Respondent Demographics and Contraceptive Use Patterns in the United States: A National Survey of Family Growth Analysis.

INTRODUCTION: Contraception is an important tool for helping to prevent both unintended pregnancies and sexually transmitted infections (STIs). Medical costs related to STIs are high and impose a large burden on both patients and the healthcare system. In addition, unintended pregnancies account for a large portion of pregnancies in the United States (US) and are associated with adverse maternal and infant health outcomes. Both STIs and unintended pregnancies are continuous public health concerns, and this study aims to identify patterns in contraceptive method use in relation to specific social determinants of health. METHODS: Utilizing the Centers for Disease Control and Prevention (CDC)'s 2017-2019 National Survey of Family Growth report on current contraceptive status, we isolated data from 3,572 respondents who reported using one of the following contraceptive methods: oral contraceptive pills (OCPs), male condoms, partner's vasectomy, female sterilization, withdrawal, medroxyprogesterone acetate injections (Depo-Provera), hormonal implant, or an intrauterine device (IUD). We analyzed these contraceptive methods among age, race, education, marital status, and insurance status. Data were analyzed in RStudio 2022.02.0 (RStudio Team, RStudio: Integrated Development for R. RStudio, PBC, Boston, MA) through a test of equal proportions for a significance of P < 0.05. A concurrent Yates' continuity correction was performed in order to limit erroneous significant findings based on small sample sizes where applicable. The study conception and data analysis were performed independently with oversight from our preceptor at HCA Florida Brandon Hospital, Brandon, Florida. RESULTS: There were statistically significant differences for all our selected methods of contraception across different age groups. There were statistically significant differences for OCPs, male condoms, partner's vasectomy, female sterilization, Depo-Provera, hormonal implant, and IUD across different race groups and different insurance statuses. There were statistically significant differences for OCPs, male condoms, partner's vasectomy, female sterilization, withdrawal, hormonal implant, and IUD across different education levels and different marital statuses. CONCLUSION: This analysis highlights gaps that are present in female reproductive autonomy through the statistical differences in contraceptive methods across various demographics and warrants continued focus on the role that social determinants of health play in the prevention of unintended pregnancies and STIs. In order to promote fairness and equality in healthcare, it is essential to increase education on these topics both within and beyond medical settings. This effort aims to provide patients with equitable access to healthcare and attempt to address health disparities that are prevalent in multiple different sectors.

Comparison of lidocaine and lidocaine-xylazine for distal paravertebral anesthesia in dairy cattle.

OBJECTIVE: To determine the time of onset and duration of action of distal paravertebral blocks (DPB) in dairy cattle using lidocaine and lidocaine plus xylazine (LX). ANIMALS: 10 healthy adult Holstein cows. METHODS: Unilateral DPB were performed in 6 cows at L1, L2, and L4. They received 2 treatments (lidocaine and LX) in a blinded random crossover design. Due to treatment failure, 4 additional cows were enrolled. The lidocaine treatment received 1,800 mg (90 mL) of lidocaine, and treatment LX received 1,784 mg (89.2 mL) of lidocaine and 16 mg (0.8 mL) of xylazine. Anesthesia was assessed by response (rapid movements of the tail, directed movements of the feet, or turning of the head towards the site of the needle pricks) to 6 approximately 1-cm deep needle pricks to the paralumbar fossa with a 22-gauge hypodermic needle. The time of onset, duration of action, maximum sedation score, and average heart rate (HR) were compared between treatments. RESULTS: Duration of anesthesia was significantly prolonged after DPB in cows treated with LX (251.6 ± 96.94 minutes) compared to lidocaine (105.8 ± 35.9 minutes; P = .01). Treatment with LX was associated with significantly lower average heart rate (56 ± 3 beats/min) compared to cows treated with lidocaine (59 ± 3 beats/min; P = .045). The LX treatment was associated with mild sedation but was not significant (P = .063). CLINICAL RELEVANCE: The addition of xylazine to a lidocaine DPB provides a longer duration of anesthesia, is inexpensive and practical, and can be implemented with ease.

