Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment.

Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment. VIDEO ABSTRACT.

Racial Disparity in Length of Stay Following Implementation of a Bariatric Enhanced Recovery Program.

INTRODUCTION: Enhanced Recovery Programs (ERPs) mitigate racial disparities in postoperative length of stay (LOS) for colorectal populations. It is unclear, however, if these effects exist in the bariatric surgery population. Therefore, this study aimed to evaluate the racial disparities in LOS before and after implementation of bariatric surgery ERP. METHODS: A retrospective cohort study was performed using data from a single institution. Patients undergoing minimally invasive sleeve gastrectomy or Roux-en-Y gastric bypass from 2017 to 2019 (pre-ERP) or 2020-2022 (ERP) were included. Chi-square, Kruskal-Wallis, and analysis of variance were used to compare groups, and estimated LOS (eLOS) was assessed via multivariable regression. RESULTS: Seven hundred sixty four patients were identified, including 363 pre-ERPs and 401 ERPs. Pre-ERP and ERP cohorts were similar in age (median 44.3 years versus 43.8 years, P = 0.80), race (53.4% Black versus 56.4% Black, P = 0.42), and preoperative body mass index (median 48.3 versus 49.4, P = 0.14). Overall median LOS following bariatric surgery decreased from 2 days pre-ERP to 1 day following ERP (P < 0.001). Average LOS for Black and White patients decreased by 0.5 and 0.48 days, respectively. However, overall eLOS remained greater for Black patients compared with White patients despite ERP implementation (eLOS 0.21 days, P = 0.01). CONCLUSIONS: Implementation of a bariatric surgery ERP was associated with decreased LOS for both Black and White patients. However, Black patients did have slightly longer LOS than White patients in both pre-ERP and ERP eras. More work is needed to understand the driving mechanism(s) of these disparities to eliminate them.

A synopsis of the SAGES ADOPT course for foregut surgery and its positive impact on surgeons' confidence levels.

BACKGROUND: The Acquisition of Data for Outcomes and Procedure Transfer (ADOPT) program was established by SAGES to develop and expand individual surgeon's comfort with specific, complex operations using hands-on teaching and longitudinal mentoring. The 2022-2023 Foregut (Dominating the Hiatus) section of the course focused on hiatal hernia dissection and gastric fundoplication techniques. Our aim was to describe the experience of surgeons who participated in the course. METHODS: The hands-on component occurred in March 2022 at the SAGES annual meeting. Each expert mentor was matched to two participants. The mentors guided the surgeons through steps of a laparoscopic paraesophageal (PEH) hernia repair and fundoplication using a cadaveric model. Afterwards, monthly group webinars occurred and participants could receive individual coaching from their assigned mentor for a year. Each participant was given a pre-course survey with 3 and 12-month follow-up questionnaires. RESULTS: The majority of the 16 participants were employed in non-academic settings (87.5%). Years in practice ranged from 1 to 26, and 69% completed a fellowship. 100% completed the pre-course survey, and 53.8% responded to the 12-month post-course survey. Participant-reported effectiveness in performing a PEH hernia repair with fundoplication increased from 37.5% pre-course to 85.7% by the conclusion of the course. Confidence levels for the six core steps of the operation also increased: pre-course only 56-75% were confident with each step, this improved to 100% in four out of six steps. 85.7% said the course has changed their practice. DISCUSSION: Since inception, the ADOPT program has aimed to provide expert instruction for practicing surgeons to learn new techniques or improve their confidence in performing operations. The data for the 2022 ADOPT Foregut course shows that 1 year of participation made a positive impact on these surgeons' practices. This helps to fill in the learning gap that occurs after formal surgical training ends.

Disparities in Perioperative Use of Patient Engagement Technologies - Not All Use is Equal.

