conductive. Hearing deficits were addressed in 70.4% of patients with external hearing aids, bone anchored hearing aids, or canaloplasty. Of all variables, improvement of psychosocial function was correlated only to hearing loss treatment of any type (P = 0.01). CONCLUSIONS: On evaluation of surgical and patient characteristics, severity of microtia predicted the total number of surgical revisions performed and aesthetic ratings. In addition, we found that the only factor that correlated with improved patient and parent-reported psychosocial outcomes was treatment of hearing loss.

Safety and efficacy of ledipasvir/sofosbuvir for the treatment of genotype 1 hepatitis C in subjects aged 65 years or older.

UNLABELLED: Elderly subjects have been historically underrepresented in clinical trials involving antiviral hepatitis C therapies. The aim of this analysis was to retrospectively evaluate the safety and efficacy of ledipasvir/sofosbuvir (LDV/SOF) by age groups of <65 years versus ≥65 years among subjects enrolled in phase 3 trials. Four open-label phase 3 clinical trials evaluated the safety and efficacy of LDV/SOF with or without ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C virus. Sustained virological response at 12 weeks, treatment-emergent adverse events (AEs), and graded laboratory abnormalities were analyzed according to age group. Of the 2293 subjects enrolled in four phase 3 trials, 264 (12%) were ≥65 years of age, of whom 24 were aged ≥75 years. Sustained virological response at 12 weeks was achieved by 97% (1965/2029) of subjects aged <65 years and 98% (258/264) of subjects aged ≥65 years. The most common AEs in both LDV/SOF groups that occurred in ≥10% of subjects were headache and fatigue. The rate of study discontinuation due to AEs was similar in the two age cohorts. The use of RBV in 1042 (45%) subjects increased the number of AEs, treatment-related AEs, and AEs leading to study drug modification/interruption, particularly among elderly subjects. CONCLUSIONS: LDV/SOF with or without RBV was highly effective for treatment of genotype 1 chronic hepatitis C virusin subjects aged 65 and older. Addition of RBV did not increase sustained virological response at 12 weeks rates but led to higher rates of AEs, especially in elderly subjects.

Variability in United States Allopathic Medical School Tuition.

BACKGROUND: Over the course of the last generation, the cost of medical school attendance and medical student debt has increased drastically. Medical student debt has been reported as high as $350,000, and the Association of American Medical Colleges (AAMC) reports that medical school tuition continues to increase annually. The increasing cost of medical education and associated financial burden is now beginning to deter potential applicants from pursuing a career in medicine. In this study we aimed to assess medical school tuition across the US. We hypothesized that the cost of medical school attendance is variable across all regions of the US, and as a result, the financial burden on medical students is inconsistent. METHODS: All 123 allopathic medical schools accredited by the AAMC were assessed in this investigation. In-state and out-of-state tuitions for the year 2016 were obtained from U.S. News and World Report. Additionally, medical school size was collected. Regions were defined according to the US Census Bureau definition, with the US being divided into 4 regions: Northeast, Midwest, South, and West. RESULTS: There was no difference in average medical school size among the 4 regions (P > .05). Average in-state tuition was $38,291.56 ± $9801.38 (95% confidence interval [CI], $34,658.07-$41,513.46) in the Midwest, $45,923.04 ± $9178.87 (95% CI, $42,566.28-$49,216.78) in the Northeast, $32,287.78 ± $12,277.53 (95% CI, $28,581.90-$35,378.68) in the South, and $37,745.40 ± $11,414.37 (95% CI, $30,063.28-$40,458.99) in the West. In-state tuition in the South was significantly lower than in the Northeast, West, and Midwest (P < .05). In-state tuition in the Northeast was significantly higher than in the South, West, and Midwest (P < .05). Average out-of-state tuition is $54,104.04 ± $8227.65 (95% CI, $51,207.6-$57,000.39) in the Midwest, $53,180.10 ± $3963.71 (95% CI, $51,761.71-$54,598.50) in the Northeast, $48,191.86 ± $12,578.13 (95% CI, $44,595.84-$51,787.89) in the South, and $52,920.47 ± $7400.83 (95% CI, $49,175.13-$56,665.80) in the West. Out-of-state tuition was significantly lower in the South in comparison with the Midwest and Northeast (P < .05), but was not significantly different than the West (P > .05). CONCLUSION: Despite no significant difference in medical school size among the 4 regions of the US that were assessed, there is significant regional variation in tuition, with higher tuition in private vs public schools. This study suggests that medical schools place a variable financial burden on the medical students based on region. The ongoing increases in medical school tuition are unsustainable, as future trainees will face substantial financial stress as they attempt to pay off their debt while initiating medical practice after residency and fellowship training.

Medical Students' Perceptions of Surgeons: Implications for Teaching and Recruitment.

OBJECTIVE: The purpose of this study was to assess first-year medical students' implicit perceptions of surgeons, focusing on the roles of gender and demeanor (communal = supportive, associated with women; agentic = assertive, associated with men). DESIGN: Survey study. Each survey had 1 of 8 possible scenarios; all began with a short description of a surgeon who was described as accomplished and well trained, then varied by surgeon gender (male/female), surgeon demeanor (agentic/communal), and type of surgery (breast cancer/lung cancer). Using a 0 to 5 scale, respondents rated their perception of the surgeon through 5 questions. These 5 items were averaged to create a composite perception score scaled from 0 to 5. SETTING: Surveys were administered at the University of California, San Francisco, and the University of California, Los Angeles. PARTICIPANTS: We administered surveys to 333 first-year medical students who could read English and voluntarily agreed to participate. RESULTS: A total of 238 students responded (71.5%). They preferred the communal vs agentic surgeon (4.2 ± 0.7 vs 3.9 ± 0.7, p = 0.002) and male medical students perceived surgeons more favorably than female medical students did (4.2 ± 0.6 vs 4.0 ± 0.8, p = 0.036). The preference score did not differ according to surgeon gender (female 4.12 vs male 3.98, p = 0.087). There were no significant interactions between the factors of student gender, surgeon gender, or demeanor. Students who reported an interest in surgery as a career did not perceive surgeons more favorably than the students interested in other fields (4.3 ± 0.7 vs 4.0 ± 0.7 respectively, p = 0.066). CONCLUSIONS: Based on our findings, surgeon educators would likely find success in teaching and recruiting medical students by employing a communal demeanor in their interactions with all students, regardless of the students' gender or stated interest in surgery.