Hypokinetic Biliary Dyskinesia in a Pediatric Patient: A Case Report.

The diagnosis of biliary dyskinesia (BD) in pediatric patients lacks uniformity across the literature. BD is among the most common reasons for cholecystectomy in pediatric patients. Even still, diagnostic criteria for this disorder, including symptomatology and gallbladder ejection fraction, as well as the symptomatic relief after cholecystectomy, are inconsistent across the literature for the pediatric population. We share the case of an 18-year-old female patient who presented to our clinic for cholecystectomy for a diagnosis of BD. After 10 months of seeking a diagnosis, an eventual nuclear medicine HIDA scan revealed a biliary ejection fraction of 18%, leading her to our care. The patient underwent robotic-assisted laparoscopic cholecystectomy and tolerated the procedure well, reporting a resolution of symptoms on follow-up. The diagnosis and management of BD are complicated by the combination of vague and varied symptomatology and a lack of definitive, uniform diagnostic criteria in the pediatric population. Variability in diagnostic requirements varies between sources. While some look to the interpretation of gallbladder emptying studies, others rely on surgical outcomes. To further complicate diagnosis, some patients experience symptoms that do not correlate with their gallbladder emptying studies. The controversy extends beyond diagnosis as some studies argue against cholecystectomy as a treatment for BD, as it has been shown to not always resolve symptoms. More research should be conducted to identify and establish more consistent diagnostic criteria for BD in the pediatric population, as well as to study symptomatic improvement following cholecystectomy to establish optimal treatment for these patients. Biliary dyskinesia is a relatively common but rather inconsistent diagnosis in the pediatric population, and attention should be turned toward developing uniform and consistent diagnostic criteria in order to optimally recognize, diagnose, and treat these patients, ensuring a shorter time-to-diagnosis and improved quality of life.

An Immunohistochemical Anomaly: A Case Report and Systematic Review of Myofibroblastoma of the Breast.

Myofibroblastoma (MFB) is a rare but benign mesenchymal tumor most commonly appearing within breast tissue. Most cases of MFB occur in postmenopausal women and are treated by surgical excision. The diagnosis of MFB is made through immunohistochemical (IHC) analysis, with the most common biomarkers being CD34+, desmin+, smooth muscle actin+, and vimentin+. In this article, we describe a case of an MFB in a premenopausal female with variance from classic IHC findings. We also performed a systemic review of the MFB of the breast. The systemic review compiles the most common IHC findings of MFB, patient demographics, treatment methods, lesion size, and the presence or absence of pain associated with the lesion. As MFB can share many features with other breast lesions, including potentially malignant ones, this article sought to underline the most common IHC findings and characteristics of MFB to aid in the proper diagnosis of MFB.

Non-steroidal Anti-inflammatory Drugs and Osteopathic Manipulative Treatment for Pain Management in Patients With Osteoarthritis: A Literature Review.