OBJECTIVE: To determine the association of patient-level characteristics on the use of a patient engagement technology during the perioperative period. SUMMARY OF BACKGROUND DATA: As implementation of patient engagement technologies continues to grow, it remains unclear who uses, and not uses, these technologies. Existing literature suggests significant disparities in usage of other technologies by patient age, race, sex, and geographic location, however, have yet to characterize patient usage of patient engagement technologies. METHODS: This is a retrospective cohort study of patients undergoing elective surgery by a colorectal surgeon between January 2018 and March 2020 who enrolled in a patient engagement technology at a single institution. Patients enrolled received educational content, healthcare reminders, patient reported outcome (PRO) surveys, and health checks preoperatively, in-hospital, and for 30-days postdischarge. The primary outcome was patient activation of the patient engagement technology. Secondary outcomes were completion of at least 1 PRO survey, 1 in-hospital health check, and 1 postdischarge health check. RESULTS: Of 549 patients who enrolled in the patient engagement technology, 473 (86.2%) activated. On multivariable stepwise regression, female patients [odds ratio (OR) 2.4, confidence interval (CI) 1.4-4.0, P = 0.001] and privately insured patients (OR 2.0, CI 1.1-3.8, P = 0.03) were more likely to activate. Black patients were less likely to activate (OR 0.5, CI 0.3-0.9, P = 0.02). Once activated, privately insured patients were more likely to complete PRO surveys (OR 2.3, CI 1.2-4.3, P = 0.01), in-hospital health checks (OR 2.4, CI 1.4-4.1, P = 0.002), and postdischarge health checks (OR 1.9, CI 1.1 -3.3, P < 0.001) than uninsured patients. Black patients were less likely to complete PRO surveys (OR 0.4, CI 0.3-0.7, P = 0.001) and in-hospital health checks (OR 0.6, CI 0.4-0.9, P = 0.03) than White patients. CONCLUSIONS: Use of a patient engagement technology in the perioperative period differs significantly by sex, race/ethnicity, and insurance status. These technologies may not be used equally by all patients, which should be considered during implementation of interventions to improve surgical outcomes.

Novel Umbilical Catheter Securement and Protection Device for Umbilical Line Securement during Laparotomy.

OBJECTIVE: Umbilical catheter malposition rate is high. We compared a Novel Umbilical Securement Device (NUSD) to standard methodologies for neonatal invasive care unit patients undergoing laparotomy. STUDY DESIGN: Retrospective study was performed on infants undergoing laparotomy from April 2019 to January 2023. Two neonatologists compared position of umbilical arterial catheter/umbilical venous catheter (UVC) on perioperative chest X-ray (CXRs) in patients with or without NUSD. RESULTS: Eighteen patients underwent laparotomy, of which 8 patients had NUSD (9 lines) and 10 patients did not (14 lines). In NUSD group, mean gestational age was 37 ± 4 weeks and mean birth weight was 2.3 ± 0.9 kg compared with 31 ± 8 weeks and 2.1 ± 1.4 kg in non-NUSD group, respectively. The mean age at surgery was 5 ± 7 and 5 ± 3 days, respectively. No malposition was seen in NUSD group, while 57% of UVCs (28% of lines) were malpositioned postoperatively in non-NUSD group (p = 0.048). CONCLUSION: NUSD is an umbilical catheter securement device with low malposition rate, specifically during perioperative period with heightened risk for dislodgement. KEY POINTS: · Umbilical catheters provide reliable access for neonates but have a high rate of malpositioning.. · NUSD is an umbilical catheter securement device with low malposition rate.. · NUSD can be kept in place during laparotomy and can decrease the risk of malpositioning..

Concurrent application of interferon-gamma and vincristine inhibits tumor growth in an orthotopic neuroblastoma mouse model.

PURPOSE: Tumor-associated macrophages are present within neuroblastoma, and interferon-gamma (IFN-γ) can polarize macrophages into cancer-inhibiting M1 type. We hypothesize that treating neuroblastoma with interferon-gamma (IFN-γ) can suppress tumor growth, and the concurrent treatment with IFN-γ and vincristine can lead to enhanced tumor killing as compared to vincristine alone. METHODS: We loaded IFN-γ or vincristine into silk biomaterials and recorded the amount released over time. Orthotopic, syngeneic neuroblastoma xenografts were generated by injecting 9464D cells into adrenal gland of C57BL/6 mice, and IFN-γ-loaded and/or vincristine-loaded silk biomaterials were implanted into the tumor once the tumors reached 100 mm3. Drug release at different timepoints was measured and tumor growth after different treatments were compared. RESULTS: 1-2% of IFN-γ and 70% of vincristine were released from the biomaterials by the fifth day. Combining IFN-γ and vincristine significantly slowed tumor growth as compared to the controls (12.2 ± 2.7 days to reach 800 mm3 versus 5.7 ± 1.2 days, p = 0.01), and IFN-γ alone also delayed tumor growth as compared to the controls (10.9 ± 1.5 days versus 5.7 ± 1.2 days, p = 0.001). Hematoxylin and eosin staining demonstrated tumor necrosis adjacent to the drug-loaded silk biomaterials. CONCLUSION: Local delivery of sustained release IFN-γ can inhibit neuroblastoma tumor growth by itself and in combination with vincristine.

