Breast cancer in a transgender man and hypofractionated radiotherapy: A case report and review of literature.

A 77-year-old transgender man (assigned female sex at birth, gender identity male, i.e. female-to-male) was referred for a palpable mass of the right chest wall. Biopsies revealed invasive lobular breast carcinoma. After discussion by a multidisciplinary tumour board meeting, the patient was treated with total mastectomy, adjuvant hypofractionated radiation therapy, and hormone therapy. At 1.5-year follow-up, there was no sign of recurrence or long-term radiation side effects. To our knowledge, this is the first reported case of adjuvant hypofractionated radiation therapy in a transgender patient with breast cancer.

Phenotyping Hepatic Immune-Related Adverse Events in the Setting of Immune Checkpoint Inhibitor Therapy.

PURPOSE: We present and validate a rule-based algorithm for the detection of moderate to severe liver-related immune-related adverse events (irAEs) in a real-world patient cohort. The algorithm can be applied to studies of irAEs in large data sets. METHODS: We developed a set of criteria to define hepatic irAEs. The criteria include: the temporality of elevated laboratory measurements in the first 2-14 weeks of immune checkpoint inhibitor (ICI) treatment, steroid intervention within 2 weeks of the onset of elevated laboratory measurements, and intervention with a duration of at least 2 weeks. These criteria are based on the kinetics of patients who experienced moderate to severe hepatotoxicity (Common Terminology Criteria for Adverse Events grades 2-4). We applied these criteria to a retrospective cohort of 682 patients diagnosed with hepatocellular carcinoma and treated with ICI. All patients were required to have baseline laboratory measurements before and after the initiation of ICI. RESULTS: A set of 63 equally sampled patients were reviewed by two blinded, clinical adjudicators. Disagreements were reviewed and consensus was taken to be the ground truth. Of these, 25 patients with irAEs were identified, 16 were determined to be hepatic irAEs, 36 patients were nonadverse events, and two patients were of indeterminant status. Reviewers agreed in 44 of 63 patients, including 19 patients with irAEs (0.70 concordance, Fleiss' kappa: 0.43). By comparison, the algorithm achieved a sensitivity and specificity of identifying hepatic irAEs of 0.63 and 0.81, respectively, with a test efficiency (percent correctly classified) of 0.78 and outcome-weighted F1 score of 0.74. CONCLUSION: The algorithm achieves greater concordance with the ground truth than either individual clinical adjudicator for the detection of irAEs.

Hepatic steatosis induced by nicotine plus Coca-Cola™ is prevented by nicotinamide riboside (NR).

Introduction: Cigarettes containing nicotine (Nic) are a risk factor for the development of cardiovascular and metabolic diseases. We reported that Nic delivered via injections or e-cigarette vapor led to hepatic steatosis in mice fed with a high-fat diet. High-fructose corn syrup (HFCS) is the main sweetener in sugar-sweetened beverages (SSBs) in the US. Increased consumption of SSBs with HFCS is associated with increased risks of non-alcoholic fatty liver disease (NAFLD). Nicotinamide riboside (NR) increases mitochondrial nicotinamide adenine dinucleotide (NAD+) and protects mice against hepatic steatosis. This study evaluated if Nic plus Coca-Cola™ (Coke) with HFCS can cause hepatic steatosis and that can be protected by NR. Methods: C57BL/6J mice received twice daily intraperitoneal (IP) injections of Nic or saline and were given Coke (HFCS), or Coke with sugar, and NR supplementation for 10 weeks. Results: Our results show that Nic+Coke caused increased caloric intake and induced hepatic steatosis, and the addition of NR prevented these changes. Western blot analysis showed lipogenesis markers were activated (increased cleavage of the sterol regulatory element-binding protein 1 [SREBP1c] and reduction of phospho-Acetyl-CoA Carboxylase [p-ACC]) in the Nic+Coke compared to the Sal+Water group. The hepatic detrimental effects of Nic+Coke were mediated by decreased NAD+ signaling, increased oxidative stress, and mitochondrial damage. NR reduced oxidative stress and prevented mitochondrial damage by restoring protein levels of Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1) signaling. Conclusion: We conclude that Nic+Coke has an additive effect on producing hepatic steatosis, and NR is protective. This study suggests concern for the development of NAFLD in subjects who consume nicotine and drink SSBs with HFCS.