The pathophysiology of osteoarthritis (OA) involves the destruction of articular cartilage and the overgrowth of bone with lipping and spur formation. Nerve endings in the joint capsule and adjacent tissues play a major role in the pain mechanisms of osteoarthritis. This often requires patients to seek pain control measures beyond over-the-counter drugs, such as local anesthetics. Osteopathic manipulation treatment (OMT) is a conservative, non-pharmacological treatment that can be used to help treat chronic pain associated with OA. Other non-pharmacologic therapies include weight loss, exercise, physical therapy (PT), and assistive devices. However, pharmacologic management may be added synergistically to control flares and maintain baseline activities of daily living. While oral non-steroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of treatment for pain and inflammation associated with OA, they have a non-selective inhibitory action that often results in negative side effects when used chronically. The possibility of minimizing these complications through alternate treatments such as topical NSAIDs provides an opportunity for patients to receive adequate pain relief from OA without suffering unnecessary consequences. This literature review seeks to assess the state of research regarding topical NSAIDs and OMT as alternatives to the current gold-standard treatment of OA. The significant inclusion criteria consisted of articles that described the effects of OMT on OA or the use of topical NSAIDs such as Voltaren on OA. Due to the limited articles found, a qualitative analysis was performed, and the salient conclusions are outlined. Alternative pharmacological and non-pharmacological treatments, such as topical diclofenac gel and OMT, have shown promising results in the treatment of pain in OA. It is seen that a majority of patients achieve pain management using NSAIDs, acetaminophen, or topical analgesics. Both diclofenac sodium and OMT have individually been shown to be effective treatments of OA when compared to the use of oral NSAIDs. A holistic treatment approach that utilizes both topical diclofenac sodium and OMT may provide OA patients with an effective option to reduce their moderate to severe chronic pain with limited side effects. Further, high-quality randomized controlled trials are needed to identify whether synergistic effects occur when combining diclofenac sodium gel and OMT for pain relief in patients with OA.

Exploring the interagency collaboration between a pediatric oncology health care setting and community schools.

Globally, approximately 400,000 youth are diagnosed with pediatric cancer each year. Treatment-related side effects, psychosocial challenges, and frequent school absences may adversely impact learning and the education experience among these youth. Efforts to enhance interagency collaboration between health care settings and community schools are imperative to facilitate school reintegration. The Standards for the Psychosocial Care of Children with Cancer and Their Families outline specific guidelines related to the continuity of education for students impacted by pediatric cancer. In particular, the Academic Continuity and School Reentry Support and Monitoring and Assessment of Neuropsychological Outcomes standards of care highlighted within this article align with extant programmatic efforts for transitioning hospitalized school-aged children back into community schools. This article aims to describe systematic programmatic efforts within hospital-based psychosocial programs that are consistent with the Standards for the Psychosocial Care of Children with Cancer and Their Families, as well as interagency collaboration with community schools to support student-centered education for youth impacted by pediatric cancer. Resources for school psychologists, teachers, hospital-based programs, and others involved in student-centered education for pediatric cancer patients and survivors are presented. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Urolithin A as a Potential Agent for Prevention of Age-Related Disease: A Scoping Review.

The aging of an organism is hallmarked by systemic loss of functional tissue, resulting in increased fragility and eventual development of age-related neurodegenerative, musculoskeletal, cardiovascular, and neoplastic diseases. Growing scientific evidence points to mitochondrial dysfunction as a key contributor in the aging process and subsequent development of age-related pathologies. Under normal physiologic conditions, the body removes dysfunctional mitochondria via an autophagic process known as mitophagy. Urolithin A (UA), a metabolite produced when gut microflora digests the polyphenol compounds ellagitannin and ellagic acid, is a known inducer of mitophagy via several identified mechanisms of action. The primary objective of this scoping review is to identify and summarize the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases. A computer-assisted literature review was performed using PubMed and EMBASE for primary source research articles examining UA supplementation and aging-related pathologies. A total of 293 articles were initially identified from a database search, and 15 articles remained for inclusion in this review, based on predetermined criteria. Analysis of the 15 identified publications demonstrated that UA holds potential as a dietary intervention for slowing the progression of aging and preventing the development of age-related disease. This review also illustrates the potential role that mitochondrial health and inflammation play in the progression of age-related pathology. Identifying the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases will help further the focus of research on treatments that may improve the longevity and quality of life in patients at risk for these comorbidities.

Appendiceal Endometriosis Presenting As Chronic Appendicitis: A Case Report.