Stem cell activation during distraction enterogenesis in the murine colon.

PURPOSE: Short bowel syndrome (SBS) is a devastating disease. We have proposed spring-mediated distraction enterogenesis for intestinal lengthening. Colonic lengthening is a potential treatment option for SBS to enhance fluid absorption capacity. We hypothesized that intraluminal spring-mediated colonic lengthening is associated with stem cell proliferation. METHODS: C57BL/6 mice underwent placement of a gelatin-encapsulated compressed or uncompressed nitinol spring in a cecal segment. Animals were given clear liquid diet until postoperative day (POD) 7, followed by regular diet until POD 14. Cecal lengths were measured at euthanasia, and tissue was formalin fixed for histological processing. For Lgr5-GFP mice, immunohistochemistry against GFP was performed to localize Lgr5+ cells within crypts. RESULTS: Significant cecal lengthening with compressed springs and shortening with uncompressed springs were observed on POD 7 and 14. Mucosa of the compressed spring group was significantly thicker on POD 14. The density of Lgr5+ cells within the crypts in the compressed spring groups was higher than that in the uncompressed spring groups on both POD 7 and 14. CONCLUSION: Expandable springs can be used to lengthen the colon in the mouse model. Colonic lengthening was associated with gradual mucosal thickening and correlated with an increased density of stem cells within the crypts.

Generation of Porcine Ileum Through Spring-Mediated Mechanical Distraction.

INTRODUCTION: Short bowel syndrome is a devastating gastrointestinal disorder in which decreased bowel length results in inadequate absorption causing nutritional deficiencies. Current treatment options are accompanied by significant morbidity. We have proposed spring-mediated distraction enterogenesis as a method to lengthen bowel with success seen in porcine jejunum. We hypothesize that spring-mediated distraction enterogenesis can be demonstrated in porcine ileum with preservation of ileal structure and function. MATERIALS AND METHODS: Laparotomy was performed on juvenile female mini-Yucatan pigs and a gelatin-encapsulated compressed nitinol spring was inserted into the ileal lumen and affixed proximally and distally. A control segment distal to the spring segment was marked with sutures. Postoperatively, pigs were placed on a liquid diet and euthanized on postoperative day 7. Spring and control segments were measured and processed for immunohistochemistry to evaluate for the presence of vitamin B12-intrinsic factor cotransporter, chromogranin A-producing cells, and 5-HT producing cells. RESULTS: All seven pigs survived to postoperative day 7 with no adverse effects. On average, pigs gained 84.3 ± 66.4 g/d. Spring segments lengthened 1.5 ± 0.7 cm with a relative lengthening by 128% ± 56%, which was statistically significant when compared to control (P < 0.01). The average density of chromogranin-A cells in control compared to spring segments was not significantly changed (2.9 ± 1.1 cells/mm versus 3.2 ± 1.2 cells/mm, P = 0.17). Both vitamin B12-intrinsic factor cotransporter and 5-HT producing cells were present in both control and lengthened ileum. CONCLUSIONS: Intraluminal nitinol springs significantly lengthened porcine ileum. The increase in density of enteroendocrine cells may indicate enhanced endocrine function of the lengthened ileum.

Gastrointestinal Myoelectric Measurements via Simultaneous External and Internal Electrodes in Pigs.