Continuing Insurance Coverage for Flap-Based Breast Reconstruction: Is There a Reservation Cost Related to a Woman's Abdominal Flap Choice?

BACKGROUND: The recent proposed alterations to the Centers for Medicare and Medicaid Services regulations, although subsequently reversed on August 21, 2023, have engendered persistent concerns regarding the impact of insurance policies on breast reconstruction procedures coverage. This study aimed to identify factors that would influence women's preferences regarding autologous breast reconstruction to better understand the possible consequences of these coverage changes. METHODS: A survey of adult women in the United States was conducted via Amazon Mechanical Turk to assess patient preferences for breast reconstruction options, specifically deep inferior epigastric perforator (DIEP) and transverse rectus abdominis myocutaneous (TRAM) flap surgery. The Cochrane-Armitage test evaluated trends in flap preferences concerning incremental out-of-pocket payment increases. RESULTS: Of 500 total responses, 485 were completed and correctly answered a verification question to ensure adequate attention to the survey, with respondents having a median (interquartile range) age of 26 (25-39) years. When presented with the advantages and disadvantages of DIEP versus TRAM flaps, 78% of respondents preferred DIEP; however, as DIEP's out-of-pocket price incrementally rose, more respondents favored the cheaper TRAM option, with $3804 being the "indifference point" where preferences for both procedures converged (P < 0.001). Notably, respondents with a personal history of breast reconstruction showed a higher preference for DIEP, even at a $10,000 out-of-pocket cost (P = 0.04). CONCLUSIONS: Out-of-pocket cost can significantly influence women's choices for breast reconstruction. These findings encourage a reevaluation of emergent insurance practices that could potentially increase out-of-pocket costs associated with DIEP flaps, to prevent cost from decreasing equitable patient access to most current reconstructive options.

Subcapsular sinus macrophages maximize germinal center development in non-draining lymph nodes during blood-borne viral infection.

Lymph node (LN) germinal centers (GCs) are critical sites for B cell activation and differentiation. GCs develop after specialized CD169+ macrophages residing in LN sinuses filter antigens (Ags) from the lymph and relay these Ags into proximal B cell follicles. Many viruses, however, first reach LNs through the blood during viremia (virus in the blood), rather than through lymph drainage from infected tissue. How LNs capture viral Ag from the blood to allow GC development is not known. Here, we followed Zika virus (ZIKV) dissemination in mice and subsequent GC formation in both infected tissue-draining and non-draining LNs. From the footpad, ZIKV initially disseminated through two LN chains, infecting LN macrophages and leading to GC formation. Despite rapid ZIKV viremia, non-draining LNs were not infected for several days. Non-draining LN infection correlated with virus-induced vascular leakage and neutralization of permeability reduced LN macrophage attrition. Depletion of non-draining LN macrophages significantly decreased GC B cells in these nodes. Thus, although LNs inefficiently captured viral Ag directly from the blood, GC formation in non-draining LNs proceeded similarly to draining LNs through LN sinus CD169+ macrophages. Together, our findings reveal a conserved pathway allowing LN macrophages to activate antiviral B cells in LNs distal from infected tissue after blood-borne viral infection.

From Case Reports to Molecular Insight: Examining the Outcomes and Underlying Mechanisms of Squamous Cell Carcinoma in Breast Implant Patients-A Systematic Review.

