Outcomes in solid organ transplant recipients receiving organs from a donor with Fusarium solani species complex meningitis.

BACKGROUND: Five organs (heart, right lung, liver, right, and left kidneys) from a deceased patient were transplanted into five recipients in four US states; the deceased patient was identified as part of a healthcare-associated fungal meningitis outbreak among patients who underwent epidural anesthesia in Matamoros, Mexico. METHODS: After transplant surgeries occurred, Fusarium solani species complex, a fungal pathogen with a high case-mortality rate, was identified in cerebrospinal fluid from the organ donor by metagenomic next-generation sequencing (mNGS) and fungal-specific polymerase chain reaction and in plasma by mNGS. RESULTS: Four of five transplant recipients received recommended voriconazole prophylaxis; four were monitored weekly by serum (1-3)-ß-d-glucan testing. All five were monitored for signs of infection for at least 3 months following transplantation. The liver recipient had graft failure, which was attributed to an etiology unrelated to fungal infection. No fungal DNA was identified in sections of the explanted liver, suggesting that F. solani species complex did not contribute to graft failure. The remaining recipients experienced no signs or symptoms suggestive of fusariosis. CONCLUSION: Antifungal prophylaxis may be useful in preventing donor-derived infections in recipients of organs from donors that are found to have Fusarium meningitis.

Allogeneic, off-the-shelf, SARS-CoV-2-specific T cells (ALVR109) for the treatment of COVID-19 in high-risk patients.

Defects in T-cell immunity to SARS-CoV-2 have been linked to an increased risk of severe COVID-19 (even after vaccination), persistent viral shedding and the emergence of more virulent viral variants. To address this T-cell deficit, we sought to prepare and cryopreserve banks of virus-specific T cells, which would be available as a partially HLA-matched, off-the-shelf product for immediate therapeutic use. By interrogating the peripheral blood of healthy convalescent donors, we identified immunodominant and protective T-cell target antigens, and generated and characterized polyclonal virus-specific T-cell lines with activity against multiple clinically important SARS-CoV-2 variants (including 'delta' and 'omicron'). The feasibility of making and safely utilizing such virus-specific T cells clinically was assessed by administering partially HLA-matched, third-party, cryopreserved SARS-CoV-2-specific T cells (ALVR109) in combination with other antiviral agents to four individuals who were hospitalized with COVID-19. This study establishes the feasibility of preparing and delivering off-the-shelf, SARS-CoV-2-directed, virus-specific T cells to patients with COVID-19 and supports the clinical use of these products outside of the profoundly immune compromised setting (ClinicalTrials.gov number, NCT04401410).

Controlling astrocyte-mediated synaptic pruning signals for schizophrenia drug repurposing with deep graph networks.

Schizophrenia is a debilitating psychiatric disorder, leading to both physical and social morbidity. Worldwide 1% of the population is struggling with the disease, with 100,000 new cases annually only in the United States. Despite its importance, the goal of finding effective treatments for schizophrenia remains a challenging task, and previous work conducted expensive large-scale phenotypic screens. This work investigates the benefits of Machine Learning for graphs to optimize drug phenotypic screens and predict compounds that mitigate abnormal brain reduction induced by excessive glial phagocytic activity in schizophrenia subjects. Given a compound and its concentration as input, we propose a method that predicts a score associated with three possible compound effects, i.e., reduce, increase, or not influence phagocytosis. We leverage a high-throughput screening to prove experimentally that our method achieves good generalization capabilities. The screening involves 2218 compounds at five different concentrations. Then, we analyze the usability of our approach in a practical setting, i.e., prioritizing the selection of compounds in the SWEETLEAD library. We provide a list of 64 compounds from the library that have the most potential clinical utility for glial phagocytosis mitigation. Lastly, we propose a novel approach to computationally validate their utility as possible therapies for schizophrenia.

Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries.

With pharmaceutical companies shrinking their research departments and exiting out of efforts related to unprofitable diseases, society has become increasingly dependent on academic institutions to perform drug discovery and early-stage translational research. Academic drug discovery and translational research programs assist in shepherding promising therapeutic opportunities through the so-called valley of death in the hope that a successful new drug will result in saved lives, improved health, economic growth, and financial return. We have interviewed directors of 16 such academic programs in the United States and found that these programs and the projects therein face numerous challenges in reaching the clinic, including limited funding, lack of know-how, and lack of a regional drug development ecosystem. If these issues can be addressed through novel industry partnerships, the revision of government policies, and expanded programs in translational education, more effective new therapies are more likely to reach patients in need.

p38 MAPK inhibition: A promising therapeutic approach for COVID-19.

COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.

Gastric myotomy length affects severity but not rate of post-procedure reflux: 3-year follow-up of a prospective randomized controlled trial of double-scope per-oral endoscopic myotomy (POEM) for esophageal achalasia.

BACKGROUND: Since Inoue performed the first POEM in 2008, safety and efficacy have been well-established. Early studies focused on refining the technique and avoiding incomplete myotomy. Following the discovery that many patients with abnormal acid exposure are asymptomatic, the focus shifted to post-POEM reflux, but no studies have identified any associated procedural factors. In this study, we examined the intermediate-term results of our previous randomized controlled trial, with particular attention to post-POEM reflux. METHODS: Previously, 100 consecutive patients were randomized to either double- or single-scope POEM. Endoscopy was conducted 2 months post-POEM and annually thereafter. Patients were included in the present study if they completed endoscopy ≥ 6 months post-POEM, and the clinical results of both groups were analyzed with particular attention to clinical efficacy and post-POEM reflux. RESULTS: Median follow-up was 3 years, and most myotomies were performed in the posterior location. The final gastric myotomy length was longer in the double-scope group (3.3 vs. 2.6 cm). Clinical efficacy (≥ 80%) and rates of post-POEM reflux (~ 60%) were similar; however, there was a higher incidence of moderate esophagitis (Los Angeles Grade B) in the double-scope group (25% vs. 4%). There were no cases of severe esophagitis (Los Angeles Grade C/D). Among patients with normal endoscopy at 2 months, > 40% developed erosive esophagitis on intermediate-term follow-up. CONCLUSIONS: This is the first study to demonstrate a procedural factor that increases post-POEM esophagitis. Gastric myotomy > 2.5 cm results in increased rates of moderate esophagitis without improving clinical efficacy. Some patients developed esophagitis in a delayed fashion, emphasizing the importance of ongoing surveillance. We also believe that preserving the gastric sling fibers may help to reduce reflux rates. The double-scope method may help to control myotomy length (2.0-2.5 cm) and direction (lesser curve to avoid the gastric sling) to help maximize clinical efficacy while minimizing post-POEM reflux.

Statement for gastroesophageal reflux disease after peroral endoscopic myotomy from an international multicenter experience.

It has been 10 years since peroral endoscopic myotomy (POEM) was reported for the first time, and POEM has currently become the standard treatment for achalasia and related disorders globally because it is less invasive and has a higher curative effect than conventional therapeutic methods. However, there are limited studies comparing the long-term outcomes of POEM with those of conventional therapeutic methods, particularly in the occurrence of gastroesophageal reflux disease (GERD) after therapy. With this background, we held a consensus meeting to discuss the pathophysiology and management of GERD after POEM based on published papers and experiences of each expert and to discuss the prevention of GERD and dealing with anti-acid drug refractory GERD. This meeting was held on April 27, 2018 in Tokyo to establish statements and finalize the recommendations using the modified Delphi method. This manuscript presents eight statements regarding GERD after POEM.

Peroral endoscopic myotomy (POEM) for complex achalasia and the POEM difficulty score.