INTRODUCTION: Currently, there is no accurate noninvasive measurement system to diagnose gastrointestinal (GI) motility disorders. Wireless skin patches have been introduced to provide an accurate noninvasive measurement of GI myoelectric activity which is essential for developing neuro-stimulation devices to treat GI motility disorders. The aim of this study is to compare the external and internal electrical signal measurements in ambulatory pigs. METHODS: Yucatan pigs underwent placement of internal electrodes on the stomach, small intestine, and colon. Wires were brought through the abdominal wall. Signals were collected by a wireless receptor. Four external patches were placed on the abdominal skin to record the signals simultaneously. Pigs were kept for 6 d while the sensors were continuously recording the data from both systems. RESULTS: Internal sensors detected rich signals from each organ. The stomach had a dominant frequency that ranged from 4 to 4.5 cpm, with occasional higher frequencies at 2, 3 and 4 times that. Small intestine signals had their primary energy in the 12-15 cpm range. Colon signals primarily displayed a dominant broad peak in the 4-6 cpm region. External skin patches detected a substantial fraction of the activities measured by the internal electrodes. A clear congruence in the frequency spectrum was observed between the internal and external readings. CONCLUSIONS: Internally measured myoelectrical signals confirmed different patterns of rhythmic activity of the stomach, small intestine, and colon. Skin patches provided GI myoelectric measurement with a range of frequencies that could be useful in the diagnosis and treatment of motility disorders.

The effect of spring diameter on porcine ileal distraction enterogenesis.

PURPOSE: Spring-mediated distraction enterogenesis has proven to be successful for intestinal lengthening. We aimed to evaluate the effect of spring diameter mismatch on intestinal adaptation. METHODS: Juvenile mini-Yucatan pigs underwent placement of compressed nitinol springs with diameter of 10, 11, or 12 mm into the ileal lumen. Pigs were euthanized on postoperative day 7. The lengths, histology, total area of blood vessels, and enteric ganglia were evaluated. RESULTS: All spring groups exhibited significant ileal lengthening. Across the different diameters, spring-expanded segments were similar in terms of ileal lengthening, crypt height, muscular thickness, blood vessels, and enteric ganglia area. CONCLUSION: Spring-mediated distraction enterogenesis is successful in the porcine ileum. A smaller diameter spring is as effective as a larger diameter spring in lengthening the ileum. Springs of varying diameters result in comparable structural changes in the ileum.

Inertial Sensor Estimation of Initial and Terminal Contact during In-Field Running.

Given the popularity of running-based sports and the rapid development of Micro-electromechanical systems (MEMS), portable wireless sensors can provide in-field monitoring and analysis of running gait parameters during exercise. This paper proposed an intelligent analysis system from wireless micro-Inertial Measurement Unit (IMU) data to estimate contact time (CT) and flight time (FT) during running based on gyroscope and accelerometer sensors in a single location (ankle). Furthermore, a pre-processing system that detected the running period was introduced to analyse and enhance CT and FT detection accuracy and reduce noise. Results showed pre-processing successfully detected the designated running periods to remove noise of non-running periods. Furthermore, accelerometer and gyroscope algorithms showed good consistency within 95% confidence interval, and average absolute error of 31.53 ms and 24.77 ms, respectively. In turn, the combined system obtained a consistency of 84-100% agreement within tolerance values of 50 ms and 30 ms, respectively. Interestingly, both accuracy and consistency showed a decreasing trend as speed increased (36% at high-speed fore-foot strike). Successful CT and FT detection and output validation with consistency checking algorithms make in-field measurement of running gait possible using ankle-worn IMU sensors. Accordingly, accurate IMU-based gait analysis from gyroscope and accelerometer information can inform future research on in-field gait analysis.

Novel Neonatal Umbilical Catheter Protection and Stabilization Device in In vitro Model of Catheterized Human Umbilical Cords: Effect of Material and Venting on Bacterial Colonization.

OBJECTIVE: Umbilical central lines deliver life-saving medications and nutrition for neonates; however, complications associated with umbilical catheters (UCs) occur more frequently than in adults with central lines (i.e., line migration, systemic infection). We have developed a device for neonatal UC protection and stabilization to reduce catheter exposure to bacteria compared with the standard of care: "goal post" tape configuration. This study analyzes the effect of device venting and material on bacterial load of human umbilical cords in vitro. STUDY DESIGN: Catheters were inserted into human umbilical cord segments in vitro, secured with plastic or silicone vented prototype versus tape, and levels of bacterial colonization were compared between groups after 7 days of incubation. RESULTS: Nonvented plastic prototype showed increased bacterial load compared with goal post (p = 0.04). Colonization was comparable between the goal post and all vented plastic prototypes (p ≥ 0.30) and when compared with the vented silicone device (p = 1). CONCLUSION: A novel silicone device does not increase external bacterial colonization compared with the current standard of care for line securement, and may provide a safe, convenient alternative to standard adhesive tape for UC stabilization. Future studies are anticipated to establish safety in vivo, alongside benefits such as migration and infection reduction.

