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We informed women who inject drugs about different preexposure prophylaxis (PrEP) formulations; they then ranked their preferences. Daily oral PrEP was most preferred, followed by injectable PrEP and vaginal rings/gels, especially among women of color. Multiple PrEP options should be discussed with women who inject drugs to increase uptake. [ABSTRACT FROM AUTHOR]

Background: Data collection and cleaning procedures to exclude bot-generated responses are used to maintain the data integrity of samples from online surveys. However, these procedures may be time-consuming and difficult to implement. Thus, we aim to evaluate the validity of a single-step geolocation algorithm for recruiting eligible gay, bisexual, and men who have sex with men in Philadelphia for an online study. Methods: We used a 4-step approach, based on common practices for evaluating bot-generated and fraudulent responses, to assess the validity of participants' Qualtrics survey data as our referent standard. We then compared it to Qualtrics' single-step geolocation algorithm that used the MaxMind commercial database to map participants' Internet protocol address to their approximate location. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the single-step geolocation approach relative to the 4-step approach. Results: There were 826 respondents who completed the survey and 440 (53%) were eligible for enrollment based on the 4-step approach. The single-step geolocation approach yielded a sensitivity of 91% (95% CI = 88%, 93%), specificity of 79% (95% CI = 74%, 83%), PPV of 83% (95% CI = 80%, 86%), and NPV of 88% (95% CI = 85%, 91%). Conclusions: Geolocation alone provided a moderately high level of agreement with the 4-step approach for identifying geographically eligible participants in the online sample, but both approaches may be subject to additional misclassification. Researchers may want to consider multiple procedures to ensure data integrity in online samples. [ABSTRACT FROM AUTHOR]

Introduction: To guide future preexposure prophylaxis (PrEP) implementation for women who inject drugs (WWID), a population increasingly represented in new HIV cases in the United States, we present results from a demonstration project integrated within a syringe services program (SSP) in Philadelphia, PA. Methods: WWID ≥18 years were educated about and offered 24 weeks of daily PrEP. Participants completed surveys and clinical assessments at baseline and at weeks 1, 3, 12, and 24. We used descriptive statistics to estimate feasibility/acceptability, engagement in the care cascade, HIV/sexually transmitted diseases (STI) and pregnancy, issues of safety/tolerability, and preferences/satisfaction with PrEP services. Multivariable logistic regression with generalized estimating equations was used to identify factors associated with PrEP uptake and retention. Results: We recruited 136 WWID. Of those, 95 were included in the final sample, and 63 accepted a PrEP prescription at week 1. Uptake was associated with greater baseline frequency of SSP access [adjusted odds ratio (aOR) = 1.85; 95% confidence interval (CI): 1.24 to 2.77], inconsistent condom use (aOR = 3.38; 95% CI: 1.07 to 10.7), and experiencing sexual assault (aOR = 5.89; 95% CI: 1.02, 33.9). Of these 95, 42 (44.2%) were retained at week 24. Retention was higher among women who reported more frequent baseline SSP access (aOR = 1.46; 95% CI: 1.04 to 2.24). Self-reported adherence was high but discordant with urine-based quantification of tenofovir. Baseline STI prevalence was 17.9%; there were 2 HIV seroconversions and 1 pregnancy. Safety/tolerability issues were uncommon, and acceptability/satisfaction was high. Conclusions: Integrating PrEP with SSP services is feasible and acceptable for WWID. This suggests that daily PrEP is a viable prevention tool for this vulnerable population. [ABSTRACT FROM AUTHOR]