The origin of endometriosis has multiple theories, with controversy over which may demonstrate the prominent pathophysiology. The most common extra-pelvic organ system affected by endometriosis is the gastrointestinal tract. Gastrointestinal endometriosis (GE) accounts for 3 to 37% of all endometriosis cases, and appendiceal endometriosis is present in around 3% of GE cases, therefore constituting less than 1% of all endometriosis cases. In this report, we present a 24-year-old female with a past medical history significant for endometriosis status post two excisional laparoscopies who presented with eight months' duration of right lower quadrant pain, constant and stabbing, with rebound tenderness. Appendectomy and histopathology demonstrated focal endometriosis, diffuse serosal fibrovascular adhesions involving the appendiceal serosa/subserosa, as well as a dilated lumen filled with hemorrhagic content. When the appendix is not considered in endometriosis pathology, patients are at increased risk for unresolved pain and further laparoscopic procedures. Prophylactic appendectomy appears to be a worthwhile consideration in patients with chronic pelvic pain, given the high frequency of appendiceal pathology.

Influence of Aerosolization on Endothelial Cells for Efficient Cell Deposition in Biohybrid and Regenerative Applications.

The endothelialization of gas exchange membranes can increase the hemocompatibility of extracorporeal membrane oxygenators and thus become a long-term lung replacement option. Cell seeding on large or uneven surfaces of oxygenator membranes is challenging, with cell aerosolization being a possible solution. In this study, we evaluated the endothelial cell aerosolization for biohybrid lung application. A Vivostat® system was used for the aerosolization of human umbilical vein endothelial cells with non-sprayed cells serving as a control. The general suitability was evaluated using various flow velocities, substrate distances and cell concentrations. Cells were analyzed for survival, apoptosis and necrosis levels. In addition, aerosolized and non-sprayed cells were cultured either static or under flow conditions in a dynamic microfluidic model. Evaluation included immunocytochemistry and gene expression via quantitative PCR. Cell survival for all tested parameters was higher than 90%. No increase in apoptosis and necrosis levels was seen 24 h after aerosolization. Spraying did not influence the ability of the endothelial cells to form a confluent cell layer and withstand shear stresses in a dynamic microfluidic model. Immunocytochemistry revealed typical expression of CD31 and von Willebrand factor with cobble-stone cell morphology. No change in shear stress-induced factors after aerosolization was reported by quantitative PCR analysis. With this study, we have shown the feasibility of endothelial cell aerosolization with no significant changes in cell behavior. Thus, this technique could be used for efficient the endothelialization of gas exchange membranes in biohybrid lung applications.

The World-Wide Adaptations of Diabetic Management in the Face of COVID-19 and Socioeconomic Disparities: A Scoping Review.

Diabetes is an increasingly prevalent chronic disease throughout the world. It is imperative for patients to have access to reliable treatment and resources in order to avoid long-term complications. Economic and social factors contribute to the accessibility of these resources and have a direct impact on diabetes management. Socioeconomic status (SES) presents challenges to diabetic management due to financial and geographical access to care, medications, educational resources, healthy food options, and physical activity. The coronavirus (COVID-19) pandemic exacerbated these challenges, especially during the height of lockdowns. Therefore, it is important to gain insight into how the pandemic challenged diabetes management, taking into consideration socioeconomic disparities. The objective is to assess how the COVID-19 pandemic has impacted the care of chronic diabetic patients internationally and determine how these outcomes vary between patients of different socioeconomic classes. The following study was designed as a scoping review and utilized PubMed, EMBASE, CINAHL, and Web of Science. A Boolean search strategy combined search terms as follows: (((COVID-19) AND (diabetes)) AND ((socioeconomic factors) OR (social inequality OR standard of living))) AND (treatment OR management). Inclusion criteria included studies addressing diabetic patients, socioeconomic variables (income, occupation, level of education, and ethnicity), glycemic control, and degree of access to quality healthcare. Studies exploring the pathophysiology of COVID-19 or diabetes mellitus were excluded. In addition, studies were chosen between the years 2020 and 2022. The search resulted in 214 articles. The full-text assessment was then conducted on the remaining 67 articles. After screening for eligibility and relevance, 19 articles were retained for this review. The results of this study indicate that 8 out of the 18 studies revealed worse outcomes for those with diabetes mellitus and concomitant COVID-19 infection. Patients with diabetes were more likely to be hospitalized and represent a larger percentage of COVID-19 fatalities. In addition, patients with diabetes and co-morbid COVID-19 infection were more likely to have a higher hemoglobin A1c (HbA1c), belong to a lower SES, and have worse glycemic control due to pandemic-associated lockdown. In order to combat the effects of the pandemic, many countries created novel and innovative management strategies. Overall, there are positive and negative effects from the pandemic on diabetic management strategies. This scoping review identified successes in diabetic treatment under pandemic conditions and areas that need optimization. The successful adaptations of many nations convey the capacity for new policy implementation to care for diabetic patients regardless of SES.