Irreversible Electroporation for De-epithelialization of Murine Small Intestine.

BACKGROUND: Nonthermal irreversible electroporation (NTIRE) has been shown to ablate the small intestinal epithelium while maintaining submucosal and muscularis propriae integrity. NTIRE is used here in a first-in-mouse study to eliminate the native intestinal stem cell population to understand optimal parameters and timeline of mucosal regeneration. METHODS: Adult C57 background mice underwent laparotomy and electroporation of 1.5 cm of jejunum using a BTX 830 ECM electroporator and electrode calipers. Parameters were varied by voltage, pulse number, interval, and duration to determine optimal de-epithelialization. Electroporated segments were extracted 1 to 3 d after intervention with same-animal control segment. Cross sections were preserved, and measurements were taken to compare effects of parameters on villi height, crypt depth, crypt obliteration, and serosal thickness. RESULTS: Morbidity was limited at a standard set of electroporation parameters (14%), and increased with higher voltage, longer interval, and shorter or longer pulses. Serosa/muscularis thickness was unaffected by varying interventions. Crypt depth and obliterated crypts were most affected by modulating pulse number, intervals, and duration. Villi height was most significantly shortened by altering pulse duration, with limited recovery by day 3, otherwise mucosal regeneration was observed in most cases by this point. CONCLUSIONS: NTIRE is an effective method of denuding small intestinal epithelium in mice and temporarily ablating crypts while sparing the support scaffold for native regeneration. This first-in-mouse study of electroporation suggests it is a practical tool that can be utilized in a small mammalian system.

The Job Demands-Resources Model as a Framework to Identify Factors Associated With Burnout in Surgical Residents.

BACKGROUND: Surgical residents are a population at high risk for burnout. We hypothesized that surgical residents' burnout would be inversely related to emotional intelligence (EI) and job resources and directly related to experiences of disruptive behavior. MATERIALS AND METHODS: All general surgery residents at a single institution were invited to complete a survey in 2018 that included the Maslach Burnout Inventory, Trait EI Questionnaire Short Form, focused questions assessing disruptive behaviors, job resources, and demographic characteristics. Burnout was defined as scoring high in depersonalization (≥10 points) or emotional exhaustion (≥27 points). Student's t-tests and Wilcoxon tests were used to compare continuous variables; chi-square and Fisher's exact tests were used to compare categorical variables. RESULTS: The survey response rate was 87%. The median respondent age was 30, 51.7% were female, and 48.3% were single. Thirty-five met criteria for burnout (58%). Residents with burnout had lower scores for job resources than residents without burnout (19 versus 26, P < 0.01). Job resources subdomain scores for meaningful feedback and professional development had an inverse association with burnout (P < 0.01 for both). Having experienced any disruptive behavior was associated with burnout (68% versus 32%, P = 0.01). Mean EI scores were also lower for those with burnout (5.18 versus 5.64, P < 0.01). Among EI subcategories, burnout was associated with lower well-being and emotionality (P < 0.01 and P = 0.02, respectively). CONCLUSIONS: Burnout is prevalent among surgery residents, including those at our institution. Experiencing disruptive behaviors and lower perceptions of job resources were associated with higher burnout scores, along with lower scores in EI, and may inform future efforts toward interventions.

A flow cytometry-based screen identifies MBNL1 modulators that rescue splicing defects in myotonic dystrophy type I.

Myotonic dystrophy Type 1 (DM1) is a rare genetic disease caused by the expansion of CTG trinucleotide repeats ((CTG)exp) in the 3' untranslated region of the DMPK gene. The repeat transcripts sequester the RNA binding protein Muscleblind-like protein 1 (MBNL1) and hamper its normal function in pre-mRNA splicing. Overexpressing exogenous MBNL1 in the DM1 mouse model has been shown to rescue the splicing defects and reverse myotonia. Although a viable therapeutic strategy, pharmacological modulators of MBNL1 expression have not been identified. Here, we engineered a ZsGreen tag into the endogenous MBNL1 locus in HeLa cells and established a flow cytometry-based screening system to identify compounds that increase MBNL1 level. The initial screen of small molecule compound libraries identified more than thirty hits that increased MBNL1 expression greater than double the baseline levels. Further characterization of two hits revealed that the small molecule HDAC inhibitors, ISOX and vorinostat, increased MBNL1 expression in DM1 patient-derived fibroblasts and partially rescued the splicing defect caused by (CUG)exp repeats in these cells. These findings demonstrate the feasibility of this flow-based cytometry screen to identify both small molecule compounds and druggable targets for MBNL1 upregulation.

Lack of uniformity among United States recommendations for diagnosis and management of acute, uncomplicated cystitis.

INTRODUCTION AND HYPOTHESIS: Acute, uncomplicated cystitis is one of the most common bacterial infections seen in clinical practice. Quality improvement and antibiotic stewardship efforts to optimize cystitis management rely on clinicians managing patients in a manner recommended by experts and guidelines. However, it is unclear if recent recommendations for cystitis from experts and guidelines from US medical societies that provide recommendations are well aligned. METHODS: We examined recommendations and guidelines for acute, symptomatic cystitis in women published in US medical societies' journals from January 1, 2008, to December 31, 2016, within the fields of family medicine, obstetrics and gynecology, internal medicine, female pelvic medicine and reconstructive surgery, and infectious diseases. RESULTS: All recommendations endorsed the use of symptoms and urine dipstick to diagnose cystitis. Some societies did not recommend urine dipstick in patients with recurrent urinary tract infection (UTI), classic UTI symptoms, or a lack of underlying conditions or competing diagnoses. All endorsed nitrofurantoin, trimethoprim-sulfamethoxazole, and fosfomycin as first-line agents. Some guidelines classified fluoroquinolones as second- or third-line, while others considered them first-line treatment for UTI. Avoiding use of amoxicillin and ampicillin, antibiotic agents with high prevalence of resistance in the US, was recommended by some societies. CONCLUSIONS: US recommendations differed in their approach to the treatment of acute, uncomplicated cystitis. Lack of uniformity likely contributes to clinical management variance for patients with UTI and hampers quality improvement and antibiotic stewardship efforts aimed at promoting optimal management. Our findings emphasize the need for more consistent recommendations for cystitis management.

Cancer vaccine strategies: translation from mice to human clinical trials.

We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells ("epitope enhancement"). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen (PSA) slope is prognostic of time to radiographic evidence of metastases and death. With no difference between arms, 74% of combined subjects had a decreased PSA slope at 1 year compared to their own baseline slopes (p = 0.0004). For patients vaccinated with DCs, response inversely correlated with a tolerogenic DC signature. A randomized placebo-controlled phase II trial is underway. (2) HER2 is a driver surface oncogene product expressed in multiple tumors. We made an adenoviral vector vaccine expressing the extracellular and transmembrane domains of HER2 and cured mice with large established HER2+ tumors, dependent on antibodies to HER2, not T cells. The mechanism differed from that of trastuzumab. We tested a human version in advanced metastatic cancer patients naïve to HER2-directed therapies. At the second and third dose levels, 45% of evaluable patients showed clinical benefit. Circulating tumor cells also declined in some vaccinated patients. Thus, cancer vaccines developed in mice were successfully translated to humans with promising early results.

Is it Safe to Reduce Water Intake in the Overactive Bladder Population? A Systematic Review.

