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BACKGROUND: Women are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. METHODS: Microglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 μg/side, n = 5-6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 μg/side, n = 13-14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. RESULTS: Intra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1β (IL-1β). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1β. Intra-central amygdala m-CLD had no effect on WS-evoked behavior. CONCLUSIONS: These studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses.

ProblemThe COVID-19 pandemic restricted in-person gatherings, including residency conferences. The pressure to quickly reorganize educational conferences and convert content to a remote format overwhelmed many programs. This article describes the pilot event of a large-scale, interactive, virtual educational conference modeled, designed, and implemented by Academic Life in Emergency Medicine (ALiEM), called ALiEM Connect.ApproachThe pilot ALiEM Connect event was conceptualized and implemented within a 2-week period in March 2020. The pilot was livestreamed via a combination of Zoom and YouTube and was archived by YouTube. Slack was used as a backchannel to allow interaction with other participants and engagement with the speakers (via moderators who posed questions from the backchannel to the speakers live during the videoconference).OutcomesThe RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework was used for program evaluation, showing that 64 U.S. Accreditation Council for Graduate Medical Education-accredited emergency medicine residency programs participated in the pilot event, with 1,178 unique users during the event (reach). For effectiveness, 93% (139/149) of trainees reported the pilot as enjoyable and 85% (126/149) reported it was equivalent to or better than their usual academic proceedings. Adoption for ALiEM Connect was fairly good with 64/237 (27%) of invited residency programs registering and participating in the pilot event. Implementation was demonstrated by nearly half of the livestream viewers (47%, 553/1,178) interacting in the backchannel discussion, sending a total of 4,128 messages in the first 4 hours.Next stepsThe final component of the RE-AIM framework, maintenance, will take more time to evaluate. Further study is required to measure the educational impact of events like the ALiEM Connect pilot. The ALiEM Connect model could potentially be used to replace educational conferences that have been canceled or to implement and/or augment a large-scale, shared curriculum among residency programs in the future.

PURPOSE: The cohort of patients with locally advanced prostate cancer (PC) and positive surgical margin(s) at radical prostatectomy (RP) who would benefit from salvage or adjuvant treatment is unclear. This study examines the risk of prostate-specific antigen (PSA) relapse in a large population of men with PC after margin-positive RP. METHODS AND MATERIALS: Using a multi-institutional database, patients with clinically localized PC who underwent RP between 2002 and 2010 with recorded follow-up PSA were retrospectively selected. Patients were excluded for pathologic seminal vesicle or lymph node involvement, metastatic disease, pre-RP PSA ≥ 30, or adjuvant (nonsalvage) radiation therapy or hormone therapy. The primary endpoint was biochemical relapse free survival (bRFS), where PSA failure was defined as PSA > 0.10 ng/mL and rising, or at salvage intervention. The Kaplan-Meier method was employed for bRFS estimates; recursive partitioning analysis using cumulative or single maximal margin extent (ME) and Gleason grade (GG) at RP was applied to identify variables associated with bRFS. RESULTS: At median follow-up of 105 months, 210 patients with positive margins at RP were eligible for analysis, and 89 had experienced PSA relapse. Median age was 61 years (range, 43-76), and median pre-RP PSA 5.8 ng/mL (1.6-26.0). Recursive partitioning analysis yielded 5 discrete risk groups, with the lowest risk group (GG1, ≤ 2 mm ME) demonstrating a bRFS of 92% at 8 years compared with the highest risk group (GG3-5, ≥ 3 mm ME) of 11%. CONCLUSIONS: This retrospective study suggests that it may be possible to risk-stratify patients undergoing margin-positive RP using commonly acquired clinical and pathologic variables. Patients with low-grade tumors and minimally involved margins have a very low recurrence risk and may be able to forego postprostatectomy radiation. Meanwhile, those with higher grade and greater involvement could benefit from adjuvant or early salvage radiation therapy.

Introduction: Recent research demonstrates burnout prevalence rates as high as 76% in emergency medicine (EM) residents. In 2017 the Accreditation Council for Graduate Medical Education (ACGME) required that all training programs provide dedicated wellness education for their trainees as a requirement for accreditation. We aimed to conduct a systematic review of published wellness interventions conducted in EM residency programs following the implementation of the 2017 ACGME Common Program Requirements change in order to characterized published intervention and evaluate their effectiveness.Methods: We applied a published approach to conducting systematic reviews of the medical education literature. We performed a search of the literature from January 1, 2017–February 1, 2020. Studies were included for final review if they described a specific intervention and reported outcomes with the primary goal of improving EM resident wellness. Outcomes were characterized using the Kirkpatrick training evaluation model.Results: Eight of 35 identified studies met inclusion criteria. Most described small convenience samples of EM residents from single training programs and used the satisfaction rates of participants as primary outcome data. Only quantitative assessment methods were used. Studies addressed only a limited number of factors affecting resident wellness. The majority of interventions focused on personal factors, although a few also included sociocultural factors and the learning and practice environment.Conclusion: There is a relative dearth of literature in the area of research focused on interventions designed to improve EM resident wellness. Furthermore, the studies we identified are narrow in scope, involve relatively few participants, and describe programmatic changes of limited variety.  Future directions include an increase and emphasis on multi-institutional studies, randomized controlled trials, qualitative methodology, and opportunities for funded research.

PURPOSE: The majority of colorectal cancers are resistant to cancer immune checkpoint inhibitors. Ionizing radiation (IR) and several radiosensitizers, including PARP inhibitors, can enhance responsiveness to immune checkpoint inhibitors by potentially complementary mechanisms of action. We assessed the ability of radiation and PARP inhibition to induce proimmunogenic changes in tumor cells and enhance their in vivo responsiveness to anti-PD-1 antibodies. METHODS AND MATERIALS: We performed a candidate drug screen and used flow cytometry to assess effects of the PARP inhibitor veliparib on IR-mediated changes in MHC-1 antigen presentation and surface localization of immune-modulating proteins including PD-L1 and calreticulin in colorectal cancer tumor models. Reverse transcription polymerase chain reaction was used to assess the effects of veliparib and radiation on the expression of proinflammatory and immunosuppressive cytokines. The ability of concurrent PARP inhibition and subablative doses of radiation therapy to enhance in vivo responsiveness to anti-PD-1 antibodies was assessed using unilateral flank-tumor models with or without T-cell depletion. RESULTS: Veliparib was a potent radiosensitizer in both cell lines. Radiation increased surface localization of MHC-1 and PD-L1 in a dose-dependent manner, and veliparib pretreatment significantly enhanced these effects with high (8 Gy) but not with lower radiation doses. Enhancement of MHC-1 and PD-L1 surface localization by IR and IR+ veliparib remained significant 1, 3, and 7 days after treatment. IR significantly increased delayed tumoral expression of proinflammatory cytokines interferon-Ƴ and CXCL10 but had no significant effect on the expression of IL-6 or TGF-β. Concurrent administration of veliparib and subablative radiation therapy (8 Gy × 2) significantly prolonged anti-PD-1-mediated in vivo tumor growth delay and survival in both tumor models. Moreover, these effects were more pronounced in the microsatellite instability-mutated MC38 tumor model. Enhancement of anti-PD-1 mediated tumor growth delay with veliparib and IR was attenuated by CD8+ T-cell depletion. CONCLUSIONS: We provide preclinical evidence for a novel therapeutic strategy to enhance responsiveness of colorectal tumors to immune checkpoint inhibitors.

STUDY OBJECTIVE:Previous work shows that emergency medicine attending physicians have higher-than-average rates of burnout. Preliminary data suggest that emergency medicine residents are also at risk for burnout. The objective of this study was to conduct the first national survey assessment of US emergency medicine residents to determine the prevalence of burnout. METHODS:This prospective 2017 National Emergency Medicine Resident Wellness Survey study was conducted through the Wellness Think Tank, whereby emergency medicine residents from 247 residencies across the United States were invited to participate in a national survey. The primary measure of burnout was the Maslach Burnout Inventory-Human Services Survey. In accordance with others' work, "burnout" was defined as a dichotomous variable represented by high levels of emotional exhaustion or depersonalization. Because of interpretative variability with the survey tool, we also calculated burnout rates by using a more restrictive definition and a more inclusive definition that have been reported in the literature. RESULTS:Surveys were completed by 1,522 residents (21.1% of all US emergency medicine residents), representing 193 of 247 US emergency medicine residency programs (78.1%). Within this sample, the prevalence of burnout was 76.1% (95% confidence interval 74.0% to 78.3%). With alternative definitions applied, burnout prevalence rates for this same sample were 18.2% (95% confidence interval 16.3% to 20.1%) with the more restrictive definition and 80.9% (95% confidence interval 78.9% to 82.9%) with the more inclusive definition. CONCLUSION:The majority of US emergency medicine residents responding to this survey reported symptoms consistent with burnout, highlighting that physician burnout in the emergency medicine profession seems to begin as early as residency training. These findings may provide a baseline against which future work can be compared.

Objectives: To investigate the role of pretreatment neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) in the prediction of response to sequential intravesical therapy, gemcitabine and docetaxel (Gem/Doce), given to patients with bacille Calmette–Guérin (BCG)‐ naïve high‐risk non‐muscle‐invasive bladder cancer (NMIBC). Patients and Methods: A retrospective analysis was conducted on 115 patients who received intravesical Gem/Doce for high‐risk NMIBC between January 2011 and December 2021. Data were computed as the median (interquartile range [IQR]) or mean (standard deviation [sd]). Cox regression analysis was performed to determine if neutrophilia, NLR, platelet counts, and PLR before instillation therapy were predictive of recurrence‐free survival (RFS) and overall survival (OS). Predictive performance was estimated using Uno's C‐statistic. Results: The median (IQR) follow‐up for the overall cohort was 23 (13–36) months. The mean (sd) values for NLR, PLR and platelet counts were 3.4 (2.3), 142.2 (85.5), and 225.2 (75.1) × 109/L, respectively. NLR was associated with RFS, with a hazard ratio of 1.32 (95% confidence interval CI 1.19–1.46). Concordance analysis showed that NLR had a good ability to predict RFS (C‐index: 0.7, P < 0.01). The PLR and platelet count were not associated with RFS and did not predict recurrence. In terms of OS, none of these cellular inflammatory markers showed any prediction value. Conclusion: Pre‐treatment NLR provides some predictive accuracy for RFS in high‐risk BCG‐naïve patients receiving Gem/Doce. Further prospective trials are needed to validate this finding. [ABSTRACT FROM AUTHOR]

Simple Summary: After failing multiple treatments for non-muscle invasive bladder cancer (NMIBC), patients with this disease face the prospect of radical bladder removal. However, many patients will wish to pursue additional bladder-sparing therapies or lack candidacy for such an invasive procedure. We aimed to report on a tertiary intravesical regimen of sequential doxorubicin and gemcitabine alternating weekly with docetaxel and mitomycin (Quad Chemo) for patients with high-risk NMIBC failing multiple previous treatments. We found in a population of 29 patients with 39 treated units (bladder and/or upper urinary tracts), 80% of the units were disease-free at 3 months and 43% were disease-free at 2 years following Quad Chemo treatment. However, disease progression was a concern with an estimated 43% of patients experiencing disease progression at 5 years. Lastly, side effects were not uncommon with 19 (66%) patients reporting any side effect and 7 (24%) ultimately stopping Quad Chemo due to side effects. Background: After first-line treatment failure, patients with non-muscle invasive urothelial carcinoma (NMIUC) are recommended to undergo radical cystectomy. However, those unable to pursue radical surgery or desiring bladder preservation require effective salvage therapies. Multi-agent treatment regimens are particularly useful for targeting the complex resistance mechanisms of recurrent UC. Herein, we report a regimen of sequential doxorubicin and gemcitabine alternating weekly with sequential docetaxel and mitomycin (Quad Chemo) for patients with recurrent high-risk NMIUC. Materials and Methods: We retrospectively identified all patients sequentially treated with 50 mg of doxorubicin followed by 1000 mg of gemcitabine alternating weekly with sequential 37.5 mg of docetaxel followed by 40 mg mitomycin-C between 2007–2024. Induction consisted of 8 weekly treatments, and, if disease-free, patients were initiated on monthly maintenance treatments for 2 years. Results: In total, 29 patients (39 treated units; 26 lower urinary tract, 13 upper urinary tract) with high-grade NMIUC were included in the final analysis. The cohort had high-risk features with a median of three prior induction therapies and with 38 (97%) units presented with either biopsy-proven CIS or presumed CIS in the context of high-grade urine cytology in the absence of tumorous lesions. There were 26 recurrences during follow-up, 17 in the lower tract and 9 in the upper tract. Among all of the treated units, the complete response rate was 80%, and 1- and 2-year recurrence-free survival was 60% and 43%, respectively. In total, 10 patients experienced disease progression yielding a 5-year progression-free survival of 57%. Five patients ultimately died due to bladder cancer yielding a 5-year cancer-specific survival of 83%. A total of 19 (66%) patients reported side effects during treatment, and 7 (24%) stopped treatment secondary to side effects. Conclusions: In a high-risk heavily pre-treated cohort, Quad Chemo rescued a significant portion of patients with recurrent NMIUC from disease relapse. However, progression events were considerable in the long term. Further prospective evaluation of this treatment regimen is warranted. [ABSTRACT FROM AUTHOR]

Background: Indices of tumor heterogeneity on somatostatin receptor PET/CT scans may potentially serve as predictive biomarkers of treatment efficacy in neuroendocrine tumor (NET) patients undergoing [177Lu]Lu-DOTA-TATE PRRT. Methods: NET patients who underwent [177Lu]Lu-DOTA-TATE therapy at the University of Iowa from August 2018 to February 2021 were retrospectively evaluated. Radiomic features on the pre-PRRT somatostatin receptor PET/CT were evaluated using a custom MIM Software® LesionID workflow. Conventional PET/CT metrics of tumor burden, such as somatostatin receptor expression and tumor volume, were calculated in addition to the indices of tumor heterogeneity for each lesion (intra-lesional) and then summarized across all lesions throughout the body (inter-lesional). Endpoints included post-PRRT 24-month time to progression (TTP) and overall survival (OS). Cox regression models were used to assess the predictive ability of the imaging factors on post-PRRT 24-month TTP and OS. LASSO-penalized Cox regression was used to build a multivariable model for each outcome. Results: Eighty patients with a mean age of 65.1 years were included, with most (71.3%) completing 4 cycles of PRRT. Median TTP was 19.1 months, and OS at 60 months was 50%. A large degree of variability between patients was evidenced for imaging features related to somatostatin receptor expression. On multivariable analysis, total receptor expression and mean liver-corrected SUVmean were selected for 24-month TTP. The model was not able to significantly predict progression (C-statistic = 0.58, 95% CI 0.50–0.62). Total receptor expression and mean skewness were selected for OS. The resulting model was able to significantly predict death (C-statistic = 0.62, 95% CI 0.53–0.67), but the predictive ability was limited, as evidenced by the low C-statistic. Conclusions: Our exploratory analysis provides preliminary results showing that imaging indices of inter- and intra-tumor heterogeneity from pretreatment PET/CT images may potentially predict treatment efficacy in NET patients undergoing [177Lu]Lu-DOTA-TATE therapy. However, prospective evaluation in a larger cohort is needed to further assess whether a comprehensive characterization of tumor heterogeneity within a patient can help guide treatment decisions. [ABSTRACT FROM AUTHOR]

ABSTRACT: History of present illness: A 64-year-old female presented to the emergency department feeling like she had “pills stuck in [her] throat,” specifically calcium and a multivitamin, which she tried to relieve with drinking, eating and sticking two fingers down her throat. She was sitting upright, speaking in full sentences but had a hoarse voice. She was tolerating her secretions but had frothy sputum in the posterior oropharynx. Significant findings: Soft tissue lateral X-ray of neck was performed. The lateral soft tissue X-ray of the neck showed a metallic foreign body at the level cricoid. Discussion: Most swallowed foreign bodies enter the esophagus. Larger foreign bodies tend to obstruct proximally and may cause airway compromise in addition to esophageal trauma.1 Foreign bodies tend to lodge at areas of anatomic narrowing, most commonly the upper and lower esophageal sphincters, physiologic angulation, and areas of pathologic stricture.2,3 Ensuring airway patency and ability to manage secretions is paramount and any concern for compromise should prompt emergent consultation with otolaryngology and/or gastrointestinal. Determination of which service to consult should be made based on the suspected location of obstruction and associated symptoms. In addition to obtaining a complete history of the ingestion including type of foreign body, size, and shape, it is prudent to ask what measures, if any, the patient has already taken to remove the object.In this case, flexible fiberoptic laryngoscopy revealed swollen arytenoids and some small abrasions proximal to the vocal cords, which themselves appeared normal. She had copious secretions with no foreign bodies seen. On endoscopy, a metallic finger ring was found at the cricopharyngeus muscle along with non- obstructing laryngeal edema. The ring was removed with rat-toothed forceps. No pills were found. The patient had no recollection of swallowing the ring, but presumably, it slipped off her finger in the process of attempting to make herself vomit. After brief observation, she passed a bedside swallow assessment and was discharged in good condition. Repeat upper endoscopy 8 days later revealed a tortuous esophagus but was otherwise unremarkable. Topics: Foreign body, laryngoscopy, endoscopy, airway management.

BackgroundPlatelet clumping is a common occurrence during peripheral blood hematopoietic stem cell (HSC) collection using the Spectra Optia mononuclear cell (MNC) protocol. If clumping persists, it may prevent continuation of the collection and interfere with proper MNC separation. This study is the first to report the incidence of clumping, identify precollection factors associated with platelet clumping, and describe the degree to which platelet clumping interferes with HSC product yield.Study design and methodsIn total, 258 HSC collections performed on 116 patients using the Optia MNC protocol were reviewed. Collections utilized heparin in anticoagulant citrate dextrose to facilitate large-volume leukapheresis. Linear and logistic regression models were utilized to determine which precollection factors were predictive of platelet clumping and whether clumping was associated with product yield or collection efficiency.ResultsPlatelet clumping was observed in 63% of collections. Multivariable analysis revealed that a lower white blood cell count was an independent predictor of clumping occurrence. Chemotherapy mobilization and a lower peripheral blood CD34+ cell count were predictors of the degree of clumping. Procedures with clumping had higher collection efficiency but lower blood volume processed on average, resulting in no difference in collection yields. Citrate toxicity did not correlate with clumping.ConclusionAlthough platelet clumping is a common technical problem seen during HSC collection, the total CD34+ cell-collection yields were not affected by clumping. WBC count, mobilization approach, and peripheral blood CD34+ cell count can help predict clumping and potentially drive interventions to proactively manage clumping.

The study aimed to examine the impact of diabetes mellitus type 2 (DMII) on the oncological outcomes of non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) using comprehensive real-world data. We performed an analysis of data on NMIBC patients treated with BCG from the United States (US) National Phase II BCG/Interferon (IFN) trial database (125 centers) and pooled databases from three tertiary care institutions: France (FR), Lebanon (LB) (2000–2021), and the US (University of Iowa) (2011–2021). There were 867 patients from the Phase II trial, 1232 from the FR/LB cohort, and 233 from the US (Iowa) cohort (n = 2332). DM II was reported in 13% of the Phase II trial cohort, 14.4% of the FR/LB cohort, and 33.5% of the US (Iowa) cohort. The median follow-up was 24 months in the Phase II trial cohort, 25 months in the FR/LB cohort, and 48 months in the US (Iowa) cohort. In multivariable Cox regression analyses, DMII was not significantly associated with recurrence or progression of the tumor in any of the cohorts included in this study. DMII may not be a clinical prognostic factor for NMIBC patients treated with BCG. Prospective evaluation is needed. [ABSTRACT FROM AUTHOR]

Background: Patients with small cell lung cancer (SCLC) often respond to first-line chemoimmunotherapy. However, relapse is inevitable and is associated with a poor prognosis. Treatments for relapsed SCLC, such as lurbinectedin and topotecan, are limited bymodest efficacy and significant hematologic adverse events, leaving a need for newer therapeutic agents or regimens. The combination of gemcitabine and nabpaclitaxel is active and safe in other types of malignancies, such as pancreatic cancer. Patients and methods: We conducted a phase II trial evaluating the efficacy and safety of gemcitabine and nab-paclitaxel in patients with relapsed/refractory SCLC. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with confirmed complete or partial response. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety. Results: Between October 2016 and May 2021, 32 patients were enrolled. Patients were followed for a median of 9.3months (range 1.8-65.2). Median age was 65 years (range 48-81). Fifty percent of patients were female. Fifty-three percent of patients had platinum-resistant/refractory relapsed SCLC. The ORR was 28.1% (95% confidence interval [CI] 15.5-100%). Median PFS was 2.9 months (95% CI 2.4-3.6), and median OS was 9.3 months (95%CI 5.2-12.4). Seven patients (21.9%) developed grade 3 or 4 neutropenia. Conclusion: Our study showed that the combination of gemcitabine and nabpaclitaxel led to encouraging outcomes in relapsed/refractory SCLC. Further studies are needed to compare this combination with other treatments used for relapsed SCLC, including lurbinectedin, temozolomide, and topotecan. [ABSTRACT FROM AUTHOR]