Effervescent Atomizer as Novel Cell Spray Technology to Decrease the Gas-to-Liquid Ratio.

Cell spraying has become a feasible application method for cell therapy and tissue engineering approaches. Different devices have been used with varying success. Often, twin-fluid atomizers are used, which require a high gas velocity for optimal aerosolization characteristics. To decrease the amount and velocity of required air, a custom-made atomizer was designed based on the effervescent principle. Different designs were evaluated regarding spray characteristics and their influence on human adipose-derived mesenchymal stromal cells. The arithmetic mean diameters of the droplets were 15.4−33.5 µm with decreasing diameters for increasing gas-to-liquid ratios. The survival rate was >90% of the control for the lowest gas-to-liquid ratio. For higher ratios, cell survival decreased to approximately 50%. Further experiments were performed with the design, which had shown the highest survival rates. After seven days, no significant differences in metabolic activity were observed. The apoptosis rates were not influenced by aerosolization, while high gas-to-liquid ratios caused increased necrosis levels. Tri-lineage differentiation potential into adipocytes, chondrocytes, and osteoblasts was not negatively influenced by aerosolization. Thus, the effervescent aerosolization principle was proven suitable for cell applications requiring reduced amounts of supplied air. This is the first time an effervescent atomizer was used for cell processing.

Monolithic highly multi-mode XLMA-fiber resonator for high power operation.

Highly multi-mode fiber resonators can be an excellent solution to achieve high output power with homogeneous beam profiles, while nonlinear effects are suppressed due to the high number of modes and high mode-field areas. While highly reflective fiber-Bragg-gratings (HR-FBGs) are a well-developed technology in single-mode fibers, in multi-mode fibers HR-FBGs are under investigation to enable monolithic resonators. Here, we present a monolithic multi-mode fiber resonator in a > 50 µm core diameter XLMA-fiber. We achieve a slope efficiency of up to 50%, stable wavelength operation at 1074 nm and homogeneous beam profiles using an HR-FBG with app. 70% reflectivity.

Frequent hypoxemia found in infants with bronchopulmonary dysplasia after weaning home oxygen.

OBJECTIVE: Parental reports and brief clinical examinations are the primary information used to assist clinicians in weaning home supplemental oxygen in infants with bronchopulmonary dysplasia (BPD). Recorded nocturnal oximetry provides an objective assessment of hypoxemia; however, it is unknown if it identifies clinically undetected hypoxemia in the home setting. Our objective was to determine if nocturnal oximetry can identify unreported hypoxemia in infants with BPD who appear ready to wean from supplemental oxygen. STUDY DESIGN: We conducted a retrospective chart review of infants born <32 weeks gestation with BPD who were discharged to home receiving supplemental oxygen and completed recorded nocturnal oximetry in room air during an 18-month period. Abnormal oximetry was defined as >5 min with SpO2 < 90% and/or an oxyhemoglobin desaturation index (ODI4) >5. Comparative analysis of patients with normal and abnormal overnight oximetry was performed using Fisher Exact and Wilcoxon signed-rank test. RESULTS: Thirty-five former premature infants completed nocturnal oximetry at 5.8 (3.4-8.3) months corrected age. Nocturnal oximetry was abnormal as defined in 67% of the cohort (n = 21). Five percent of patients were hypoxemic, 52% had frequent desaturation events, and 43% had both. No significant differences existed in neonatal characteristics between patients with normal and abnormal studies. CONCLUSIONS: Nocturnal oximetry was abnormal in the majority of infants with BPD who were otherwise clinically ready to wean from oxygen support, suggesting that recorded home oximetry could be a feasible and useful tool to evaluate for otherwise clinically unapparent nocturnal hypoxemia in patients with BPD.