BACKGROUND: Peroral endoscopic myotomy (POEM) for achalasia is technically challenging to carry out in patients with type III, multiple prior treatments, prior myotomy, and sigmoid type. Herein, we present a series of consecutive patients with complex achalasia and introduce the POEM difficulty score (PDS). AIM: To demonstrate the application and discuss the utility of PDS and present the feasibility, safety, and efficacy of POEM in complex achalasia patients. METHODS: Forty consecutive POEM were carried out with 28 meeting the criteria for complex achalasia. Primary outcome was clinical success (Eckardt score ≤3) at a minimum of 3 months follow-up. Secondary outcomes included adverse events, procedural velocity and PDS. RESULTS: Twenty-eight complex and 12 non-complex POEM procedures were carried out with 100% and 92% clinical success, respectively, without any major adverse events with a median follow up of 15 months (complex) and 8 months (non-complex). Mean velocities for non-complex, type III, prior myotomy, ≥4 procedures and sigmoid type were as follows: 4.4 ± 1.6, 4.8 ± 1.5, 5.9 ± 2.2, 6.9 ± 2.2 and 8.2 ± 3.2 min/cm, respectively. Median PDS for non-complex, type III, prior myotomy, ≥4 treatments and sigmoid type were 1 (0-3), 2 (0-4), 2.5 (1-6), 3 (2-6) and 3.5 (1-6), respectively. PDS was shown to correlate well with procedural velocity with a correlation coefficient of 0.772 (Spearman's P < 0.001). CONCLUSIONS: PDS identifies the factors that contribute to challenging POEM procedures and correlates well with procedural velocity. The order of increasing difficulty of POEM in complex achalasia appears to be type III, prior myotomy, ≥4 treatments and sigmoid type.

Efficacy of a new hemostatic forceps during gastric endoscopic submucosal dissection: A prospective randomized controlled trial.

BACKGROUND AND AIM: Currently, endoscopic submucosal dissection (ESD) is a widely accepted standard treatment for early gastric cancer, but one challenging aspect of ESD is hemostasis. We developed a new hemostatic forceps (FD-Y0007) with the aim of achieving more effective hemostasis and investigated the hemostatic ability of the FD-Y0007 during gastric ESD in humans. METHODS: This study was a prospective randomized controlled trial, which was conducted at a cancer referral center. Sixty-six patients who were scheduled to undergo ESD were enrolled and randomly assigned to either the Coagrasper or the FD-Y0007, which was used for hemostasis throughout the case. The primary end point was the time required to obtain hemostasis, which was measured for the first episode of bleeding during each case. RESULTS: Hemostasis time for the first bleeding episode during ESD was 73.0 s for the Coagrasper and 21.5 s for the FD-Y0007 (P < 0.001). When all episodes of bleeding were included, hemostasis time was 56.8 s in the Coagrasper group and 25.5 s in FD-Y0007group (P < 0.0001). The frequency of adverse events (perforation: 3.4% vs 7.1%; delayed bleeding: 0% vs 0%) was not significantly different between the two groups. CONCLUSIONS: Compared with the Coagrasper, the FD-Y0007 efficiently reduces the hemostatic time during gastric ESD with no increase in adverse events.

Troubleshooting common endoscopic malfunctions: a study integrating a preoperative checklist and troubleshooting guide into surgical resident training.

INTRODUCTION: This study assessed the utility of a checklist in troubleshooting endoscopic equipment. Prior studies have demonstrated that performance in simulated tasks translates into completion of similar tasks in the operating room. Checklists have been shown to decrease error and improve patient safety. There is currently limited experience with the use of simulation and checklists to improve troubleshooting of endoscopic equipment. We propose the use of a checklist during a simulated colonoscopy to improve performance during endoscopic troubleshooting. METHODS: This study randomized 20 surgical residents (PGY1-3) who were blinded to the purpose of the simulation. Participants were asked to complete two consecutive colonoscopies in a mock endoscopy suite. Prior to each trial, a standard set of equipment malfunctions were created; the equipment was returned to working order if the subjects were unable to successfully troubleshoot the equipment within the first 3 min of the simulation. Between trials, the intervention group was provided a troubleshooting checklist, which they were permitted to utilize during the second trial. The control group had no intervention. Scores were calculated for each task by subtracting time to completion from total time allowed (180 s), with 0 indicating the task was not completed. Groups were compared utilizing unpaired Student's t-test with p < 0.05 threshold for significance. RESULTS: Average scores were compared for 5 tasks in the first trial and 6 tasks in the second trial. During the first trial, there were no significant differences. However, during the second trial, there was a significant improvement with the checklist for 5/6 tasks. CONCLUSION: Use of a checklist, with no further intervention, significantly improves the ability of novice endoscopists to identify and remedy common equipment malfunctions. Introduction of a troubleshooting checklist may represent a simple and low-cost way to improve both efficiency and safety in the endoscopy suite.

Efficacy and cost-effectiveness of voriconazole prophylaxis for prevention of invasive aspergillosis in high-risk liver transplant recipients.