There is extensive coverage in the existing literature on implant-associated lymphomas like anaplastic large-cell lymphoma, but breast implant-associated squamous cell carcinoma (BIA-SCC) has received limited scholarly attention since its first case in 1992. Thus, this study aims to conduct a qualitative synthesis focused on the underexplored association between breast implants and BIA-SCC. A systematic review was conducted utilizing the PubMed, Web of Science, and Cochrane databases to identify all currently reported cases of BIA-SCC. Additionally, a literature review was performed to identify potential biochemical mechanisms that could lead to BIA-SCC. Studies were vetted for quality using the NIH quality assessment tool. From an initial pool of 246 papers, 11 met the quality criteria for inclusion, examining a total of 14 patients aged between 40 and 81 years. BIA-SCC was found in a diverse range of implants, including those with smooth and textured surfaces, as well as those filled with saline and silicone. The condition notably manifested a proclivity for aggressive clinical progression, as evidenced by a mortality rate approximating 21.4% within a post-diagnostic interval of six months. Our literature review reveals that chronic inflammation, driven by various external factors such as pathogens and implants, can initiate carcinogenesis through epigenetic modifications and immune system alterations. This includes effects from exosomes and macrophage polarization, showcasing potential pathways for the pathogenesis of BIA-SCC. The study highlights the pressing need for further investigation into BIA-SCC, a subject hitherto inadequately addressed in the academic sphere. This necessitates the urgency for early screening and intervention to improve postoperative outcomes. While the review is confined by its reliance on case reports and series, it serves as a valuable reference for future research endeavors.

The live biotherapeutic SYNB1353 decreases plasma methionine via directed degradation in animal models and healthy volunteers.

Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss of function in cystathionine ß-synthase (CBS) cause classic homocystinuria (HCU), which is managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that can be engineered to replicate the benefits of dietary restriction. In this study, we assess whether SYNB1353, an E. coli Nissle 1917 derivative, impacts circulating methionine and homocysteine levels in animals and healthy volunteers. In both mice and nonhuman primates (NHPs), SYNB1353 blunts the appearance of plasma methionine and plasma homocysteine in response to an oral methionine load. A phase 1 clinical study conducted in healthy volunteers subjected to an oral methionine challenge demonstrates that SYNB1353 is well tolerated and blunts plasma methionine by 26%. Overall, SYNB1353 represents a promising approach for methionine reduction with potential utility for the treatment of HCU.

Matching Patients to Accelerate Clinical Trials (MPACT): Enabling Technology for Oncology Clinical Trial Workflow.

Clinical trial enrollment is impeded by the significant time burden placed on research coordinators screening eligible patients. With 50,000 new cancer cases every year, the Veterans Health Administration (VHA) has made increased access for Veterans to high-quality clinical trials a priority. To aid in this effort, we worked with research coordinators to build the MPACT (Matching Patients to Accelerate Clinical Trials) platform with a goal of improving efficiency in the screening process. MPACT supports both a trial prescreening workflow and a screening workflow, employing Natural Language Processing and Data Science methods to produce reliable phenotypes of trial eligibility criteria. MPACT also has a functionality to track a patient's eligibility status over time. Qualitative feedback has been promising with users reporting a reduction in time spent on identifying eligible patients.

Selective Glycan Labeling of Mannose-Containing Glycolipids in Mycobacteria.