Support for Community School Personnel Working with Pediatric Cancer Patients: A Quality Improvement Initiative.

Improved therapies and increased survival rates are sending more pediatric cancer patients and survivors back to their classrooms; however, most community school personnel lack training or experience in working with these students. The aim of this quality improvement project was twofold: (a) to evaluate community school personnel's perceptions of their preparedness to work with patients and childhood cancer survivors who have reentered the classroom; and (b) to standardize school reentry supports to improve community school personnel preparedness. Twenty community school personnel, prekindergarten through 12-grade teachers, guidance counselors, and administrators, who had previously worked with a pediatric cancer patient were surveyed regarding their experiences with the patient's school reentry. Responses were coded and analyzed, and a thematic map was created. School personnel reported concerns related to student functioning, such as academic readiness, cognitive impacts of treatment, social-emotional adjustment, physical ability to participate in school, and medical fragility. They also reported concerns related to their own ability to accommodate the student's needs. These results were used to design educational guides for community personnel consisting of information and resources to support them in managing the unique academic, social-emotional, physical, and medical needs of pediatric cancer patients and survivors in the classroom.

Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses.

PD-1 expression marks activated T cells susceptible to PD-1-mediated inhibition but not whether a PD-1-mediated signal is being delivered. Molecular predictors of response to PD-1 immune checkpoint blockade (ICB) are needed. We describe a monoclonal antibody (mAb) that detects PD-1 signaling through the detection of phosphorylation of the immunotyrosine switch motif (ITSM) in the intracellular tail of mouse and human PD-1 (phospho-PD-1). We showed PD-1+ tumor-infiltrating lymphocytes (TILs) in MC38 murine tumors had high phosphorylated PD-1, particularly in PD-1+TIM-3+ TILs. Upon PD-1 blockade, PD-1 phosphorylation was decreased in CD8+ TILs. Phospho-PD-1 increased in T cells from healthy human donors after PD-1 engagement and decreased in patients with Hodgkin lymphoma following ICB. These data demonstrate that phosphorylation of the ITSM motif of PD-1 marks dysfunctional T cells that may be rescued with PD-1 blockade. Detection of phospho-PD-1 in TILs is a potential biomarker for PD-1 immunotherapy responses.

EndOxy: Mid-term stability and shear stress resistance of endothelial cells on PDMS gas exchange membranes.

Endothelialized oxygenator devices (EndOxy) with a physiological, nonthrombogenic, and anti-inflammatory surface offer the potential to overcome current shortcomings of conventional extracorporeal membrane oxygenation such as complications like thromboembolism and bleeding that deteriorate adequate long-term hemocompatibility. The approach of endothelialization of gas exchange membranes, and thus the formation of a nonthrombogenic and anti-inflammatory surface, is promising. In this study, we investigated the mid-term shear stress resistance as well as gas transfer rates and cell densities of endothelial cells seeded on RGD-conjugated polydimethylsiloxane (RGD-PDMS) gas exchange membranes under dynamic conditions. Human umbilical vein endothelial cells were seeded on RGD-PDMS and exposed to defined shear stresses in a microfluidic bioreactor. Endothelial cell morphology was assessed by bright field microscopy and immunocytochemistry. Furthermore, gas transfer measurement of blank, RGD-conjugated, and endothelialized PDMS oxygenator membranes was performed. RGD-PDMS gas exchange membranes proved suitable for the dynamic culture of endothelial cells for up to 21 days at a wall shear stress of 2.9 dyn/cm2 . Furthermore, the cells resisted increased wall shear stresses up to 8.6 dyn/cm2 after a previous dynamic preculture of each one hour at 2.9 dyn/cm2 and 5.7 dyn/cm2 . Also, after a longer dynamic preculture of three days at 2.9 dyn/cm2 and one hour at 5.7 dyn/cm2 , increased wall shear stresses of 8.6 dyn/cm2 were tolerated by the cells and cell integrity could be remained. Gas transfer (GT) tests revealed that neither RGD conjugation nor endothelialization of RGD-PDMS significantly decrease the gas transfer rates of the membranes during short-term trials. Gas transfer rates are stable for at least 72 hours of dynamic cultivation of endothelial cells. Immunocytochemistry showed that the cell layer stained positive for typical endothelial cell markers CD31 and von Willebrand factor (VWF) after all trials. Cell density of EC on RGD-PDMS increased between 3 and 21 days of dynamic culture. In this study, we show the suitability of RGD-PDMS membranes for flow resistant endothelialization of gas-permeable membranes, demonstrating the feasibility of this approach for a biohybrid lung.