Aspergillus infection remains a significant and deadly complication after liver transplantation (LT). We sought to determine whether the antifungal prophylactic use of voriconazole reduces the incidence of invasive aspergillosis (IA) in high-risk LT recipients without prohibitively increasing cost. During the study era (April 2008 to April 2014), 339 deceased donor LTs were performed. Of those patients, 174 high-risk recipients were administered antifungal prophylaxis with voriconazole. The median biological Model for End-Stage Liver Disease score at the time of LT was 33 (range, 18-49) with 56% requiring continuous renal replacement therapy and 50% requiring ventilatory support immediately before transplantation. Diagnosis of IA was stratified as proven, probable, or possible according to previously published definitions. No IA was documented in patients receiving voriconazole prophylaxis. At 90 days after LT, the institutional cost of prophylaxis was $5324 or 5.6% of the predicted cost associated with post-LT aspergillosis. There was no documentation of resistant strains isolated from any recipient who received voriconazole. In conclusion, these data suggest that voriconazole prophylaxis is safe, clinically effective, and cost-effective in high-risk LT recipients.

Double-scope per oral endoscopic myotomy (POEM): a prospective randomized controlled trial.

BACKGROUND: Since its introduction in 2010, per oral endoscopic myotomy (POEM) has offered an alternative to laparoscopic Heller myotomy for the treatment of achalasia. A gastric myotomy length of 3 cm has been recommended; however, it can be difficult to ensure that adequate submucosal dissection has been performed during the procedure. Commonly accepted endoscopic markers of the gastric side can be inaccurate, particularly in patients with prior endoscopic treatments, such as balloon dilation or Botox injection of the lower esophageal sphincter. We hypothesized that the use of a second endoscope would result in a more complete gastric myotomy. METHODS: One hundred consecutive achalasia patients were randomized into single- and double-scope POEM groups. In the treatment group, a second endoscope was used to obtain a retroflexed view of the gastric cardia, while the dissecting scope transilluminated from the end of the submucosal tunnel. Prospectively collected data were analyzed, including myotomy lengths, procedure times, adverse events, and clinical outcomes. RESULTS: POEM was completed with high rates of technical (98-100%) and clinical success (93-97%) in both groups, with a low rate of serious adverse events (2%). The second endoscope resulted in a 17 min increase in procedure time (94 vs. 77 min), myotomy extension in 34% of cases, and an increase in the average gastric myotomy length from 2.6 to 3.2 cm (p = 0.01). CONCLUSION: A second endoscope is useful for ensuring a complete gastric myotomy during POEM. With minimal increase in procedure time and no increase in morbidity, it may be particularly useful in cases of sigmoid esophagus or otherwise altered anatomy that makes identification of the gastroesophageal junction difficult.

Greater curvature myotomy is a safe and effective modified technique in per-oral endoscopic myotomy (with videos).

BACKGROUND: Per-oral endoscopic myotomy (POEM) for achalasia with esophagocardiomyotomy in the lesser curvature (LC myotomy) is now established and accepted widely. However, in some cases LC myotomy is precluded by previous procedures, such as Heller myotomy, or by other anatomic considerations that obscure the normal dissection planes. It may also be difficult to identify the esophagogastric junction (EGJ), which can result in an incomplete gastric myotomy and poor rates of symptom relief. On the other hand, the angle of His is always located in the greater curvature of the stomach and serves as a consistent, definite landmark of the gastric side. OBJECTIVE: To evaluate esophagocardiomyotomy in the greater curvature (GC myotomy) as an alternative POEM technique in cases where a prior LC myotomy or supervening anatomic constraints make identification of the EGJ technically challenging. DESIGN: Prospective. SETTING: Single-center study. PATIENTS: Twenty-one achalasia patients who received POEM with GC myotomy. INTERVENTIONS: POEM. MAIN OUTCOME MEASUREMENTS: Efficacy and safety of GC myotomy measured in terms of reduction in lower esophageal sphincter (LES) pressures, improvement in Eckardt scores, and development of intraoperative or postoperative adverse events. RESULTS: Identification of the EGJ was achieved in all cases, resulting in a mean gastric myotomy length of 2.6±1.1 cm. Mean LES pressure and Eckardt symptom scores decreased significantly (21.2±7.3 vs 10.5±2.7 mm Hg, 5 [2-8] vs 1 [0-5], respectively) (P<.01). Endoscopic evidence of gastroesophageal reflux was identified in 52% of patients (11/21) postmyotomy; however, only 9.5% (2/11) were symptomatic, and these patients were successfully controlled with proton pump inhibitors. No severe adverse events were encountered. LIMITATIONS: Single center. CONCLUSIONS: GC myotomy is a promising, safe modification of the POEM technique and may be especially useful in cases of redo POEM, POEM post-Heller myotomy, or when the EGJ is difficult to recognize because of supervening anatomic constraints.

Complications of laparoscopic transgastric ERCP in patients with Roux-en-Y gastric bypass.

BACKGROUND: The altered anatomy of Roux-en-Y gastric bypass presents a challenge when duodenal access is required for ERCP. One technique, laparoscopic transgastric ERCP, was first described in 2002. Since that time, a total of 77 laparoscopic or percutaneous transgastric ERCPs have been reported. The largest case series includes 26 ERCPs, and no reports specifically address complications. We reviewed our experience with 85 transgastric ERCPs and report the limitations and complications associated with access and ERCP. METHODS: Retrospective review was conducted of gastric bypass patients who underwent transgastric ERCP in our practice from 2004-2014. RESULTS: Forty-one patients underwent 85 transgastric ERCPs during the study period. Conversion from laparoscopic to open procedure occurred in 4.8%, and selective cannulation rate was 93%. Forty-seven percent of cases were repeat ERCPs performed through a gastrostomy tube tract. During 15-month median follow-up, the overall complication rate was 19%, with 88% of complications related to access rather than ERCP. Most complications were minor; there were no deaths or cases of severe pancreatitis. Additional intervention, including repair of a posterior stomach laceration or transfusion for bleeding, occurred in 4.7% of cases. Operative intervention occurred in two cases: repair of a duodenal perforation, and debridement of an abdominal wall abscess. Post-ERCP hyperamylasemia was common but did not result in increased length of stay or significant clinical pancreatitis. CONCLUSIONS: Roux-en-Y gastric bypass eliminates the normal approach to the duodenum for ERCP. Transgastric access has a high rate of successful cannulation but is associated with complications. Conversion to open procedure occurred in 4.8%, and 16% developed a complication related to the access site, though the rate of operative intervention was low (2.4%). Our study is limited by its retrospective design, which may underestimate the complication rate, and by our homogenous patient population (94% female, 68% sphincter of Oddi dysfunction).

Bloodstream infections in prolonged use of axillary-placed, intra-aortic balloon-pump support: A single-center study.

Infections from prolonged use of axillary intra-aortic balloon pumps (IABPs) have not been well studied. Bloodstream infection (BSI) occurred in 13% of our patients; however, no difference in outcome was noted between those with BSI and those without. Further studies regarding protocol developments that minimize BSI risk are needed.

Bloodstream infections after solid organ transplantation: clinical epidemiology and antimicrobial resistance (2016-21).

Background: Solid organ transplant (SOT) recipients are at risk of bloodstream infections (BSIs) with MDR organisms (MDROs). Objectives: To describe the epidemiology of BSI in the year after several types of SOT, as well as the prevalence of MDRO infections in this population. Methods: We conducted a single-centre, retrospective study of kidney, liver, heart, and multi-organ transplantation patients. We examined BSIs ≤1 year from SOT and classified MDRO phenotypes for Staphylococcus aureus, enterococci, Enterobacterales, Pseudomonas aeruginosa and Candida spp. We compared BSI characteristics between SOT types and determined risk factors for 90 day mortality. Results: We included 2293 patients [1251 (54.6%) kidney, 663 (28.9%) liver, 219 (9.6%) heart and 160 (7.0%) multi-organ transplant]. Overall, 8.5% of patients developed a BSI. BSIs were most common after multi-organ (23.1%) and liver (11.3%) transplantation (P < 0.001). Among 196 patients with BSI, 323 unique isolates were recovered, 147 (45.5%) of which were MDROs. MDROs were most common after liver transplant (53.4%). The most frequent MDROs were VRE (69.8% of enterococci) and ESBL-producing and carbapenem-resistant Enterobacterales (29.2% and 27.2% of Enterobacterales, respectively). Mortality after BSI was 9.7%; VRE was independently associated with mortality (adjusted OR 6.0, 95% CI 1.7-21.3). Conclusions: BSI incidence after SOT was 8.5%, with a high proportion of MDROs (45.5%), especially after liver transplantation. These data, in conjunction with local antimicrobial resistance patterns and prescribing practices, may help guide empirical antimicrobial selection and stewardship practices after SOT.

Single-center Outcomes After Liver Transplantation With SARS-CoV-2-Positive Donors: An Argument for Increased Utilization.

Background: The COVID-19 pandemic has led to an increase in SARS-CoV-2-test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19-positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19-positive donors at a single center are presented here. Methods: A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19-positive (n = 29 total; 25 index, 4 redo) and COVID-19-negative (n = 472 total; 454 index, 18 redo) deceased donor liver grafts were compared. Results: COVID-19-positive donors were significantly younger (P = 0.04) and had lower kidney donor profile indices (P = 0.04) than COVID-19-negative donors. Recipients of COVID-19-positive donor grafts were older (P = 0.04) but otherwise similar to recipients of negative donors. Donor SARS-CoV-2 infection status was not associated with a overall survival of recipients (hazard ratio, 1.11; 95% confidence interval, 0.24-5.04; P = 0.89). There were 3 deaths among recipients of liver grafts from COVID-19-positive donors. No death seemed virally mediated because there was no qualitative association with peri-LT antispike antibody titers, post-LT prophylaxis, or SARS-CoV-2 variants. Conclusions: The utilization of liver grafts from COVID-19-positive donors was not associated with a decreased overall survival of recipients. There was no suggestion of viral transmission from donor to recipient. The results from this large single-center study suggest that COVID-19-positive donors may be used safely to expand the deceased donor pool.

An electronic health record cohort of Veterans with amyotrophic lateral sclerosis.

Objective: To assemble and characterize an electronic health record (EHR) dataset for a large cohort of US military Veterans diagnosed with ALS (Amyotrophic Lateral Sclerosis). Methods: An EHR dataset for 19,662 Veterans diagnosed with ALS between January 1, 2000 to December 31, 2020 was compiled from the Veterans Health Administration (VHA) EHR database by a query for ICD9 diagnosis (335.20) or ICD10 diagnosis (G12.21) for Amyotrophic Lateral Sclerosis. Results: The cohort is predominantly male (98.94%) and white (72.37%) with a median age at disease onset of 68 years and median survival from the date of diagnosis of 590 days. With the designation of ALS as a compensable illness in 2009, there was a subsequent increase in the number of Veterans diagnosed per year in the VHA, but no change in median survival. The cohort included a greater-than-expected proportion of individuals whose branch of service at the time of separation was the Army. Conclusions: The composition of the cohort reflects the VHA population who are at greatest risk for ALS. The greater than expected proportion of individuals whose branch of service at the time of separation was the Army suggests the possibility of a branch-specific risk factor for ALS.

Existing and Developing Preclinical Models for Neurofibromatosis Type 1-Related Cutaneous Neurofibromas.

Neurofibromatosis type 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.

Beta-2 adrenergic receptor agonism alters astrocyte phagocytic activity and has potential applications to psychiatric disease.

Schizophrenia is a debilitating condition necessitating more efficacious therapies. Previous studies suggested that schizophrenia development is associated with aberrant synaptic pruning by glial cells. We pursued an interdisciplinary approach to understand whether therapeutic reduction in glial cell-specifically astrocytic-phagocytosis might benefit neuropsychiatric patients. We discovered that beta-2 adrenergic receptor (ADRB2) agonists reduced phagocytosis using a high-throughput, phenotypic screen of over 3200 compounds in primary human fetal astrocytes. We used protein interaction pathways analysis to associate ADRB2, to schizophrenia and endocytosis. We demonstrated that patients with a pediatric exposure to salmeterol, an ADRB2 agonist, had reduced in-patient psychiatry visits using a novel observational study in the electronic health record. We used a mouse model of inflammatory neurodegenerative disease and measured changes in proteins associated with endocytosis and vesicle-mediated transport after ADRB2 agonism. These results provide substantial rationale for clinical consideration of ADRB2 agonists as possible therapies for patients with schizophrenia.