Mycobacterium tuberculosis (Mtb) is one of history's most successful human pathogens. By subverting typical immune responses, Mtb can persist within a host until conditions become favorable for growth and proliferation. Virulence factors that enable mycobacteria to modulate host immune systems include a suite of mannose-containing glycolipids: phosphatidylinositol mannosides, lipomannan, and lipoarabinomannan (LAM). Despite their importance, tools for their covalent capture, modification, and imaging are limited. Here, we describe a chemical biology strategy to detect and visualize these glycans. Our approach, biosynthetic incorporation, is to synthesize a lipid-glycan precursor that can be incorporated at a late-stage step in glycolipid biosynthesis. We previously demonstrated selective mycobacterial arabinan modification by biosynthetic incorporation using an exogenous donor. This report reveals that biosynthetic labeling is general and selective: it allows for cell surface mannose-containing glycolipid modification without nonspecific labeling of mannosylated glycoproteins. Specifically, we employed azido-(Z,Z)-farnesyl phosphoryl-ß-d-mannose probes and took advantage of the strain-promoted azide-alkyne cycloaddition to label and directly visualize the localization and dynamics of mycobacterial mannose-containing glycolipids. Our studies highlight the generality and utility of biosynthetic incorporation as the probe structure directs the selective labeling of distinct glycans. The disclosed agents allowed for direct tracking of the target immunomodulatory glycolipid dynamics in cellulo. We anticipate that these probes will facilitate investigating the diverse biological roles of these glycans.

Implementation of Specialty Tobacco Use Disorder Services in a Community Health Setting: Support for Enhanced Prescription Practices.

OBJECTIVES: Although public efforts to reduce tobacco use have been successful, millions of US adults currently smoke tobacco. Reducing the public health burden of tobacco use disorder (TUD) and eliminating disparities experienced by underresourced communities requires increased accessibility to services. The goal of this study was to assess whether prescriptions for evidence-based medications for tobacco treatment showed steeper growth rates among community health clinics providing specialty TUD services as compared with treatment as usual. METHODS: Clinic-wide data on prescriptions for smoking cessation pharmacotherapy at 18 primary care or mental health community clinics operated by Los Angeles County were retrieved for 4 years of an ongoing implementation trial. Specialty services included behavioral counseling and medications for tobacco treatment. Descriptive statistics characterized prescriptions rates across clinics and time. Analyses compared the slopes of the changes between intervention groups across time for primary care and mental health sites. RESULTS: Within primary care clinics, the most commonly prescribed smoking cessation medications were nicotine patches, nicotine gum, and varenicline. Throughout the trial, all clinics displayed increased rates of prescribing smoking cessation medications. Analytic results supported overall steeper increases in prescription rates for these medications among clinics randomized to specialty services versus treatment as usual within primary care ( P = 0.020) and mental health sites ( P = 0.004). CONCLUSIONS: This work provides support for the effectiveness of community-based implementation interventions that promote prescribing smoking cessation medications with the potential to reduce health disparities among communities at greater risk for TUD and its consequences.

Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML.

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Impact of Implementation of a New Weapons Screening at an Urban Emergency Department.

BACKGROUND: Violence in the emergency department (ED) setting is well documented in medical literature. Weapons can be used to cause significant injury or mortality, although there is a paucity of literature on weapons and weapons screening in the ED. OBJECTIVES: The purpose of this study was to assess the impact of initiating a weapons screening process on the identification and removal of weapons. METHODS: Multiple aspects of a weapons screening program were evaluated at 2 and 6 months prior to and after a weapons screening protocol was initiated at an urban ED. In the Pre-Screen periods, only patients primarily seeking care for mental health were screened prior to entry. In the Post-Screen periods, all patients and visitors were screened with walk-through magnetometers or wand metal detectors, and additional screening checks were initiated. The number of individuals screened and numbers of weapons found were measured. Descriptive statistics comparing Pre- and Post-Screen periods were performed. RESULTS: Prior to the new screening process, 511 and 1701 patients primarily seeking care for mental health were screened, with 15 and 103 weapons confiscated at 2 and 6 months, respectively. After the screening process was initiated, 13,149 and 43,321 ED patients and visitors were screened, with 194 and 567 weapons confiscated at 2 and 6 months, respectively. Persons screened increased by 25-fold at both 2 and 6 months after implementing the screening process. Weapons confiscated increased approximately 13-fold and sixfold at the respective 2- and 6-month Pre- and Post-Screen periods, respectively. CONCLUSION: Implementation of weapons screening significantly increased the number of weapons identified and confiscated prior to entry in the ED by patients and visitors.

The lipolysis inhibitor acipimox reverses the cardiac phenotype induced by electronic cigarettes.

Electronic cigarettes (e-cigarettes) are a prevalent alternative to conventional nicotine cigarettes among smokers and people who have never smoked. Increased concentrations of serum free fatty acids (FFAs) are crucial in generating lipotoxicity. We studied the effects of acipimox, an antilipolytic drug, on e-cigarette-induced cardiac dysfunction. C57BL/6J wild-type mice on high fat diet were treated with saline, e-cigarette with 2.4% nicotine [e-cigarette (2.4%)], and e-cigarette (2.4%) plus acipimox for 12 weeks. Fractional shortening and ejection fraction were diminished in mice exposed to e-cigarettes (2.4%) compared with saline and acipimox-treated mice. Mice exposed to e-cigarette (2.4%) had increased circulating levels of inflammatory cytokines and FFAs, which were diminished by acipimox. Gene Set Enrichment Analysis revealed that e-cigarette (2.4%)-treated mice had gene expression changes in the G2/M DNA damage checkpoint pathway that was normalized by acipimox. Accordingly, we showed that acipimox suppressed the nuclear localization of phospho-p53 induced by e-cigarette (2.4%). Additionally, e-cigarette (2.4%) increased the apurinic/apyrimidinic sites, a marker of oxidative DNA damage which was normalized by acipimox. Mice exposed to e-cigarette (2.4%) had increased cardiac Heme oxygenase 1 protein levels and 4-hydroxynonenal (4-HNE). These markers of oxidative stress were decreased by acipimox. Therefore, inhibiting lipolysis with acipimox normalizes the physiological changes induced by e-cigarettes and the associated increase in inflammatory cytokines, oxidative stress, and DNA damage.

Preferences and Barriers of Male Patients Seeking Aesthetic Procedures.

BACKGROUND: As social attitudes toward plastic surgery continue to evolve, the prevalence of men seeking plastic surgery has been increasing. By delving into the factors that encourage male patients to seek plastic surgery and the obstacles they encounter, this study aims to facilitate the development of more inclusive and effective approaches for this population. METHOD: An anonymous 41-question survey was conducted among adult men in the USA via the Amazon Mechanical Turk crowdsourcing platform. Questions assessed demographic information and identified factors that influenced males to seek plastic surgery care, the barriers they experienced while seeking care, and their preferences. Multivariate logistic regression was used to assess relationships between demographic variables and likelihood of undergoing cosmetic surgery. RESULTS: Four hundred and eleven complete responses were analyzed. The median (IQR) age of respondents was 32 (30, 40) years old. Of the respondents, 60% had undergone cosmetic surgery. Functional improvement (40%), personal aspiration (32%), and partners' opinions (22%) were the most commonly cited reasons for undergoing procedures. The most common barriers faced by this population were recovery time following a procedure (52%), perceived risk of complications (48%), cost (43%), fear of being identified as having had plastic surgery (32%), and surgeons not being able to meet expectations (31%). Eighty-nine percent of respondents who underwent plastic surgery procedures reported facing at least one barrier. Multivariate regression demonstrated that higher education levels were strongly associated with a likelihood of undergoing cosmetic surgery (p < 0.001). Income (p = 0.44) and region (p = 0.23) did not significantly affect the likelihood of undergoing plastic surgery. CONCLUSION: Despite improving societal stigma, many male patients continue to face barriers when obtaining plastic surgery care. Efforts may be made to alleviate these barriers and surgeons looking to expand their practice may benefit from increased outreach to male patients. This may be compounded with improved education targeting stigma and risks of procedures, increasing male-specific marketing communications to make them feel welcome in an industry predominantly focused on female patients, and offering male-tailored procedures. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis.

CARF (CDKN2AIP) regulates cellular fate in response to various stresses. However, its role in metabolic stress is unknown. We found that fatty livers from mice exhibit low CARF expression. Similarly, overloaded palmitate inhibited CARF expression in HepG2 cells, suggesting that excess fat-induced stress downregulates hepatic CARF. In agreement with this, silencing and overexpressing CARF resulted in higher and lower fat accumulation in HepG2 cells, respectively. Furthermore, CARF overexpression lowered the ectopic palmitate accumulation in HepG2 cells. We were interested in understanding the role of hepatic CARF and underlying mechanisms in the development of NAFLD. Mechanistically, transcriptome analysis revealed that endoplasmic reticulum (ER) stress and oxidative stress pathway genes significantly altered in the absence of CARF. IRE1α, GRP78, and CHOP, markers of ER stress, were increased, and the treatment with TUDCA, an ER stress inhibitor, attenuated fat accumulation in CARF-deficient cells. Moreover, silencing CARF caused a reduction of GPX3 and TRXND3, leading to oxidative stress and apoptotic cell death. Intriguingly, CARF overexpression in HFD-fed mice significantly decreased hepatic steatosis. Furthermore, overexpression of CARF ameliorated the aberrant ER function and oxidative stress caused by fat accumulation. Our results further demonstrated that overexpression of CARF alleviates HFD-induced insulin resistance assessed with ITT and GTT assay. Altogether, we conclude that excess fat-induced reduction of CARF dysregulates ER functions and lipid metabolism leading to hepatic steatosis.

Racial/ethnic and gender disparity in the severity of NAFLD among people with diabetes or prediabetes.

Aim: Non-alcoholic fatty liver disease (NAFLD) exhibits a racial disparity. We examined the prevalence and the association between race, gender, and NAFLD among prediabetes and diabetes populations among adults in the United States. Methods: We analyzed data for 3,190 individuals ≥18 years old from the National Health and Nutrition Examination Survey (NHANES) 2017-2018. NAFLD was diagnosed by FibroScan® using controlled attenuation parameter (CAP) values: S0 (none) < 238, S1 (mild) = 238-259, S2 (moderate) = 260-290, S3 (severe) > 290. Data were analyzed using Chi-square test and multinomial logistic regression, adjusting for confounding variables and considering the design and sample weights. Results: Of the 3,190 subjects, the prevalence of NAFLD was 82.6%, 56.4%, and 30.5% (p < 0.0001) among diabetes, prediabetes and normoglycemia populations respectively. Mexican American males with prediabetes or diabetes had the highest prevalence of severe NAFLD relative to other racial/ethnic groups (p < 0.05). In the adjusted model, among the total, prediabetes, and diabetes populations, a one unit increase in HbA1c was associated with higher odds of severe NAFLD [adjusted odds ratio (AOR) = 1.8, 95% confidence level (CI) = 1.4-2.3, p < 0.0001; AOR = 2.2, 95% CI = 1.1-4.4, p = 0.033; and AOR = 1.5, 95% CI = 1.1-1.9, p = 0.003 respectively]. Conclusion: We found that prediabetes and diabetes populations had a high prevalence and higher odds of NAFLD relative to the normoglycemic population and HbA1c is an independent predictor of NAFLD severity in prediabetes and diabetes populations. Healthcare providers should screen prediabetes and diabetes populations for early detection of NAFLD and initiate treatments including lifestyle modification to prevent the progression to non-alcoholic steatohepatitis or liver cancer.

Zika virus spreads through infection of lymph node-resident macrophages.

To disseminate through the body, Zika virus (ZIKV) is thought to exploit the mobility of myeloid cells, in particular monocytes and dendritic cells. However, the timing and mechanisms underlying shuttling of the virus by immune cells remains unclear. To understand the early steps in ZIKV transit from the skin, at different time points, we spatially mapped ZIKV infection in lymph nodes (LNs), an intermediary site en route to the blood. Contrary to prevailing hypotheses, migratory immune cells are not required for the virus to reach the LNs or blood. Instead, ZIKV rapidly infects a subset of sessile CD169+ macrophages in the LNs, which release the virus to infect downstream LNs. Infection of CD169+ macrophages alone is sufficient to initiate viremia. Overall, our experiments indicate that macrophages that reside in the LNs contribute to initial ZIKV spread. These studies enhance our understanding of ZIKV dissemination and identify another anatomical site for potential antiviral intervention.

prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis.

Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state-dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM+ virions can also contribute to pathogenesis during primary DENV infections.

Procalcitonin as a Predictive Tool for Death and ICU Admission among Febrile Neutropenic Patients Visiting the Emergency Department.

Background and Objectives: Risk stratification tools for febrile neutropenia exist but are infrequently utilized by emergency physicians. Procalcitonin may provide emergency physicians with a more objective tool to identify patients at risk of decompensation. Materials and Methods: We conducted a retrospective cohort study evaluating the use of procalcitonin in cases of febrile neutropenia among adult patients presenting to the Emergency Department compared to a non-neutropenic, febrile control group. Our primary outcome measure was in-hospital mortality with a secondary outcome of ICU admission. Results: Among febrile neutropenic patients, a positive initial procalcitonin value was associated with significantly increased odds of inpatient mortality after adjusting for age, sex, race, and ethnicity (AOR 9.912, p < 0.001), which was similar, though greater than, our non-neutropenic cohort (AOR 2.18, p < 0.001). All febrile neutropenic patients with a positive procalcitonin were admitted to the ICU. Procalcitonin had a higher sensitivity and negative predictive value (NPV) in regard to mortality and ICU admission for our neutropenic group versus our non-neutropenic control. Conclusions: Procalcitonin appears to be a valuable tool when attempting to risk stratify patients with febrile neutropenia presenting to the emergency department. Procalcitonin performed better in the prediction of death and ICU admission among patients with febrile neutropenia than a similar febrile, non-neutropenic control group.

Subspecialty and Training Preferences for U.S. Neurosurgery Faculty with International Training.

BACKGROUND: Academic neurosurgeons with international medical training play a large role in the U.S. neurosurgical workforce. We aimed to compare U.S.-trained neurosurgeons with internationally trained neurosurgeons to reveal differences in subspecialty preferences and training opportunities abroad. METHODS: We identified 1671 neurosurgeons from 115 Accreditation Council for Graduate Medical Education (ACGME)-accredited neurosurgical residency programs. Data on demographics, institution characteristics, and chosen subspecialty were collected, and faculty were divided based on location of training. Univariate analysis and multivariable logistic regression compared faculty characteristics between training locations. RESULTS: Compared with the U.S. medical school + U.S. residency group, the international medical graduate + U.S. residency group was more likely to subspecialize in oncology/skull base and vascular neurosurgery and complete a fellowship in the United States or internationally (P < 0.05). The international medical graduate + international residency group was more likely to subspecialize in oncology/skull base neurosurgery, more likely to complete an international fellowship, and less likely to practice general neurosurgery (P < 0.05). Neurosurgeons in pediatrics, radiosurgery, and vascular subspecialties were more likely to receive fellowship training in any location (P < 0.05). Additionally, functional neurosurgeons were more likely to complete fellowships internationally, spinal neurosurgeons were less likely to pursue international fellowships, and peripheral nerve neurosurgeons were more likely to have dual fellowship training in both the United States and abroad (P < 0.05). CONCLUSIONS: International medical training affected subspecialty choice and fellowship training. Internationally trained neurosurgeons more often specialized in oncology and vascular neurosurgery. Functional neurosurgeons were more likely to complete international fellowships, spine neurosurgeons were less likely to complete international fellowships, and peripheral nerve neurosurgeons more often had both U.S. and international fellowships.