PURPOSE: Overactive bladder imposes a significant socioeconomic burden on the health care system. It is a commonly held belief that increased fluid intake (8 glasses of water per day) is beneficial for health. However, increased fluid intake exacerbates overactive bladder symptoms. Thus, it is imperative that clinicians appropriately educate patients for whom increased water intake may be detrimental (women with overactive bladder), in contrast to patients with comorbidities that necessitate increased water intake (nephrolithiasis). We systematically reviewed the literature to determine the potential health advantages of increased water intake and identify specific subpopulations that need increased hydration. MATERIALS AND METHODS: We systematically reviewed published articles from 1972 through 2017 on PubMed® and the Cochrane Library. The data were reviewed independently by 2 individuals. Studies were included if they explored water intake in relation to the risk of a particular disease. RESULTS: Level 1 evidence supported increased fluid intake in patients with nephrolithiasis. There was no available evidence to support increased fluid intake in patients with cardiovascular disease, constipation, venous thromboembolism, headaches, cognitive function or bladder cancer. Dehydration may exacerbate some conditions, specifically chronic constipation and headache intensity. Increased fluid intake may have a role in preventing stroke recurrence but not in preventing primary stroke. CONCLUSIONS: The available reviewed literature suggests no benefit to drinking 8 glasses of water per day in patients without nephrolithiasis. Also, excess fluid intake can exacerbate symptoms of overactive bladder.

Non-linear shift from grassland to shrubland in temperate barrier islands.

Woody plant encroachment into grasslands is a major land cover change taking place in many regions of the world, including arctic, alpine and desert ecosystems. This change in plant dominance is also affecting coastal ecosystems, including barrier islands, which are known for being vulnerable to the effects of climate change. In the last century, the woody plant species Morella cerifera L. (Myricaceae), has encroached into grass covered swales in many of the barrier islands of Virginia along the Atlantic seaboard. The abrupt shift to shrub cover in these islands could result from positive feedbacks with the physical environment, though the underlying mechanisms remain poorly understood. We use a combination of experimental and modeling approaches to investigate the role of climate warming and the ability of M. cerifera to mitigate its microclimate thereby leading to the emergence of alternative stable states in barrier island vegetation. Nighttime air temperatures were significantly higher in myrtle shrublands than grasslands, particularly in the winter season. The difference in the mean of the 5% and 10% lowest minimum temperatures between shrubland and grassland calculated from two independent datasets ranged from 1.3 to 2.4°C. The model results clearly show that a small increase in near-surface temperature can induce a non-linear shift in ecosystem state from a stable state with no shrubs to an alternative stable state dominated by M. cerifera. This modeling framework improves our understanding and prediction of barrier island vegetation stability and resilience under climate change, and highlights the existence of important nonlinearities and hystereses that limit the reversibility of this ongoing shift in vegetation dominance.

Plasma from some cancer patients inhibits adenoviral Ad5f35 vector transduction of dendritic cells.

BACKGROUND: Pooled AB serum is often used as a media supplement for cell culture but it has the potential to transmit infectious diseases. To avoid this risk, we used autologous plasma as a media supplement for manufacturing dendritic cells (DCs) for cancer immunotherapy. We noticed inconsistencies in the DCs and investigated their nature and cause. METHODS: Adenovirus human epidural growth factor receptor 2 (adHER2/neu) DCs for 21 patients were manufactured from autologous peripheral blood monocytes that were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 for 3 days, transduced with Ad5f35HER2ECTM and then treated with lipopolysaccharide and interferon (IFN)-γ for 1 day. The cells were cultured in RPMI-1640 supplemented with either 10% heat inactivated autologous or AB plasma. RESULTS: Twenty-eight adHER2/neu DCs were manufactured for 21 patients using autologous plasma and 68 were manufactured for 20 of those patients using AB plasma. The expression of human epidural growth factor receptor 2 (HER2/neu) was less for DCs manufactured with autologous plasma (70.3 ± 33.3% versus 86.1 ± 22.8%; P <0.01). Manufacturing adHER2/neu DCs using monocytes from three healthy subjects and plasma from one patient with low HER2/neu expression (18%) resulted in low HER2/neu expression by all three DCs (13%, 16% and 23%). Analysis of the levels of 1322 proteins in eight plasma samples associated with low HER2/neu expression and in 12 associated with high HER2/neu expression revealed that the levels of 14 predicted HER2/neu transduction efficiency. CONCLUSION: The manufacture of adHER2/neu DC using autologous plasma as a media supplement resulted in inconsistent HER2/neu expression. It is likely that variability in the levels of multiple proteins in autologous plasma contributed to low HER2/neu expression.