EndOxy: Dynamic Long-Term Evaluation of Endothelialized Gas Exchange Membranes for a Biohybrid Lung.

In the concept of a biohybrid lung, endothelial cells seeded on gas exchange membranes form a non-thrombogenic an anti-inflammatory surface to overcome the lacking hemocompatibility of today's oxygenators during extracorporeal membrane oxygenation. To evaluate this concept, the long-term stability and gas exchange performance of endothelialized RGD-conjugated polydimethylsiloxane (RGD-PDMS) membranes was evaluated. Human umbilical vein endothelial cells (ECs) were cultured on RGD-PDMS in a model system under physiological wall shear stress (WSS) of 0.5 Pa for up to 33 days. Gas exchange performance was tested with three biological replicates under elevated WSS of 2.5 Pa using porcine blood adjusted to venous values following ISO 7199 and blood gas analysis. EC morphology was assessed by immunocytochemistry (n = 3). RGD-PDMS promoted endothelialization and stability of endothelialized membranes was shown for at least 33 days and for a maximal WSS of 2.5 Pa. Short-term exposure to porcine blood did not affect EC integrity. The gas transfer tests provided evidence for the oxygenation and decarboxylation of the blood across endothelialized membranes with a decrease of transfer rates over time that needs to be addressed in further studies with larger sample sizes. Our results demonstrate the general suitability of RGD-PDMS for biohybrid lung applications, which might enable long-term support of patients with chronic lung failure in the future.

Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma.

Background: Combined immunotherapy approaches are promising cancer treatments. We evaluated anti-programmed cell death protein 1 (PD-1) treatment combined with gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing nonreplicating adenovirus (AdV-tk), providing in situ chemotherapy and immune stimulation. Methods: The effects of GMCI on PD ligand 1 (PD-L1) expression in glioblastoma were investigated in vitro and in vivo. The efficacy of the combination was investigated in 2 syngeneic mouse glioblastoma models (GL261 and CT-2A). Immune infiltrates were analyzed by flow cytometry. Results: GMCI upregulated PD-L1 expression in vitro and in vivo. Both GMCI and anti-PD-1 increased intratumoral T-cell infiltration. A higher percentage of long-term survivors was observed in mice treated with combined GMCI/anti-PD-1 relative to single treatments. Long-term survivors were protected from tumor rechallenge, demonstrating durable memory antitumor immunity. GMCI led to elevated interferon gamma positive T cells and a lower proportion of exhausted double positive PD1+TIM+CD8+ T cells. GMCI also increased PD-L1 levels on tumor cells and infiltrating macrophages/microglia. Our data suggest that anti-PD-1 treatment improves the effectiveness of GMCI by overcoming interferon-induced PD-L1-mediated inhibitory signals, and GMCI improves anti-PD-1 efficacy by increasing tumor-infiltrating T-cell activation. Conclusions: Our data show that the GMCI/anti-PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients.