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Objective: The objective of this study is to analyze the outcomes of patients with resectable/borderline resectable PDAC who receive total neoadjuvant therapy vs upfront surgery., Methods and Analysis: Patients who were treated at a single institution from 2006 to 2021 were included. The primary outcome was overall survival (OS). Secondary outcomes included disease free survival (DFS), rates of lymph node positivity, and R0 resection. All survival analyses were performed with intention-to-treat., Results: 26 patients received neoadjuvant chemotherapy and radiation (TNT), 28 received neoadjuvant chemotherapy only (NAC), and 168 received upfront surgery. Demographics were comparable across all three groups. Patients who received TNT or NAC had longer OS and DFS compared to the surgery first patients ( P < .01). Patients who received TNT had a lymph node positivity rate of 0% at time of surgery compared to 5.3% and 13.3% in the NAC and surgery-first groups, respectively ( P < .01). The rate of R0 resection did not differ between groups ( P = .17)., Conclusion: Patients with resectable/borderline resectable PDAC who receive neoadjuvant therapy have longer OS and RFS relative to those who receive upfront surgery., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Human coronavirus (HCoV)-NL63 causes respiratory tract infections in humans and uses angiotensin-converting enzyme 2 (ACE2) as a receptor. We sought to establish a mouse model of HCoV-NL63 and determine whether prior rhinovirus (RV)-A1B infection affected HCoV-NL63 replication. HCoV-NL63 was propagated in LLC-MK2 cells expressing human ACE2. RV-A1B was grown in HeLa-H1 cells. C57BL6/J or transgenic mice expressing human ACE2 were infected intranasally with sham LLC-MK2 cell supernatant or 1 × 10 5 tissue culture infectious dose (TCID 50 ) units HCoV-NL63. Wild-type mice were infected with 1 × 10 6 plaque-forming units (PFU) RV-A1B. Lungs were assessed for vRNA, bronchoalveolar lavage (BAL) cells, histology, HCoV-NL63 nonstructural protein 3 (nsp3), and host gene expression by next-generation sequencing and qPCR. To evaluate sequential infections, mice were infected with RV-A1B followed by HCoV-NL63 infection 4 days later. We report that hACE2 mice infected with HCoV-NL63 showed evidence of replicative infection with increased levels of vRNA, BAL neutrophils and lymphocytes, peribronchial and perivascular infiltrates, and expression of nsp3. Viral replication peaked 3 days after infection and inflammation persisted 6 days after infection. HCoV-NL63-infected hACE2 mice showed increased mRNA expression of IFNs, IFN-stimulated proteins, and proinflammatory cytokines. Infection with RV-A1B 4 days before HCoV-NL63 significantly decreased both HCoV-NL63 vRNA levels and airway inflammation. Mice infected with RV-A1B prior to HCoV-NL63 showed increased expression of antiviral proteins compared with sham-treated mice. In conclusion, we established a mouse model of HCoV-NL63 replicative infection characterized by relatively persistent viral replication and inflammation. Prior infection with RV-A1B reduced HCoV-NL63 replication and airway inflammation, indicative of viral interference. NEW & NOTEWORTHY We describe a mouse model of human coronavirus (HCoV) infection. Infection of transgenic mice expressing human angiotensin-converting enzyme 2 (ACE2) with HCoV-NL63 produced a replicative infection with peribronchial inflammation and nonstructural protein 3 expression. Mice infected with RV-A1B 4 days before HCoV-NL63 showed decreased HCoV-NL63 replication and airway inflammation and increased expression of antiviral proteins compared with sham-treated mice. This research may shed light on human coronavirus infections, viral interference, and viral-induced asthma exacerbations.

Background: Telemedicine has gained traction in surgical subspecialties, particularly since the COVID-19 pandemic. This study aims to identify whether telemedicine can be appropriately integrated within surgical oncology practice., Methods: This retrospective study evaluated patients who received either telemedicine or office follow-up after undergoing surgical oncology operations between 2016 and 2021. The telemedicine group (TG) and office group (OG) received a 15-question survey regarding their satisfaction with their care. Patient outcomes and responses were analyzed utilizing propensity-score matching in 1:1 fashion., Results: Telemedicine group and OG each had 21 patients. Length of stay, complication frequency, follow-up frequency, and readmissions frequency within 90-days were comparable between groups. Telemedicine group expressed comparable satisfaction with postoperative care relative to OG (95.2% vs. 85.7%, p  = 0.61). All telemedicine patients said they would utilize telemedicine again in the future and would recommend its use to others., Conclusion: Patient satisfaction with postoperative telemedicine follow-up is comparable to those with in-person follow-up., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Same-day discharge after mastectomy has potential patient- and hospital-level benefits; however, few data are available regarding factors affecting the likelihood of same-day discharge in order to address barriers. We sought to evaluate factors contributing to same-day discharge, focusing on the timing of mastectomy during the operative day., Methods: We conducted a single-institution retrospective review of patients who underwent mastectomies for malignancy over a 3-y time frame. Clinicopathologic variables were collected along with a binary variable for mastectomy start time (morning versus afternoon). Our primary endpoint was rate of same-day discharge. A multivariable logistic regression model was constructed from significant univariate variables to determine independent predictors of same-day discharge. A secondary endpoint was a cost-utility analysis for morning versus afternoon start time, using hospital cost data., Results: There were 451 patients included in the analysis. Factors associated with same-day discharge rate included the American Society of Anesthesiologists score, use of a preoperative regional anesthesia block, type of mastectomy performed, individual surgeon variation, and a morning start for the mastectomy. On multivariable analysis, morning start was a strong independent predictor of same-day discharge (odd ratio = 2.83; 95% CI, 1.75-4.60). The cost-utility analysis favored a morning start, with average cost savings of $550 per patient., Conclusion: Despite patient- and surgeon-specific variations, simple scheduling policies can improve same-day discharge rates after mastectomy, leading to improved hospital bed use and cost reduction., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Infection of immature mice with rhinovirus (RV) induces an asthma-like phenotype consisting of type 2 inflammation, mucous metaplasia, eosinophilic inflammation, and airway hyperresponsiveness that is dependent on IL-25 and type 2 innate lymphoid cells (ILC2s). Doublecortin-like kinase 1-positive (DCLK1+) tuft cells are a major source of IL-25. We sought to determine the requirement of tuft cells for the RV-induced asthma phenotype in wild-type mice and mice deficient in Pou2f3, a transcription factor required for tuft cell development. C57BL/6J mice infected with RV-A1B on day 6 of life and RV-A2 on day 13 of life showed increased DCLK1+ tuft cells in the large airways. Compared with wild-type mice, RV-infected Pou2f3-/- mice showed reductions in IL-25 mRNA and protein expression, ILC2 expansion, type 2 cytokine expression, mucous metaplasia, lung eosinophils, and airway methacholine responsiveness. We conclude that airway tuft cells are required for the asthma phenotype observed in immature mice undergoing repeated RV infections. Furthermore, RV-induced tuft cell development provides a mechanism by which early-life viral infections could potentiate type 2 inflammatory responses to future infections.

Objective: The aim of this study is to investigate whether origins of ethnicity affect the outcomes of surgery for diverticulitis in the USA., Design: The American College of Surgeons National Surgical Quality Improvement Programme database from 2008 to 2017 was used to identify patients undergoing colectomy for diverticulitis. Patient demographics, comorbidities, procedural details and outcomes were captured and compared by ethnicity status., Results: A total of 375 311 surgeries for diverticulitis were included in the final analysis. The average age of patients undergoing surgery for diverticulitis remained consistent over the time frame of the study (62 years), although the percentage of younger patients (age 18-39 years) rose slightly from 7.8% in 2008 to 8.6% in 2017. The percentage of surgical patients with Hispanic ethnicity increased from 3.7% in 2008 to 6.6% of patients in 2017. Hispanic patients were younger than their non-Hispanic counterparts (57 years vs 62 years, p<0.01) at time of surgery. There were statistically significant differences in the proportion of laparoscopic cases (51% vs 49%, p<0.01), elective cases (62% vs 66%, p<0.01) and the unadjusted rate of postoperative mortality (2.8% vs 3.4%, p<0.01) between Hispanic patients compared with non-Hispanic patients, respectively. Multivariable logistic regression models did not identify Hispanic ethnicity as a significant predictor for increased morbidity (p=0.13) or mortality (p=0.80)., Conclusion: Despite a significant younger population undergoing surgery for diverticulitis, Hispanic ethnicity was not associated with increased rates of emergent surgery, open surgery or postoperative complications compared with a similar non-Hispanic population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: There is a lack of consensus regarding the optimal approach for patients with full-thickness rectal prolapse. The aim of this international survey was to assess the patterns in treatment of rectal prolapse., Design: A 23-question survey was distributed to the Pelvic Floor Consortium of the American Society of Colorectal Surgeons, the Colorectal Surgical Society of Australia and New Zealand, and the Pelvic Floor Society. Questions pertained to surgeon and practice demographics, preoperative evaluation, procedural preferences, and educational needs., Setting: Electronic survey distributed to colorectal surgeons of diverse practice settings., Participants: 249 colorectal surgeons responded to the survey, 65% of which were male. There was wide variability in age, years in practice, and practice setting., Main Outcome Measures: Responses to questions regarding preoperative workup preferences and clinical scenarios., Results: In preoperative evaluation, 19% would perform anorectal physiology testing and 70% would evaluate for concomitant pelvic organ prolapse. In a healthy patient, 90% would perform a minimally invasive abdominal approach, including ventral rectopexy (56%), suture rectopexy (31%), mesh rectopexy (6%) and resection rectopexy (5%). In terms of ventral rectopexy, surgeons in the Americas preferred a synthetic mesh (61.9% vs 38.1%, p=0.59) whereas surgeons from Australasia preferred biologic grafts (75% vs 25%, p<0.01). In an older patient with comorbidities 81% would perform a perineal approach. Procedure preference (Delormes vs Altmeier) varied according to location (Australasia, 85.9% vs 14.1%; Europe, 75.3% vs 24.7%; Americas, 14.1% vs 85.9%). Most participants were interested in education regarding surgical approaches, however there is wide variability in preferred methods., Conclusion: There is significant variability in the preoperative evaluation and surgery performed for rectal prolapse. Given the lack of consensus, it is not surprising that most surgeons desire further education on the topic., Competing Interests: Competing interests: BG has speaking disclosures for Intuitive. ARLS has speaking disclosures for Intuitive, Cook Biotech, and Stryker. JKK, ERH, and JWO have no competing interests to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a paucity of data comparing open, robotic, and laparoscopic approaches on unilateral, non-recurrent inguinal hernias. Our study presents a large, retrospective triple-arm outcome analysis between robotic, laparoscopic, and open unilateral, non-recurrent inguinal hernia repairs at a single institution., Methods: 706 patients who underwent elective, non-recurrent inguinal hernia repair performed by 8 general surgeons at a single institution from 2016 to 2019 were reviewed retrospectively. Patient baseline characteristics, operative times, resident involvement, and postoperative outcomes were analyzed for all repair types. A cost analysis of the different procedures was performed., Results: There were 305 laparoscopic repairs, 207 robotic repairs, and 194 open repairs. Open and laparoscopic repairs were performed on patients who were older (p =< .001) and with a higher Charlson Comorbidity Index (p =< .001). Patient BMI was higher in minimally invasive repair than open repair (P = .021). There were no significant differences in complication rates on pairwise analysis. Robotic and open repairs had significantly longer operative times than laparoscopic repairs (P < .001). There was less resident involvement in robotic repair than with the other approaches (P < .001). Resident involvement was associated with shorter OR times (P = .001) and no significant difference in postoperative complications. There was a trend over the study period toward faster operative times and more robotic repair. Robotic repair is the most expensive repair, followed by laparoscopic and open repairs., Conclusion: All 3 repair techniques can be performed without significant differences in outcomes. The technique utilized should be based on surgeon preference and patient characteristics., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Prescription opioid misuse risk is disproportionate among veterans; military veterans wounded in combat misuse prescription opioids at an even higher rate (46.2%). Opioid misuse is costly in terms of morbidity, mortality, and humanitarian and economic burden and costs the Civilian Health and Medical Program of the Department of Veterans Affairs more than US $1.13 billion annually. Preventing opioid misuse at the time of prescription is a critical component in the response to the opioid crisis. The CPMRx mobile app has been shown to decrease the odds of opioid misuse during the postoperative period., Objective: The overarching purpose of this feasibility pilot study was to explore whether deploying a mobile app (CPMRx) to track postoperative pain and medication use is feasible in a Department of Veterans Affairs medical center. In support of this goal, we had four complementary specific aims: (1) determine the technological and logistical feasibility of the mobile app, (2) assess the acceptability of the mobile app to participants, (3) measure demand for and engagement with the mobile app, and (4) explore the potential use of the mobile app to patients and providers., Methods: Participants (N=10) were veterans undergoing total knee arthroplasty within the Veterans Health Administration provided with the CPMRx app to self-manage their pain during their 7-day at-home recovery following surgery. CPMRx uses scientifically validated tools to help clinicians understand how a patient can use the least amount of medication while getting the most benefit. The suite of software includes a mobile app for patients that includes a behavioral health intervention and a clinical decision support tool for health care providers that provides feedback about pain and medication use trends. Patients filled out paper questionnaires regarding acceptability at their postoperative follow-up appointment., Results: Overall, quantitative measures of acceptability were high. The average rating for the amount of time required to use the app was 4.9 of 5 (5="very little"), and the average rating for ease of use was 4.4 of 5 (5="very easy"). Open-ended questions also revealed that most participants found ease of use to be high. Demand and engagement were high as well with a mean number of mobile app entries of 34.1 (SD 20.1) during the postoperative period. There were no reported technological or logistical issues with the mobile app. Participants took an average of 25.13 (SD 14.37) opioid tablets to manage their postoperative pain., Conclusions: Results of this study revealed that the use of a mobile app for pain and medication management during postoperative recovery was both feasible and acceptable in older veterans undergoing total knee arthroplasty within the Veterans Health Administration. The wide variation in opioid consumption across participants revealed the potential use of the mobile app to provide actionable insights to clinicians if adopted more widely., (©Jessica Kelley Morgan, Caitlin R Rawlins, Steven K Walther, Andrew Harvey, Annmarie O'Donnell, Marla Greene, Troy G Schmidt. Originally published in JMIR Perioperative Medicine (http://periop.jmir.org), 18.10.2023.)

The aim was to assess the mid-term results of the E-iliac branched device. Baseline and follow-up data of this monocentric retrospective cohort study including all consecutive patients with aortoiliac aneurysms treated with iliac branched devices between 2016 and 2023 were extracted from the hospital records. Preoperative and follow-up CT scans were analyzed regarding endoleaks, migration, aneurysm sac remodeling, and device patency. Overall, 50 devices were implanted in 38 patients with a median age of 69 (IQR 62-78) years, and 1.6 bridging stent grafts per vessel were implanted through transfemoral (22/50; 44%) or upper extremity access (28/50; 56%). Primary technical success and assisted technical success were 97% (37/38) and 100% (38/38), respectively. No migration, no type I or III endoleaks, no stroke, colonic ischemia, aneurysm rupture, or conversion during the early and mid-term follow-ups (11 months, IQR 5-26) were observed. Aneurysm sac enlargement or shrinkage was observed in 0% (0/38) and 16% (6/38) patients, respectively. E-iliac-related re-interventions were seen only during the early follow-up: two thrombectomies with bare-metal stent relining after thrombosis of the iliac limb. Bridging stent graft and E-iliac patency during the mid-term follow-up were 100%. E-iliac showed encouraging mid-term results in the treatment of aortoiliac aneurysms with high technical success and a low re-intervention rate.

Introduction: Failure of the cricopharyngeus to relax results in oropharyngeal dysphagia, which over time results in hypertrophy and increased risk for aspiration. Open myotomy is one definitive treatment option, however there are several drawbacks attributable to the long neck incision, ± drain placement, and invasiveness of the procedure. We aim to share our experience using the DaVinci robotic platform to perform a minimally invasive cricopharyngeal myotomy, which has never been described before in the literature., Methods: All robotic cricopharyngeal myotomies performed in adult patients by a single surgeon from 2021 to 2022 were retrospectively reviewed. No patients were excluded. Outcomes of interest included length of procedure, time to diet resumption, hospital length of stay, complications, symptom improvement at follow-up, and symptom recurrence., Results: Eight robotic cricopharyngeal myotomies were performed. The median age was 65 years old (62-91) and mostly female (n = 5, 56%) with a median BMI of 28.9 kg/m 2 (21.7-39.5). The median procedure length was 113 min (94-141) and there were no intraoperative complications. All patients underwent a post-procedural esophagram with no leaks were identified. All patients were started on clear liquids in recovery and transitioned to full liquids prior to discharge. All but one patient was subsequently discharged home on the same day as procedure. All patients had routine 2-week post-operative follow-up in addition to phone follow-up at a later date (6-11 months post-operative). All patients reported resolution of symptoms. There were no complications or readmissions. No instances of recurrence were reported. On cost analysis, the minimally invasive robotic approach allows for an outpatient procedure with similar cost to an open approach with a one-night stay., Conclusion: Our experience with the novel technique of minimally invasive robotic cricopharyngeal myotomy for cricopharyngeal bars with cervical dysphagia is safe, efficacious, less invasive, and cost saving, with excellent patient outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Emergent decompressive craniotomy/craniectomy can be a lifesaving surgical intervention for select patients with traumatic brain injury. Prompt management is critical as early decompression can impact traumatic brain injury outcomes., Objective: This study aims to describe the feasibility and clinical impact of a new pathway for transporting patients with severe traumatic brain injury directly to the operating room from the trauma bay for decompressive craniotomy/craniectomy., Methods: This is a retrospective cohort preintervention and postintervention study of severe traumatic brain injury patients undergoing decompressive craniectomy/craniotomy at a Midwestern U.S. Level I trauma center between 2016 and 2022. In the new pathway, the in-house trauma surgeon takes the patient directly to the operating room with the neurosurgery advanced practice provider to drape and prepare the patient for surgery while the neurosurgeon is en route to the hospital., Results: A total of 44 patients were studied, five (5/44, 11.4%) of which were in the preintervention group and 39 (39/44, 88.6%) in the postintervention group. The median arrival-to-operating room time was shorter in the postintervention cohort (1.4 hr) than in the preintervention cohort (1.5 hr). In examining night shifts only, the preintervention cohort had shorter arrival-to-operating room times (1.2 hr) than the postintervention cohort (1.5 hr)., Conclusion: The study demonstrated that the new pathway is feasible and expedites patient transport to the operating room while awaiting the arrival of the on-call neurosurgeon., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Society of Trauma Nurses.)

Background: Left atrioventricular valve (LAVV) stenosis following an atrioventricular septal defect (AVSD) repair is a rare but potentially life-threatening complication. While echocardiographic quantification of diastolic transvalvular pressure gradients is paramount in the evaluation of a newly corrected valve function, it is hypothesized that these measured gradients are overestimated immediately following a cardiopulmonary bypass (CPB) due to the altered hemodynamics when compared to postoperative valve assessments using awake transthoracic echocardiography (TTE) upon recovery after surgery., Methods: Out of the 72 patients screened for inclusion at a tertiary center, 39 patients undergoing an AVSD repair with both intraoperative transesophageal echocardiograms (TEE, performed immediately after a CPB) and an awake TTE (performed prior to hospital discharge) were retrospectively selected. The mean (MPGs) and peak pressure gradients (PPGs) were quantified using a Doppler echocardiography and other measures of interest were recorded (e.g., a non-invasive surrogate of the cardiac output and index (CI), left ventricular ejection fraction, blood pressures and airway pressures). The variables were analyzed using the paired Student's t-tests and Spearman's correlation coefficients., Results: The MPGs were significantly higher in the intraoperative measurements when compared to the awake TTE (3.0 ± 1.2 vs. 2.3 ± 1.1 mmHg; p < 0.01); however, the PPGs did not significantly differ (6.6 ± 2.7 vs. 5.7 ± 2.8 mmHg; p = 0.06). Although the assessed intraoperative heart rates (HRs) were also higher (132 ± 17 vs. 114 ± 21 bpm; p < 0.001), there was no correlation found between the MPG and the HR, or any other parameter of interest, at either time-point. In a further analysis, a moderate to strong correlation was observed in the linear relationship between the CI and the MPG (r = 0.60; p < 0.001). During the in-hospital follow-up period, no patients died or required an intervention due to LAVV stenosis., Conclusions: The Doppler-based quantification of diastolic transvalvular LAVV mean pressure gradients using intraoperative transesophageal echocardiography seems to be prone to overestimation due to altered hemodynamics immediately after an AVSD repair. Thus, the current hemodynamic state should be taken into consideration during the intraoperative interpretation of these gradients.

Background: The treatment of Zenker's diverticulum has been shifted from open cricopharyngeal myotomy and rigid endoscopy to the use of flexible endoscopy. Few studies evaluate general surgeon's performance of flexible endoscopic management of Zenker's diverticulum as the majority are performed by gastroenterologists. The objective of our case series is to show that general surgeons trained in surgical endoscopy can perform this procedure with favorable outcomes., Methods: A retrospective review of peroral cricopharyngeal myotomies performed at Spectrum Health hospital in Grand Rapids, Michigan by a single surgical endoscopist between the 2018 and 2021 was conducted. The primary outcome was the improvement of dysphagia. Intra-procedural complications, post-procedural complications, hospital length of stay, time to oral intake, and recurrence were also evaluated. Age, sex, body mass index, diverticulum size, and procedure time were abstracted. Median (ranges) and frequencies (percentages) are used to describe the patient population and outcomes., Results: Forty patients were included in the study. Median age was 74 years old (60-95) with a male predominance (n = 27, 67.5%). Median BMI was 28 kg/m2 (18-43), average procedure length of 64 min (41-119), diverticulum size of 28 mm (19-90), and average length of stay of 0.9 days (0-8). There were no intra-procedural complications. All patients had a post-procedural esophagram prior to initiation of diet. Esophageal leak was the only complication that occurred, which was found on post-procedural esophagram (n = 5). Only two patients had clinical sequelae. All leaks closed without additional surgical intervention. The majority of patients had their diet resumed and discharged the same day of the procedure. Frequency of recurrence was 17.5% (n = 7)., Conclusion: Our study demonstrates that general surgeons trained in endoscopy can perform endoscopic myotomies for Zenker's diverticula on a wide range of sizes, with favorable patient outcomes, and few complications., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To examine the alignment between graduating surgical trainee operative performance and a prior survey of surgical program director expectations., Background: Surgical trainee operative training is expected to prepare residents to independently perform clinically important surgical procedures., Methods: We conducted a cross-sectional observational study of US general surgery residents' rated operative performance for Core general surgery procedures. Residents' expected performance on those procedures at the time of graduation was compared to the current list of Core general surgery procedures ranked by their importance for clinical practice, as assessed via a previous national survey of general surgery program directors. We also examined the frequency of individual procedures logged by residents over the course of their training., Results: Operative performance ratings for 29,885 procedures performed by 1861 surgical residents in 54 general surgery programs were analyzed. For each Core general surgery procedure, adjusted mean probability of a graduating resident being deemed practice-ready ranged from 0.59 to 0.99 (mean 0.90, standard deviation 0.08). There was weak correlation between the readiness of trainees to independently perform a procedure at the time of graduation and that procedure's historical importance to clinical practice ( p = 0.22, 95% confidence interval 0.01-0.41, P = 0.06). Residents also continue to have limited opportunities to learn many procedures that are important for clinical practice., Conclusion: The operative performance of graduating general surgery residents may not be well aligned with surgical program director expectations., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Wheezing-associated rhinovirus (RV) infections are associated with asthma development. We have shown that infection of immature mice with RV induces type 2 cytokine production and mucous metaplasia which is dependent on IL-33 and type 2 innate lymphoid cells (ILC2s) and intensified by a second heterologous RV infection. We hypothesize that M2a macrophages are required for the exaggerated inflammation and mucous metaplasia in response to heterologous RV infection. Wild-type C57Bl/6J mice and LysM Cre IL4Rα KO mice lacking M2a macrophages were treated as follows: (1) sham infection on day 6 of life plus sham on day 13 of life, (2) RV-A1B on day 6 plus sham on day 13, (3) sham on day 6 and RV-A2 on day 13, or (4) RV-A1B on day 6 and RV-A2 on day 13. Lungs were harvested one or seven days after the second infection. Wild-type mice infected with RV-A1B at day 6 showed an increased number of Arg1- and Retnla -expressing lung macrophages, indicative of M2a polarization. Compared to wild-type mice infected with RV on day 6 and 13 of life, the lungs of LysM Cre IL4Rα KO mice undergoing heterologous RV infection showed decreased protein abundance of the epithelial-derived innate cytokines IL-33, IL-25 and TSLP, decreased ILC2s, decreased mRNA expression of IL-13 and IL-5, and decreased PAS staining. Finally, mRNA analysis and immunofluorescence microscopy of double-infected LysM Cre IL4Rα KO mice showed reduced airway epithelial cell IL-33 expression, and treatment with IL-33 restored the exaggerated muco-inflammatory phenotype., Conclusion: Early-life RV infection alters the macrophage response to subsequent heterologous infection, permitting enhanced IL-33 expression, ILC2 expansion and intensified airway inflammation and mucous metaplasia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Han, Breckenridge, Kuo, Singh, Goldsmith, Li, Kreger, Bentley and Hershenson.)

Objective: Workplace-based assessment is increasingly prevalent in surgical education, especially for assessing operative skill. With current implementations, not all observed clinical performances are assessed, in part because trainees often have discretion about when they seek assessment. As a result, these samples of observed operative performances may not be representative of the full breadth of experience of surgical trainees. Therefore, analyses of these samples may be biased. We aimed to benchmark patterns of procedures logged in the SIMPL operative performance assessment system against records of trainee experience in Accreditation Council for Graduate Medical Education (ACGME) case logs., Design: We analyzed SIMPL longitudinal intraoperative performance assessments from categorical trainees in US general surgery residency programs. We compared overall patterns of how procedures are logged in SIMPL and in ACGME case logs using a Pearson correlation, and we examined differences in how individual procedures are logged in each system using Fisher's exact test., Results: Total procedure frequency from the SIMPL dataset was strongly correlated with total procedure frequency from ACGME case logs (r = 0.86, 95% CI 0.80-0.90). A subset of these procedures (10 of 116 procedures) was logged more frequently in the SIMPL dataset. These 10 procedures accounted for 56% of SIMPL observations and 30% of ACGME logged cases. Case complexity was comparable for assessments initiated by residents and faculty., Conclusions: Samples of intraoperative performance ratings gathered using the SIMPL application largely resemble ACGME case logs. There is no evidence to indicate that residents preferentially select fewer complex cases for assessment., Competing Interests: DECLARATION OF COMPETING INTEREST The authors have no conflicts of interest to disclose., (Copyright © 2021 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: During our transthoracic echocardiography (TTE) courses, medical students showed difficulty in spatial orientation. We implemented the use of 3D printed cardiac models of standard TTE views PLAX, PSAX, and A4C and assessed their efficacy in TTE-teaching., Methods: One hundred fifty-three participants were split into two groups. A pre-test-retest of anatomy, 2D -, and 3D orientation was conducted. The intervention group (n = 77) was taught using 3D models; the control group (n = 76) without. Both were comparable with respect to baseline parameters. Besides test-scores, a Likert scale recorded experiences, difficulties, and evaluation of teaching instruments., Results: From the 153 students evaluated, 123 improved, 20 did worse, and ten achieved the same result after the course. The median overall pre-test score was 29 of 41 points, and the retest score was 35 (p < 0.001). However, the intervention group taught with the 3D models, scored significantly better overall (p = 0.016), and in 2D-thinking (p = 0.002) and visual thinking (p = 0.006) subtests. A backward multivariate linear regression model revealed that the 3D models are a strong individual predictor of an excellent visual thinking score. In addition, our study showed that students with difficulty in visual thinking benefited considerably from the 3D models., Conclusion: Students taught using the 3D models significantly improved when compared with conventional teaching. Students regarded the provided models as most helpful in their learning process. We advocate the implementation of 3D-printed heart models featuring the standard views for teaching echocardiography. These findings may be transferable to other evidence based medical and surgical teaching interventions., (© 2022. The Author(s).)

Rhinovirus (RV) infection is linked to early life wheezing and exacerbation of adult asthma. RV infection can be modeled in adult and neonatal mice. This chapter outlines methods for the production of standardized human rhinovirus A1B and mouse infection. The chapter also describes methods to couple infections with allergen (ovalbumin and house dust mite) administrations. The production of the virus involves its amplification, purification, and concentration. In order to standardize the concentrated RV stock, a plaque assay on HeLa cells is outlined as a method of calibrating infectivity. Once the number of plaque-forming units is determined, the standardized virus is used for mouse infection., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Compared to other RV species, RV-C has been associated with more severe respiratory illness and is more likely to occur in children with a history of asthma or who develop asthma. We therefore inoculated 6-day-old mice with sham, RV-A1B, or RV-C15. Inflammasome priming and activation were assessed, and selected mice treated with recombinant IL-1β. Compared to RV-A1B infection, RV-C15 infection induced an exaggerated asthma phenotype, with increased mRNA expression of Il5, Il13, Il25, Il33, Muc5ac, Muc5b, and Clca1; increased lung lineage-negative CD25+CD127+ST2+ ILC2s; increased mucous metaplasia; and increased airway responsiveness. Lung vRNA, induction of pro-inflammatory type 1 cytokines, and inflammasome priming (pro-IL-1β and NLRP3) were not different between the two viruses. However, inflammasome activation (mature IL-1β and caspase-1 p12) was reduced in RV-C15-infected mice compared to RV-A1B-infected mice. A similar deficiency was found in cultured macrophages. Finally, IL-1β treatment decreased RV-C-induced type 2 cytokine and mucus-related gene expression, ILC2s, mucous metaplasia, and airway responsiveness but not lung vRNA level. We conclude that RV-C induces an enhanced asthma phenotype in immature mice. Compared to RV-A, RV-C-induced macrophage inflammasome activation and IL-1β are deficient, permitting exaggerated type 2 inflammation and mucous metaplasia., (© 2021. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 10 6 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 10 5 TCID 50 units 24 h after infection, with levels declining thereafter. IFN-α, β, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rora fl/fl littermates, RV-C-infected Rora fl/fl Il7r cre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rajput, Han, Ishikawa, Lei, Goldsmith, Jazaeri, Stroupe, Bentley and Hershenson.)

Background: Many U.S. medical schools are modifying their curricula with limited understanding of the impact on students' clinical knowledge., Methods: The surgical rotations and Surgery Shelf Exam score reports of 1514 students at a single medical school over nine academic years (2010-2018), which included a four-year transition period to a condensed pre-clerkship curriculum. Subject-specific results were compared by rotation type using Mann-Whitney tests. Regression analysis was used to assess the relationship between scores and time., Results: Data from 1514 students were included. Shelf scores decreased each year of the transition curriculum compared to the reference year (2014-2015). However, clinical exposure to specific rotations resulted in better scores in related shelf subjects. For example, students who rotated on Vascular Surgery achieved statistically better scores on the related subject than their colleagues (3.62 vs. 3.44; p = 0.0014)., Conclusions: The transition curriculum was associated with a lower performance on the surgical shelf exam when compared to the traditional curriculum, regardless of when surgery was taken during their clerkship year., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Inc.)

We report a case of a 3-week-old infant who presented a heart murmur and low oxygen saturation. An echocardiography was performed and presented a common arterial trunk type B4 with an interrupted aortic arch and intact ventricular septum. We describe the surgical management and short-term follow-up., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Early-life wheezing-associated respiratory tract infection by rhinovirus (RV) is a risk factor for asthma development. Infants are infected with many different RV strains per year., Objective: We previously showed that RV infection of 6-day-old BALB/c mice induces a mucous metaplasia phenotype that is dependent on type 2 innate lymphoid cells (ILC2s). We hypothesized that early-life RV infection alters the response to subsequent heterologous infection, inducing an exaggerated asthma-like phenotype., Methods: Wild-type BALB/c mice and Rora fl/fl Il7r cre mice lacking ILC2s were treated as follows: (1) sham on day 6 of life plus sham on day 13 of life, (2) RV-A1B on day 6 plus sham on day 13, (3) sham on day 6 plus RV-A2 on day 13, and (4) RV-A1B on day 6 plus RV-A2 on day 13., Results: Mice infected with RV-A1B at day 6 and sham at day 13 showed an increased number of bronchoalveolar lavage eosinophils and increased expression of IL-13 mRNA but not expression of IFN-γ mRNA (which is indicative of a type 2 immune response), whereas mice infected with sham on day 6 and RV-A2 on day 13 of life demonstrated increased IFN-γ expression (which is a mature antiviral response). In contrast, mice infected with RV-A1B on day 6 before RV-A2 infection on day 13 showed increased expression of IL-13, IL-5, Gob5, Muc5b, and Muc5ac mRNA; increased numbers of eosinophils and IL-13-producing ILC2s; and exaggerated mucus metaplasia and airway hyperresponsiveness. Compared with Rora fl/fl mice, Rora fl/fl Il7r cre mice showed complete suppression of bronchoalveolar lavage eosinophils and mucous metaplasia., Conclusion: Early-life RV infection alters the response to subsequent heterologous infection, inducing an intensified asthma-like phenotype that is dependent on ILC2s., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease. Pellino-1 expression was examined in bronchial sections from patients with GOLD stage two COPD and healthy controls. Primary bronchial epithelial cells (PBECs) in which Pellino-1 expression had been knocked down were extracellularly challenged with the TLR3 agonist poly(I:C). C57BL/6 Peli1 -/- mice and wild type littermates were subjected to intranasal infection with clinically-relevant respiratory viruses: rhinovirus (RV1B) and influenza A. We found that Pellino-1 is expressed in the airways of normal subjects and those with COPD, and that Pellino-1 regulates TLR3 signaling and responses to airways viruses. In particular we observed that knockout of Pellino-1 in the murine lung resulted in increased production of proinflammatory cytokines IL-6 and TNFα upon viral infection, accompanied by enhanced recruitment of immune cells to the airways, without any change in viral replication. Pellino-1 therefore regulates inflammatory airway responses without altering replication of respiratory viruses., (Copyright © 2020 Marsh, Prestwich, Williams, Hart, Muir, Parker, Jonker, Heijink, Timens, Fife, Hussell, Hershenson, Bentley, Sun, Barksby, Borthwick, Stewart, Sabroe, Dockrell and Marriott.)

Background: Early-life wheezing-associated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV infection of 6-day-old immature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with the expansion of IL-13-producing type 2 innate lymphoid cells (ILC2s) and dependent on IL-25 and IL-33. We examined regulation of this asthma-like phenotype by IL-1β., Methods: Six-day-old wild-type or NRLP3-/- mice were inoculated with sham or RV-A1B. Selected mice were treated with IL-1 receptor antagonist (IL-1RA), anti-IL-1β, or recombinant IL-1β., Results: Rhinovirus infection induced Il25, Il33, Il4, Il5, Il13, muc5ac, and gob5 mRNA expression, ILC2 expansion, mucus metaplasia, and airway hyperresponsiveness. RV also induced lung mRNA and protein expression of pro-IL-1β and NLRP3 as well as cleavage of caspase-1 and pro-IL-1β, indicating inflammasome priming and activation. Lung macrophages were a major source of IL-1β. Inhibition of IL-1β signaling with IL-1RA, anti-IL-1β, or NLRP3 KO increased RV-induced type 2 cytokine immune responses, ILC2 number, and mucus metaplasia, while decreasing IL-17 mRNA expression. Treatment with IL-1β had the opposite effect, decreasing IL-25, IL-33, and mucous metaplasia while increasing IL-17 expression. IL-1β and IL-17 each suppressed Il25, Il33, and muc5ac mRNA expression in cultured airway epithelial cells. Finally, RV-infected 6-day-old mice showed reduced IL-1β mRNA and protein expression compared to mature mice., Conclusion: Macrophage IL-1β limits type 2 inflammation and mucous metaplasia following RV infection by suppressing epithelial cell innate cytokine expression. Reduced IL-1β production in immature animals provides a mechanism permitting asthma development after early-life viral infection., (© 2020 John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Importance: This is the first multisite, randomized clinical trial of stellate ganglion block (SGB) outcomes on posttraumatic stress disorder (PTSD) symptoms., Objective: To determine whether paired SGB treatments at 0 and 2 weeks would result in improvement in mean Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total symptom severity scores from baseline to 8 weeks., Design, Setting, and Participants: This multisite, blinded, sham-procedure, randomized clinical trial used a 2:1 SGB:sham ratio and was conducted from May 2016 through March 2018 in 3 US Army Interdisciplinary Pain Management Centers. Only physicians performing the procedures and the procedure nurses were aware of the intervention (but not the participants or assessors); their interactions with the participants were scripted and limited to the 2 interventions. Active-duty service members on stable psychotropic medication dosages who had a PTSD Checklist-Civilian Version (PCL-C) score of 32 or more at screening were included. Key exclusion criteria included a prior SGB treatment, selected psychiatric disorders or substance use disorders, moderate or severe traumatic brain injury, or suicidal ideation in the prior 2 months., Interventions: Paired right-sided SGB or sham procedures at weeks 0 and 2., Main Outcomes and Measures: Improvement of 10 or more points on mean CAPS-5 total symptom severity scores from baseline to 8 weeks, adjusted for site and baseline total symptom severity scores (planned a priori)., Results: Of 190 screened individuals, 113 (59.5%; 100 male and 13 female participants; mean [SD] age, 37.3 [6.7] years) were eligible and randomized (74 to SGB and 39 to sham treatment), and 108 (95.6% of 113) completed the study. Baseline characteristics were similar in the SGB and sham treatment groups, with mean (SD) CAPS-5 scores of 37.6 (11.2) and 39.8 (14.4), respectively (on a scale of 0-80); 91 (80.0%) met CAPS-5 PTSD criteria. In an intent-to-treat analysis, adjusted mean total symptom severity score change was -12.6 points (95% CI, -15.5 to -9.7 points) for the group receiving SGB treatments, compared with -6.1 points (95% CI, -9.8 to -2.3 points) for those receiving sham treatment (P = .01)., Conclusions and Relevance: In this trial of active-duty service members with PTSD symptoms (at a clinical threshold and subthreshold), 2 SGB treatments 2 weeks apart were effective in reducing CAPS-5 total symptom severity scores over 8 weeks. The mild-moderate baseline level of PTSD symptom severity and short follow-up time limit the generalizability of these findings, but the study suggests that SGB merits further trials as a PTSD treatment adjunct., Trial Registration: ClinicalTrials.gov identifier: NCT03077919.

Asthma exacerbations are often caused by rhinovirus (RV). We and others have shown that Toll-like receptor 2 (TLR2), a membrane surface receptor that recognizes bacterial lipopeptides and lipoteichoic acid, is required and sufficient for RV-induced proinflammatory responses in vitro and in vivo. We hypothesized that viral protein-4 (VP4), an internal capsid protein that is myristoylated upon viral replication and externalized upon viral binding, is a ligand for TLR2. Recombinant VP4 and myristoylated VP4 (MyrVP4) were purified by Ni-affinity chromatography. MyrVP4 was also purified from RV-A1B-infected HeLa cells by urea solubilization and anti-VP4 affinity chromatography. Finally, synthetic MyrVP4 was produced by chemical peptide synthesis. MyrVP4-TLR2 interactions were assessed by confocal fluorescence microscopy, fluorescence resonance energy transfer (FRET), and monitoring VP4-induced cytokine mRNA expression in the presence of anti-TLR2 and anti-VP4. MyrVP4 and TLR2 colocalized in TLR2-expressing HEK-293 cells, mouse bone marrow-derived macrophages, human bronchoalveolar macrophages, and human airway epithelial cells. Colocalization was absent in TLR2-null HEK-293 cells and blocked by anti-TLR2 and anti-VP4. Cy3-labeled MyrVP4 and Cy5-labeled anti-TLR2 showed an average fractional FRET efficiency of 0.24 ± 0.05, and Cy5-labeled anti-TLR2 increased and unlabeled MyrVP4 decreased FRET efficiency. MyrVP4-induced chemokine mRNA expression was higher than that elicited by VP4 alone and was attenuated by anti-TLR2 and anti-VP4. Cytokine expression was similarly increased by MyrVP4 purified from RV-infected HeLa cells and synthetic MyrVP4. We conclude that, during RV infection, MyrVP4 and TLR2 interact to generate a proinflammatory response.

Activation of the inflammasome is a key function of the innate immune response that regulates inflammation in response to microbial substances. Inflammasome activation by human rhinovirus (RV), a major cause of asthma exacerbations, has not been well studied. We examined whether RV induces inflammasome activation in vivo, molecular mechanisms underlying RV-stimulated inflammasome priming and activation, and the contribution of inflammasome activation to RV-induced airway inflammation and exacerbation. RV infection triggered lung mRNA and protein expression of pro-IL-1β and NLRP3, indicative of inflammasome priming, as well as cleavage of caspase-1 and pro-IL-1β, completing inflammasome activation. Immunofluorescence staining showed IL-1β in lung macrophages. Depletion with clodronate liposomes and adoptive transfer experiments showed macrophages to be required and sufficient for RV-induced inflammasome activation. TLR2 was required for RV-induced inflammasome priming in vivo. UV irradiation blocked inflammasome activation and RV genome was sufficient for inflammasome activation in primed cells. Naive and house dust mite-treated NLRP3-/- and IL-1β-/- mice, as well as IL-1 receptor antagonist-treated mice, showed attenuated airway inflammation and responsiveness following RV infection. We conclude that RV-induced inflammasome activation is required for maximal airway inflammation and hyperresponsiveness in naive and allergic mice. The inflammasome represents a molecular target for RV-induced asthma exacerbations.

The leading cause of genetic dilated cardiomyopathy (DCM) is due to mutations in the TTN gene, impacting approximately 15-20% of familial and 18% of sporadic DCM cases. Currently, there is potential for a personalized RNA-based therapeutic approach in titin-based DCM, utilizing antisense oligonucleotide (AON) mediated exon-skipping, which attempts to reframe mutated titin transcripts, resulting in shortened, functional protein. However, the TTN gene is massive with 363 exons; each newly identified TTN exon mutation provides a challenge to address when considering the potential application of AON mediated exon skipping. In the initial phase of this strategy, the mutated TTN exon requires specific AON design and evaluation to assess the exon skipping effectiveness for subsequent experiments. Here, we present a detailed protocol to effectively assemble and evaluate AONs for efficient exon-skipping in targeted TTN exons. We chose a previously identified TTN 1-bp deletion mutation in exon 335 as an exemplary target exon, which causes a frameshift mutation leading to truncated A-band titin in DCM. We designed two specific AONs to mask the Ttn exon 335 and confirmed successfully mediated exon skipping without disrupting the Ttn reading frame. In addition, we evaluated and confirmed AON-treated HL-1 cells show maintained store-operated calcium entry, fractional shortening as well as preserved sarcomeric formation in comparison to control samples, indicating the treated cardiomyocytes retain adequate, essential cell function and structure, proving the treated cells can compensate for the loss of exon 335. These results indicate our method offers the first systematic protocol in designing and evaluating AONs specifically for mutated TTN target exons, expanding the framework of future advancements in the therapeutic potential of antisense-mediated exon skipping in titin-based DCM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: As of 2015, more than 2.7 million US military Veterans have served in support of the Global War on Terror. The negative sequelae associated with deployment stressors and related traumas are well-documented. Although data on mental health issues are routinely collected from service members returning from deployment, these data have not been made publicly available, leaving researchers and clinicians to rely on convenience samples, outdated studies and small sample sizes., Methods: Population-based data of US Marines returning from deployment between 2004 and 2013 were analyzed, using the Post-Deployment Health Assessment., Results: Rates of Marines returning from Iraq who screened positive for depression ranged from 19.31 to 30.02%; suicidal ideation ranged from 0 to 1.44%. Marines screening positive for PTSD ranged from 3.00 to 12.41%; combat exposure ranged from 15.58 to 55.12%. Depression was indicated for between 12.54 and 30.04% of Marines returning from Afghanistan, while suicidal ideation ranged from 0 to 5.33%. PTSD percentages ranged from 6.64 to 18.18%; combat exposure ranged between 42.92 and 75%., Conclusion: Our results support the heterogeneity of experiences and mental health sequelae of service members returning from deployments. Outcomes for Afghanistan and Iraq Veterans fluctuate with changes in OPTEMPO across theaters over time., (© The Author(s) 2018. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Trauma and sneeze-induced or cough-induced intercostal and diaphragm hernias are both rare phenomena, especially in combination. Management of these hernias is not well described, and there is no good evidence to guide operative management. Here we describe a rare presentation of coexisting intercostal and diaphragm hernias and surgical management with primary repair via a thoracotomy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

This study explored U.S. Air Force service members' perceptions of high-risk situations for sexual assault victimization. Qualitative data were collected from 52 active duty Airmen, including sexual assault survivors and general population officers and enlisted personnel. Participants were recruited through posted flyers, base-wide e-mail messages, and referrals from the Sexual Assault Response Coordinator's office. Content analysis was used to summarize participants' opinions and experiences. High-risk situations for all Airmen included excessive alcohol use, specific physical settings, and situations associated with work assignments. High-risk situations identified frequently by male and female sexual assault survivors and female (but not male) general population Airmen included power imbalance; isolation in the workplace and social settings; and youth, inexperience, and unfamiliarity with the military environment. Female Airmen identified workplaces with a predominance of men or being one of very few women in a group as a high-risk situation for sexual assault victimization. And female sexual assault survivors identified implicit but unwarranted trust between Airmen as a high-risk situation. This study provides new insight into gender differences in high-risk situations for sexual assault victimization, and the data can help policymakers better prevent sexual assault by appropriately tailoring and timing sexual assault risk reduction training., (© Association of Military Surgeons of the United States 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Rhinovirus (RV) causes the common cold and asthma exacerbations. The RV genome is a 7.3 kb single-strand positive-sense RNA., Objective: Using minor group RV1A as a backbone, we sought to design and generate a recombinant RV1A accommodating fluorescent marker expression, thereby allowing tracking of viral infection., Method: Recombinant RV1A infectious cDNA clones harboring the coding sequence of green fluorescent protein (GFP), Renilla luciferase, or iLOV (for light, oxygen, or voltage sensing) were engineered and constructed. RV-infected cells were determined by flow cytometry, immunohistochemistry, and immunofluorescence microscopy., Results: RV1A-GFP showed a cytopathic effect in HeLa cells but failed to express GFP or Renilla luciferase due to deletion. The smaller fluorescent protein construct, RV1A-iLOV, was stably expressed in infected cells. RV1A-iLOV expression was used to examine the antiviral effect of bafilomycin in HeLa cells. Compared to parental virus, RV1A-iLOV infection of BALB/c mice yielded a similar viral load and level of cytokine mRNA expression. However, imaging of fixed lung tissue failed to reveal a fluorescent signal, likely due to the oxidation and bleaching of iLOV-bound flavin mononucleotide. We therefore employed an anti-iLOV antibody for immunohistochemical and immunofluorescence imaging. The iLOV signal was identified in airway epithelial cells and CD45+ CD11b+ lung macrophages., Conclusions: These results suggest that RV1A-iLOV is a useful molecular tool for studying RV pathogenesis. The construction strategy for RV1A-iLOV could be applied to other RV serotypes. However, the detection of iLOV-expressing RV in fixed tissue required the use of an anti-iLOV antibody, limiting the value of this construct., (© 2018 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Purpose: An artificial placenta (AP) utilizing extracorporeal life support (ECLS) could avoid the harm of mechanical ventilation (MV) while allowing the lungs to develop., Methods: AP lambs (n = 5) were delivered at 118 days gestational age (GA; term = 145 days) and placed on venovenous ECLS (VV-ECLS) with jugular drainage and umbilical vein reinfusion. Lungs remained fluid-filled. After 10 days, lambs were ventilated. MV control lambs were delivered at 118 ("early MV"; n = 5) or 128 days ("late MV"; n = 5), and ventilated. Compliance and oxygenation index (OI) were calculated. After sacrifice, lungs were procured and H&E-stained slides scored for lung injury. Slides were also immunostained for PDGFR-α and α-actin; alveolar development was quantified by the area fraction of alveolar septal tips staining double-positive for both markers., Results: Compliance of AP lambs was 2.79 ± 0.81 C dyn compared to 0.83 ± 0.19 and 3.04 ± 0.99 for early and late MV, respectively. OI in AP lambs was lower than early MV lambs (6.20 ± 2.10 vs. 36.8 ± 16.8) and lung injury lower as well (1.8 ± 1.6 vs. 6.0 ± 1.2). Double-positive area fractions were higher in AP lambs (0.012 ± 0.003) than early (0.003 ± 0.0005) and late (0.004 ± 0.002) MV controls., Conclusions: Lung development continues and lungs are protected from injury during AP support relative to mechanical ventilation., Level of Evidence: n/a (basic/translational science)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Enterovirus D68 (EV-D68) shares biologic features with rhinovirus (RV). In 2014, a nationwide outbreak of EV-D68 was associated with severe asthma-like symptoms. We sought to develop a mouse model of EV-D68 infection and determine the mechanisms underlying airway disease. BALB/c mice were inoculated intranasally with EV-D68 (2014 isolate), RV-A1B, or sham, alone or in combination with anti-IL-17A or house dust mite (HDM) treatment. Like RV-A1B, lung EV-D68 viral RNA peaked 12 hours after infection. EV-D68 induced airway inflammation, expression of cytokines (TNF-α, IL-6, IL-12b, IL-17A, CXCL1, CXCL2, CXCL10, and CCL2), and airway hyperresponsiveness, which were suppressed by anti-IL-17A antibody. Neutrophilic inflammation and airway responsiveness were significantly higher after EV-D68 compared with RV-A1B infection. Flow cytometry showed increased lineage-, NKp46-, RORγt+ IL-17+ILC3s and γδ T cells in the lungs of EV-D68-treated mice compared with those in RV-treated mice. EV-D68 infection of HDM-exposed mice induced additive or synergistic increases in BAL neutrophils and eosinophils and expression of IL-17, CCL11, IL-5, and Muc5AC. Finally, patients from the 2014 epidemic period with EV-D68 showed significantly higher nasopharyngeal IL-17 mRNA levels compared with patients with RV-A infection. EV-D68 infection induces IL-17-dependent airway inflammation and hyperresponsiveness, which is greater than that generated by RV-A1B, consistent with the clinical picture of severe asthma-like symptoms.

Due to the current prolonged conflicts in Iraq and Afghanistan, members of the United States National Guard and Reserve have shifted from a historically support-based role to an integral segment of combat efforts. Clinical and epidemiological research studies conducted on both civilian and military populations have documented high rates of comorbidity of stress disorders and substance use disorders. It is widely understood that excessive alcohol use is an issue among military personnel. The aim of this paper is to describe risk factors for alcohol-related serious consequences in a study of Army National Guard service members, as well as the role of resilience in protecting against these risks. Members of the National Guard (N=320) participated in the survey. We conducted a multiple regression to predict alcohol-related serious consequences and a simple moderation analysis was performed. After controlling for race, education, and deployment history, several variables emerged as significant predictors of alcohol-related consequences. Higher stressors, lower resilience, younger age, being unmarried and not living as married, being male, and identifying as non-Hispanic were associated with higher levels of serious alcohol-related consequences. Results revealed that resilience significantly moderated the relationship between stress and alcohol-related consequences. This study furthers our understanding of the alcohol-stress relationship by contextualizing it in terms of behaviors related to alcohol, as opposed to measuring consumption only. Most importantly, our work extends prior research in its examination of resilience as a moderator of the relationship between stress and serious alcohol-related consequences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Extremely premature neonates suffer high morbidity and mortality. An artificial placenta (AP) using extracorporeal life support (ECLS) is a promising therapy., Objectives: We hypothesized that intratracheal perfluorocarbon (PFC) instillation during AP support would reduce lung injury and promote lung development relative to intratracheal amniotic fluid or crystalloid., Methods: Lambs at an estimated gestational age (EGA) 116-121 days (term 145 days) were placed on venovenous ECLS with jugular drainage and umbilical vein reinfusion and intubated. Airways were managed by the instillation of amniotic fluid and tracheal occlusion (TO; n = 4), or lactated Ringer's (LR; n = 4) or perfluorodecalin (a PFC) without occlusion (n = 4). After 7 days, the animals were sacrificed. Early (EGA 116-121 days) and late (EGA 125-131 days) tissue control lambs were delivered and sacrificed. Lungs were formalin-inflated to 30 cm H2O and sectioned for histology. Injury was scored by an unbiased pathologist. Slides were immunostained for PDGFR-α and α-actin; development was quantified by the area fraction of double-positive tips. Surfactant protein-C (SP-C) concentration in bronchoalveolar lavage fluid was quantified using ELISA., Results: Total injury scores were lower in PFC lungs (1.8 ± 1.7) than in TO (6.5 ± 2.1; p = 0.01) and LR lungs (5.5 ± 2.4; p = 0.01). The area fraction of double-positive alveolar tips appeared higher in PFC lungs than in TO lungs (0.18 ± 0.007 vs. 0.008 ± 0.004; p = 0.07). SP-C concentration was higher in PFC lungs than in TO lungs (37.9 ± 7.6 vs. 20.0 ± 5.4 pg/mL; p = 0.005), and both early (12.4 ± 1.7 g/mL; p = 0.007) and late tissue control lungs (15.1 ± 5.0 pg/mL; p = 0.0008)., Conclusion: During AP support, intratracheal PFC prevents lung injury and promotes normal lung development better than crystalloid or amniotic fluid with TO., (© 2018 S. Karger AG, Basel.)

Early-life respiratory viral infection is a risk factor for asthma development. Rhinovirus (RV) infection of 6-d-old mice, but not mature mice, causes mucous metaplasia and airway hyperresponsiveness that are associated with the expansion of lung type 2 innate lymphoid cells (ILC2s) and are dependent on IL-13 and the innate cytokine IL-25. However, contributions of the other innate cytokines, IL-33 and thymic stromal lymphopoietin (TSLP), to the observed asthma-like phenotype have not been examined. We reasoned that IL-33 and TSLP expression are also induced by RV infection in immature mice and are required for maximum ILC2 expansion and mucous metaplasia. We inoculated 6-d-old BALB/c (wild-type) and TSLP receptor-knockout mice with sham HeLa cell lysate or RV. Selected mice were treated with neutralizing Abs to IL-33 or recombinant IL-33, IL-25, or TSLP. ILC2s were isolated from RV-infected immature mice and treated with innate cytokines ex vivo. RV infection of 6-d-old mice increased IL-33 and TSLP protein abundance. TSLP expression was localized to the airway epithelium, whereas IL-33 was expressed in epithelial and subepithelial cells. RV-induced mucous metaplasia, ILC2 expansion, airway hyperresponsiveness, and epithelial cell IL-25 expression were attenuated by anti-IL-33 treatment and in TSLP receptor-knockout mice. Administration of intranasal IL-33 and TSLP was sufficient for mucous metaplasia. Finally, TSLP was required for maximal ILC2 gene expression in response to IL-25 and IL-33. The generation of mucous metaplasia in immature RV-infected mice involves a complex interplay among the innate cytokines IL-25, IL-33, and TSLP., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Early-life wheezing-associated respiratory tract infection by rhinovirus (RV) is considered a risk factor for asthma development. We have shown that RV infection of 6-day-old BALB/c mice, but not mature mice, induces an asthmalike phenotype that is associated with an increase in the population of type 2 innate lymphoid cells (ILC2s) and dependent on IL-13 and IL-25. We hypothesize that ILC2s are required and sufficient for development of the asthmalike phenotype in immature mice. Mice were infected with RV1B on day 6 of life and treated with vehicle or a chemical inhibitor of retinoic acid receptor-related orphan receptor-α (RORα), SR3335 (15 mg·kg -1 ·day -1 ip for 7 days). We also infected Rora sg/sg mice without functional ILC2s. ILC2s were identified as negative for lineage markers and positive for cluster of differentiation 25 (CD25)/IL-2Rα and CD127/IL-7Rα. Effects of SR3335 on proliferation and function of cultured ILC2s were determined. Finally, sorted ILC2s were transferred into naïve mice, and lungs were harvested 14 days later for assessment of gene expression and histology. SR3335 decreased the number of RV-induced lung lineage-negative, CD25 + , CD127 + ILC2s in immature mice. SR3335 also attenuated lung mRNA expression of IL-13, Muc5ac, and Gob5 as well as mucous metaplasia. We also found reduced expansion of ILC2s in RV-infected Rora sg/sg mice. SR3335 also blocked IL-25 and IL-33-induced ILC2 proliferation and IL-13 production ex vivo. Finally, adoptive transfer of ILC2s led to development of asthmalike phenotype in immature and adult mice. RORα-dependent ILC2s are required and sufficient for type 2 cytokine expression and mucous metaplasia in immature mice., (Copyright © 2017 the American Physiological Society.)

Apoptosis (type I programmed cell death) of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response gene IER3 regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure is largely unknown. Here, we investigate the role of IER3 in an inducible heart failure mouse model. Heart failure was induced in a mouse model that imitates a human titin truncation mutation we found in a patient with dilated cardiomyopathy (DCM). Transferase dUTP nick end labeling (TUNEL) and ssDNA stainings showed induction of apoptosis in titin-deficient cardiomyocytes during heart failure development, while IER3 response was dysregulated. Chromatin immunoprecipitation and knock-down experiments revealed that IER3 proteins target the promotors of anti-apoptotic genes and act as an anti-apoptotic factor in cardiomyocytes. Its expression is blunted during heart failure development in a titin-deficient mouse model. Targeting the IER3 pathway to reduce cardiac apoptosis might be an effective therapeutic strategy to combat heart failure.

Background: Our previous research has highlighted the important link between coping behaviors and mental health symptoms in military personnel. This study seeks to extend these findings by examining each coping behavior and mental health issue individually. This study has four specific aims: (1) test cross-sectional relationships between coping and mental health at baseline and follow-up, (2) examine stability of each variable over time, (3) determine the predictive nature of baseline mental health and coping on subsequent mental health and coping, (4) assess the magnitude of each effect to evaluate the differential predictive value of coping behaviors and mental health symptoms., Methods: A convenience sample of U.S. Army platoons of the 82nd Airborne was surveyed. We used a two-wave, cross-lagged autoregression design with structural equation modeling to disentangle elements of temporality and to examine the predictive value of mental health status vis-à-vis coping behaviors and vice versa. Separate analyses were performed with each coping strategy and each set of mental health symptoms. This design allowed for the analysis of two synchronous associations (i.e., cross-sectional correlations between the coping strategy and mental health symptoms at each time point), two autoregressive effects (i.e., baseline mental health predicting mental health at follow-up and baseline coping predicting coping at follow-up), and two cross-lagged effects (i.e., baseline coping strategy predicting mental health at follow-up and baseline mental health predicting follow-up coping)., Results: Results of descriptive statistics revealed that the most frequently reported coping behavior was thinking of a plan to solve the problem, followed by talking to a friend, engaging in a hobby, and exercising or playing sports. The least often endorsed coping behaviors were smoking marijuana or using illicit drugs and thinking about hurting or killing oneself, followed by having a drink or lighting up a cigarette. We verified many cross-sectional relationships between coping behaviors and mental health symptoms. Specifically, talking to a friend, exercising or playing sports, engaging in a hobby, and thinking of a plan were associated with fewer anxiety, perceived stress, and depression symptoms, whereas smoking a cigarette, having a drink, and thinking about hurting or killing oneself were associated with more anxiety, perceived stress, and depressive symptoms. Marijuana and illicit drug use was also associated with higher depressive symptoms. Saying a prayer was not significantly related to mental health. Only four cross-lagged effects were significant. Those who reported more depressive symptoms at Time 1 reported talking to friends and family less and exercising or playing sports less as coping behaviors at Time 2. Baseline perceived stress predicted less likelihood of engaging in a hobby at follow-up, whereas exercising or playing sports as a coping behavior at baseline predicted lower perceived stress at follow-up., Discussion: This study expands the evidence for the associations between coping behaviors and psychological health or distress to specific mental health symptoms, particularly in military service members, and provides comparisons of magnitude of each association. Clinically, this knowledge is critical to more efficiently target behaviors with the greatest associations to mental health in military personnel., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

Background: Dilated cardiomyopathy (DCM) is the result of maladaptive cardiac remodeling, which involves microRNA regulation. In turn, microRNAs can contribute to the remodeling process by post-transcriptional modulation of gene expression networks. The exact role of microRNAs in the pathogenesis of DCM is largely unknown. Here, we used an inducible DCM mouse model that carries a human truncation mutation in the sarcomeric protein titin to dissect microRNA pathways in DCM development., Methods and Results: MicroRNA microarray studies revealed up-regulation of microRNA-208b in the myocardium of DCM mice and DCM patients (p<0.05 compared to controls). In order to investigate the effect of microRNA-208b on cardiac remodeling, loss-of-function and gain-of-function studies were performed by repetitive injections of LNA-modified microRNA-208b mimics and antimiR-208b. MiR-208b overexpression resulted in cardiac hypertrophy, whereas miR-208b antagonisation prevented transition of adaptive to maladaptive remodeling in the DCM mouse model. In vitro studies identified several pro-hypertrophic transcription factors as potential targets of miR-208b, suggesting that microRNA-208b plays an important role in cardiac development and growth. MiR-208b was also upregulated in DCM patients, but not in heart failure patients due to ischemic heart disease or myocarditis., Conclusion: Our data suggests that miR-208b is involved in the remodeling process and pathogenesis of DCM by post-transcriptional gene expression modulation. MicroRNA-208b might be a novel therapeutic target for DCM., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Early-life wheezing-associated infections with rhinovirus (RV) have been associated with asthma development in children. We have shown that RV infection of 6-day-old mice induces mucous metaplasia and airways hyperresponsiveness, which is dependent on IL-13, IL-25, and type 2 innate lymphoid cells (ILC2s). Infection of immature mice fails to induce lung IFN-γ expression, in contrast to mature 8-week-old mice with a robust IFN-γ response, consistent with the notion that deficient IFN-γ production in immature mice permits RV-induced type 2 immune responses. We therefore examined the effects of intranasal IFN-γ administration on RV-induced ILC2 expansion and IL-13 expression in 6-day-old BALB/c and IL-13 reporter mice. Airway responses were assessed by histology, immunofluorescence microscopy, quantitative polymerase chain reaction, ELISA, and flow cytometry. Lung ILC2s were also treated with IFN-γ ex vivo. We found that, compared with untreated RV-infected immature mice, IFN-γ treatment attenuated RV-induced IL-13 and Muc5ac mRNA expression and mucous metaplasia. IFN-γ also reduced ILC2 expansion and the percentage of IL-13-secreting ILC2s. IFN-γ had no effect on the mRNA or protein expression of IL-25, IL-33, or thymic stromal lymphoprotein. Finally, IFN-γ treatment of sorted ILC2s reduced IL-5, IL-13, IL-17RB, ST2, and GATA-3 mRNA expression. We conclude that, in immature mice, IFN-γ inhibits ILC2 expansion and IL-13 expression in vivo and ex vivo, thereby attenuating RV-induced mucous metaplasia. These findings demonstrate the antagonistic function of IFN-γ on ILC2 expansion and gene expression, the absence of which may contribute to the development of an asthma-like phenotype after early-life RV infection.

Background: We have shown that rhinovirus, a cause of asthma exacerbation, colocalizes with CD68 + and CD11b + airway macrophages after experimental infection in human subjects. We have also shown that rhinovirus-induced cytokine expression is abolished in Toll-like receptor (TLR2) -/- bone marrow-derived macrophages., Objective: We hypothesize that TLR2 + macrophages are required and sufficient for rhinovirus-induced airway inflammation in vivo., Methods: Naive and ovalbumin (OVA)-sensitized and challenged C57BL/6 wild-type and TLR2 -/- mice were infected with RV1B, followed by IgG or anti-TLR2, to determine the requirement and sufficiency of TLR2 for rhinovirus-induced airway responses. Bone marrow chimera experiments using OVA-treated C57BL/6 and TLR2 -/- mice were also performed. Finally, naive TLR2 -/- mice underwent intranasal transfer of bone marrow-derived wild-type macrophages., Results: RV1B infection of naive wild-type mice induced an influx of airway neutrophils and CD11b + exudative macrophages, which was reduced in TLR2 -/- mice. After allergen exposure, rhinovirus-induced neutrophilic and eosinophilic airway inflammation and hyperresponsiveness were reduced in TLR2 -/- and anti-TLR2-treated mice. Transfer of TLR2 -/- bone marrow into wild-type, OVA-treated C57BL/6 mice blocked rhinovirus-induced airway responses, whereas transfer of wild-type marrow to TLR2 -/- mice restored them. Finally, transfer of wild-type macrophages to naive TLR2 -/- mice was sufficient for neutrophilic inflammation after rhinovirus infection, whereas macrophages treated with IL-4 (to induce M2 polarization) were sufficient for eosinophilic inflammation, mucous metaplasia, and airways hyperresponsiveness., Conclusions: TLR2 is required for early inflammatory responses induced by rhinovirus, and TLR2 + macrophages are sufficient to confer airway inflammation to TLR2 -/- mice, with the pattern of inflammation depending on the macrophage activation state., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)