Abstract: The impact of preexposure prophylaxis uptake on sexual and injection-related behaviors among women who inject drugs is poorly understood. Over 24 weeks, preexposure prophylaxis uptake among women who inject drugs was associated with increased sharing of injection equipment but not syringes and no changes in condomless sex, providing limited evidence of risk compensation in this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: Positron emission tomography (PET)/computed tomography (CT) imaging can detect changes in arterial inflammation, but has not been used to evaluate chemotherapy-induced venous inflammation or assess risk for venous thromboembolism (VTE) in pediatric oncology. Therefore, the purpose of this study was to evaluate the prognostic value of fluorine-18-fluorodeoxyglucose PET/CT imaging of venous inflammation for predicting VTE occurrence in the 12 months after lymphoma diagnosis in pediatric, adolescent, and young adult patients. Methods: Pediatric, adolescent, and young adult patients with lymphoma diagnoses (n=71) who underwent whole-body PET/CT imaging at initial staging of disease and first therapeutic follow-up were retrospectively evaluated for serial changes in lower extremity venous uptake of fluorine-18-fluorodeoxyglucose. PET/CT images were used to segment and quantify serial changes in fluorine-18-fluorodeoxyglucose uptake for veins of interest (ie, popliteal and femoral). Incidence of VTE was assessed for 12 months after lymphoma diagnosis. Results: PET/CT detected a significantly higher inflammatory response in the femoral (P =0.012) and popliteal (P =0.013) veins of patients who experienced a VTE event compared with those who remained VTE free in the 12 months after diagnosis. The area under the curve values for receiver operator characteristics analyses were 0.76 (femoral vein) and 0.77 (popliteal vein) based on incidence of VTE occurrence. Univariate analyses demonstrated that PET/CT-derived changes in femoral (P =0.008) and popliteal (P =0.002) vein inflammation were significantly associated with VTE-free survival at 12 months after diagnosis. Conclusions: Fluorine-18-fluorodeoxyglucose PET/CT imaging detects treatment-induced venous toxicity that may provide insight into risk of VTE events in pediatric and adolescent and young adult patients with lymphoma. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly invasive breast cancer subtype that is challenging to treat due to inherent heterogeneity and absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Kinase signaling networks drive cancer growth and development, and kinase inhibitors are promising anti-cancer strategies in diverse cancer subtypes. Kinase inhibitor screens are an efficient, valuable means of identifying compounds that suppress cancer cell growth in vitro, facilitating the identification of kinase vulnerabilities to target therapeutically. The Kinase Chemogenomic Set is a well-annotated library of 187 kinase inhibitor compounds that indexes 215 kinases of the 518 in the known human kinome representing various kinase networks and signaling pathways, several of which are understudied. Our screen revealed 14 kinase inhibitor compounds effectively inhibited TNBC cell growth and proliferation. Upon further testing, three compounds, THZ531, THZ1, and PFE-PKIS 29, had the most significant and consistent effects across a range of TNBC cell lines. These cyclin-dependent kinase (CDK)12/CDK13, CDK7, and phosphoinositide 3-kinase inhibitors, respectively, decreased metabolic activity in TNBC cell lines and promote a gene expression profile consistent with the reversal of the epithelial-to-mesenchymal transition, indicating these kinase networks potentially mediate metastatic behavior. These data identified novel kinase targets and kinase signaling pathways that drive metastasis in TNBC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is increasing interest in documenting disparities in pain management for racial and ethnic minorities and patients with language barriers. Previous studies have found differential prescription patterns of opioids for racial and ethnic minority group and patients having limited English proficiency (LEP) after arthroplasty. However, there is a knowledge gap regarding how the intersection of these sociodemographic factors is associated with immediate postoperative pain management. This study aimed to explore language and racial-ethnic disparities in short-term opioid utilization after total hip and knee arthroplasty., Methods: We conducted a retrospective cohort study of adult patients who underwent total hip and knee arthroplasty from 2015 to 2019 at an urban medical center. The primary predictor variables included LEP status and racial-ethnic category, and the primary outcome variables were oral morphine equivalents (OMEs) during 2 distinct postoperative periods: the first 12 hours after surgery and from the end of surgery to the end of postoperative day (POD) 1. Patient characteristics and perioperative metrics were described by language status, race, and ethnicity using nonparametric tests, as appropriate. We performed an adjusted generalized estimating equation to assess the total effect of the intersection of LEP and racial-ethnic categories on short-term postoperative opioid use in mean ratios (MRs)., Results: This study included a total of 4090 observations, in which 7.9% (323) patients had LEP. Patients reported various racial-ethnic categories, with 72.7% (2975) non-Hispanic White, and minority groups including non-Hispanic Asian and Pacific Islander (AAPI), Hispanic/Latinx, non-Hispanic Black/African American, and Others. Patients self-identifying as non-Hispanic AAPI received fewer OME regardless of LEP status during the first 12 hours postoperatively (MR for English proficient [EP], 0.12 [95% confidence interval, CI, 0.08-0.18]; MR for LEP, 0.22 [95% CI, 0.13-0.37]) and from end of surgery to the end of POD 1 (MR for EP, 0.24 [95% CI, 0.16-0.37]; MR for LEP, 0.42, [95% CI, 0.24-0.73]) than EP non-Hispanic White. Hispanic/Latinx patients with LEP received lower amounts of OME during the first postoperative 12 hours (MR, 0.29; 95% CI, 0.17-0.53) and from end of surgery to the end of POD 1 (MR, 0.42; 95% CI 0.23-0.79) than EP non-Hispanic White. Furthermore, within the non-Hispanic White group, those with LEP received fewer OME within the first 12 hours (MR, 0.33; 95% CI, 0.13-0.83)., Conclusions: We identified an association between LEP, racial-ethnic identity, and short-term postoperative OME utilization after total knee and hip arthroplasty. The observed differences in opioid utilization imply there may be language and racial-ethnic disparities in acute pain management and perioperative care., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Competing Interests: There are no conflicts of interest for all authors.

This retrospective analysis of the Extracorporeal Life Support Organization (ELSO) registry evaluates the outcomes and identifies risk factors associated with conversion from initial venovenous extracorporeal membrane oxygenation (ECMO) support to venoarterial or hybrid ECMO in patients with coronavirus disease 2019 (COVID-19). We collected deidentified data on all adult patients (≥18 years old) diagnosed with COVID who received venovenous extracorporeal membrane oxygenation between March 2020 and November 2022. Patients initially placed on an ECMO configuration other than venovenous (VV) ECMO were excluded from the analysis. Our analysis included data from 12,850 patients, of which 393 (3.1%) transitioned from VV ECMO to an alternative mode. The primary outcome measure was in-hospital mortality, and the conversion group exhibited a higher in-hospital mortality rate. We also examined baseline variables, including demographic information, biochemical labs, and inotrope requirements. Univariate analysis revealed that pre-ECMO arrest, the need for renal replacement therapy, and the use of inotropic agents, particularly milrinone, were strongly associated with the risk of conversion. Notably, even after implementing a 3:1 propensity score matching, the impact of conversion on both mortality and complications remained substantial. Our study underscores an elevated risk of mortality for COVID-19 patients initially treated with VV ECMO who subsequently require conversion to VA-ECMO or hybrid ECMO., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Purpose of Review: This review highlights advances in understanding the epigenetic control mechanisms that regulate HIV-1 latency mechanisms in T-cells and microglial cells and describes the potential of current therapeutic approaches targeting the epigenetic machinery to eliminate or block the HIV-1 latent reservoir., Recent Findings: Large-scale unbiased CRISPR-Cas9 library-based screenings, coupled with biochemical studies, have comprehensively identified the epigenetic factors pivotal in regulating HIV-1 latency, paving the way for potential novel targets in therapeutic development. These studies also highlight how the bivalency observed at the HIV-1 5'LTR primes latent proviruses for rapid reactivation., Summary: The HIV-1 latent is established very early during infection, and its persistence is the major obstacle to achieving an HIV-1 cure. Here, we present a succinct summary of the latest research findings, shedding light on the pivotal roles played by host epigenetic machinery in the control of HIV-1 latency. Newly uncovered mechanisms permitting rapid reversal of epigenetic restrictions upon viral reactivation highlight the formidable challenges of achieving enduring and irreversible epigenetic silencing of HIV-1., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Study Design: Retrospective cohort., Objective: To report normative measurements of L1 to S1 lumbar neuroforamina on plain film radiography (PFR), computed tomography (CT), and magnetic resonance imaging (MRI), accounting for patients' sex and ethnicity., Background: The quantitative criteria fothe diagnosis of neuroforaminal stenosis remains unknown. Acquiring a thorough understanding of normative foraminal dimensions is a key step in formulating objective parameters for neuroforaminal stenosis., Patients and Methods: We measured 988 images from 494 patients between 18 and 35 years old without spinal pathology who received PFR, CT, or MRI within 1 year of each other. Neuroforaminal measurements were defined as the height, area, and sagittal and axial widths. Statistical analyses were performed to assess relationships among PFR, CT, and MRI-derived neuroforaminal measurements, as well as the influence of patients' sex and ethnicity., Results: 330 PFR, 377 CT, and 281 MRI were measured. Of these, 213 PFR and CT, 117 PFR and MRI, and 164 MRI and CT intrapatient images were compared. Statistically significant differences were observed among PFR, CT, and MRI measurements across all levels L1 to S1. PFR measurements were larger compared with those derived from CT and MRI. Weak-to-moderate correlations were observed between PFR and CT, PFR and MRI, and CT and MRI, with the magnitude of correlation decreasing caudally from L1 to S1. Variations in neuroforaminal anatomy were observed based on sex and ethnicity., Conclusion: This study reports 25,951 measurements of normal L1 to S1 neuroforaminal anatomy assessed by PFR, CT, and MRI. The values reported in this study may be used as normative reference measurements of the lumbar neuroforamina. PFR measurements of the neuroforamina are larger compared with those derived from CT and MRI across all levels from L1 to S1. There is a poor correlation between PFR, CT, and MRI when measuring the lumbar neuroforamina. Differences in neuroforaminal anatomy are evident based on patients' sex and ethnicity., Competing Interests: W.C. reports consulting for Medtronic and Orthofix, a research grant from DePuy Synthes, and speaking and consultation for Radius. O.D. declares royalties from Globus Medical, consultation for Stryker, reimbursement for travel and expenses for services as an oral examiner for the American Board of Orthopaedic Surgery (ABOS), and reimbursement for travel to the annual meeting of the Musculoskeletal Transplant Foundation as a medical board member. Uncompensated disclosures for O.D. include his service on the patient safety committee for the North American Spine Society, the spine education committee for Orthopaedic Research Society and American Academy of Orthopaedic Surgeons (AAOS), and associate editor for SpineLine and NASSJ. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants., Methods: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected., Results: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events., Conclusions: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established., Competing Interests: Disclosures None.

The indirect immunofluorescence assay (IIFA) on HEp-2 cells has been widely used for screening anti-nuclear antibodies (ANA) that are associated with systemic autoimmune rheumatic diseases (SARD). Sera containing ANA display multiple distinct fluorescence patterns on HEp-2 cells. Among them, a dense fine speckled (DFS) pattern caused by anti-DFS70 antibodies has been reported to have higher prevalence in healthy individuals than in patients with SARD. This DFS pattern is often difficult to distinguish amongst other SARD-associated ANA patterns, in particular a mixed homogeneous and speckled pattern. Furthermore, a strong DFS pattern can mask other SARD-associated patterns. Hence, we developed a novel immunoprecipitation method using magnetic beads to remove anti-DFS70 antibodies in serum prior to running IIFA. We also aimed to confirm the presence of anti-DFS70 and to uncover any SARD-associated ANA patterns masked by a strong DFS pattern. The sera used in our study were from 70 individuals who had routine ANA screen, of which 35 sera had an isolated DFS pattern with monospecific anti-DFS70 antibodies confirmed by a complementary assay, and 35 were control sera without a DFS pattern. An immunoprecipitation method using magnetic beads coated with recombinant human full length DFS70 protein was developed. The performance of this new method was evaluated in comparison to an immunoadsorption method using the same DFS70 protein. Our newly developed immunoprecipitation method demonstrated excellent sensitivity (91.4%) and specificity (100%) in confirming the DFS pattern associated with anti-DFS70 in sera. Additionally, our method was able to remove anti-DFS70 and uncover SARD-associated ANA patterns masked by a strong DFS pattern. It also showed a clearer background on IIFA than that of the immunoadsorption method. The novel magnetic bead-based immunoprecipitation method demonstrated satisfactory performance in removing anti-DFS70 without interfering with the detection of other antibodies. It can be easily integrated with IIFA to confirm anti-DFS70 associated DFS pattern. Additionally, it can simultaneously unmask other ANA patterns, which cannot be achieved by a conventional protocol that requires a complementary anti-DFS70 specific assay to be performed. Therefore, the novel method provides a more effective and accurate solution for ANA screening., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Adenoid cystic carcinoma (ACC) is one of the most common primary salivary gland cancers. ACC has several benign and malignant mimics amongst salivary gland neoplasms. An accurate diagnosis of ACC is essential for optimal management of the patients and their follow-up. Upregulation of MYB has been described in 85-90% of ACC, but not in other salivary gland neoplasms. In ACC, MYB upregulation can occur as a result of a genetic rearrangement t(6;9) (q22-23;p23-24), MYB copy number variation (CNV), or enhancer hijacking of MYB. All mechanisms of MYB upregulation result in increased RNA transcription that can be detected using RNA in situ hybridisation (ISH) methods. In this study, utilising 138 primary salivary gland neoplasms including 78 ACC, we evaluate the diagnostic utility of MYB RNA ISH for distinguishing ACC from other primary salivary gland neoplasms with a prominent cribriform architecture including pleomorphic adenoma, basal cell adenoma, basal cell adenocarcinoma, epithelial myoepithelial carcinoma, and polymorphous adenocarcinoma. Fluorescent in situ hybridisation and next generation sequencing were also performed to evaluate the sensitivity and specificity of RNA ISH for detecting increased MYB RNA when MYB gene alterations were present. Detection of MYB RNA has 92.3% sensitivity and 98.2% specificity for a diagnosis of ACC amongst salivary gland neoplasms. The sensitivity of MYB RNA detection by ISH (92.3%) is significantly higher than that of the FISH MYB break-apart probe (42%) for ACC. Next generation sequencing did not demonstrate MYB alterations in cases that lacked MYB RNA overexpression indicating high sensitivity of MYB RNA ISH for detecting MYB gene alterations. The possibility that the sensitivity may be higher in clinical practice with contemporary samples as compared with older retrospective tissue samples with RNA degradation is not entirely excluded. In addition to the high sensitivity and specificity, MYB RNA testing can be performed using standard IHC platforms and protocols and evaluated using brightfield microscopy making it a time and cost-efficient diagnostic tool in routine clinical practice., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

The Council of State and Territorial Epidemiologists (CSTE) conducted the seventh Epidemiology Capacity Assessment (ECA) from January to April 2021 in state and territorial health departments. The ECA serves to enumerate the applied epidemiology workforce and evaluate workforce capacity across the nation. The results of the ECA demonstrated a need for additional epidemiologists across jurisdictions and challenges of maintaining a trained workforce and improving public health infrastructure. The results of the ECA serve as the foundation for CSTE's workforce priorities, which focus on transforming applied epidemiology by promoting the field as a career opportunity, recruitment, and retention strategies, upskilling the workforce, and enhancing infrastructure. CSTE has outlined current and future workforce priorities, and these priorities contribute to a larger strategy to transform the field and enhance applied epidemiology capacity nationwide. This report describes the programmatic actions taken by CSTE in response to the results of the 2021 ECA., Competing Interests: There are no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The presence of monospecific dense fine speckled 70 (DFS70) pattern in indirect immunofluorescence assay (IFA) without concomitant systemic autoimmune related diseases (SARD)-associated antibodies could be an exclusion biomarker for SARD. Since interpretation of DFS pattern on IFA is subjective, an assay for confirming the presence of anti-DFS70 is required. We evaluated the performance of two commercial assays [fluorescence enzyme immunoassay (FEIA) and line immunoassay (LIA)] for detecting anti-DFS70. Sera with monospecific DFS (n=176) and without DFS (n=179) pattern from referred patients for ANA testing, in two independent laboratories and healthy donors, were investigated for anti-DFS70 by FEIA (Phadia EliA) and LIA (Euroimmun). The assay performance including sensitivity and specificity at different cut-offs was evaluated, and optimal cut-offs were determined. The newly established optimal cut-offs (2.7 U/mL on EliA, band intensity of 28 on LIA) showed significantly better assay performance in detecting anti-DFS70 and confirming monospecific DFS pattern. A relative sensitivity of 93.7% with relative specificity of 100% on EliA and a relative sensitivity of 96.6% with relative specificity of 95.3% on LIA were achieved. Superior Cohen's Kappa agreements with IFA were also achieved for both assays (0.936 for EliA and 0.906 for LIA). Application of an optimal cut-off can significantly increase the assay performance for anti-DFS70 and enhance the accuracy in reporting DFS pattern by IFA., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: Polycyclic aromatic hydrocarbons (PAHs) are endocrine-disrupting chemicals. Few studies have evaluated the association between pubertal development in girls and PAH exposures quantified by urinary biomarkers., Methods: We examined associations of urinary PAH metabolites with pubertal development in 358 girls 6-16 years of age from the San Francisco Bay Area enrolled in a prospective cohort from 2011 to 2013 and followed until 2020. Using baseline data, we assessed associations of urinary PAH metabolites with pubertal development stage. In prospective analyses limited to girls who at baseline had not yet started breast (N = 176) or pubic hair (N = 179) development or menstruation (N = 267), we used multivariable Cox proportional hazards regression to assess associations of urinary PAH metabolites with the onset of breast and pubic hair development, menstruation, and pubertal tempo (interval between the onset of breast development and menstruation)., Results: We detected PAH metabolites in >98% of girls. In cross-sectional analyses using baseline data, PAH metabolites were not associated with the pubertal development stage. In prospective analyses, higher concentrations (≥ median) of some PAH metabolites were associated with two-fold higher odds of earlier breast development (2-hydroxy naphthalene, 1-hydroxy phenanthrene, summed hydroxy phenanthrenes) or pubic hair development (1-hydroxy naphthalene) among girls overweight at baseline (body mass index-for-age percentile ≥85) compared with nonoverweight girls with lower metabolites concentrations. PAH metabolites were not associated with age at menarche or pubertal tempo., Conclusions: PAH exposures were widespread in our sample. Our results support the hypothesis that, in overweight girls, PAHs impact the timing of pubertal development, an important risk factor for breast cancer., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Early revascularization, invasive hemodynamic profiling, and initiation of temporary mechanical circulatory support (MCS) have all become routine components of cardiogenic shock (CS) management. Despite this evolution in clinical practice, patient selection and timing of treatment initiation remain a significant barrier to achieving sustained improvement in CS outcomes. Recent efforts to standardize CS management, through the development of treatment algorithms, have relied heavily on surrogate endpoints to drive therapeutic decisions. The present review aims to provide an overview of the basis of evidence for those surrogate endpoints commonly employed in clinical trials and CS management algorithms., Recent Findings: Recent publications from both observational and randomized cohorts have demonstrated the utility of surrogate endpoints in risk stratifying patients with CS. In particular, invasive hemodynamics using pulmonary artery catheters to guide initiation and weaning of MCS, biochemical markers that portend imminent end-organ failure, and clinical risk scores that combine multiple hemodynamic and laboratory parameters have demonstrated an ability to prognosticate outcomes in patients with CS., Summary: Although further validation is necessary, multiple clinical, hemodynamic, and biochemical markers have demonstrated utility as surrogate endpoints in CS, and will undoubtedly assist physicians in clinical decision-making., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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Purpose: Maxillofacial trauma is treated by two medical specialties, plastic surgery (PRS) and otolaryngology (ENT). Differences in training exposure and practice patterns exist between specialties, but their respective outcomes have never been compared., Methods: Mandible fracture data were reviewed from the National Surgical Quality Improvement Program from 2005 to 2016. Demographics variables, repair types, and adverse outcomes were compared between PRS and ENT., Results: From 2005 to 2016, one thousand two hundred eighty-two cases were identified with 756 cases managed by ENT and 526 cases managed by PRS. Mean patient age was 34.6 years for both specialties (P = 0.95). Patient demographics between both cohorts were not statistically different except for higher rates of hypertension among ENT patients (10.2% for ENT versus 6.7% for PRS, P = 0.027) and higher rates of smoking history among PRS patients (46.8% versus 52.3%, P = 0.055). Mean operative time (131.3 versus 124.0 min, P = 0.090) had a trend toward being longer for ENT and mean length of stay (1.3 versus 2.0, P = 0.002) was significantly longer for PRS. Despite a greater proportion of high ASA class patients in the ENT group (P = 0.012) and patients with dirty/infected wounds in the PRS group (P = 0.013), there were no significant differences in 30-day readmission rates, 30-day reoperation rates, or wound infection rates., Conclusions: No significant differences in 30-day readmission rates, reoperation rates, or wound infection rates for mandible fracture management exist between specialties. Despite differences in training between PRS and ENT, both specialties have comparable perioperative outcomes for mandible fracture management., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Objective: The mechanism explaining the role of detrimental HLA alleles in HIV-1 infections has been investigated in very few studies. HLA-A*29:01-B*07:05-C*15:05 is a detrimental haplotype in HIV-1 subtype A/E-infected Vietnamese individuals. The accumulation of mutations at Pol 653/657 is associated with a poor clinical outcome in these individuals. However, the detrimental HLA allele and the mechanism responsible for its detrimental effect remains unknown. Therefore, in this current study we identified the detrimental HLA allele and investigated the mechanism responsible for the detrimental effect., Design and Methods: A T-cell epitope including Pol 653/657 and its HLA restriction were identified by using overlapping HIV-1 peptides and cell lines expressing a single HLA. The effect of the mutations on the T-cell recognition of HIV-1-infected cells was investigated by using target cells infected with the mutant viruses. The effect of these mutations on the clinical outcome was analyzed in 74 HLA-C*15:05 Vietnamese infected with the subtype A/E virus., Results: We identified HLA-C*15:05-restricted SL9 epitope including Pol 653/657. PolS653A/T/L mutations within this epitope critically impaired the T-cell recognition of HIV-1-infected cells, indicating that these mutations had escaped from the T cells. T-cell responders infected with these mutants showed significantly lower CD4 T-cell counts than those with the wild-type virus or Pol S653K/Q mutants, which are not associated with HLA-C*15:05., Conclusion: The accumulation of Pol S653A/T/L escape mutants critically affected the control of HIV-1 by SL9-specific T cells and led to a poor clinical outcome in the subtype A/E-infected individuals having the detrimental HLA-C*15:05 allele.

Breast cancer affects women globally; the majority of breast cancer-related mortalities are due to metastasis. Acquisition of a mesenchymal phenotype has been implicated in the progression of breast cancer cells to an invasive, metastatic state. Triple-negative breast cancer (TNBC) subtypes have high rates of metastases, recurrence, and have poorer prognoses compared to other breast cancer types, partially due to lack of commonly targeted receptors. Kinases have diverse and pivotal functions in metastasis in TNBC, and discovery of new kinase targets for TNBC is warranted. We previously used a screening approach to identify intermediate-synthesis nonpotent, nonselective small-molecule inhibitors from the Published Kinase Inhibitor Set that reversed the mesenchymal phenotype in TNBC cells. Two of these inhibitors (GSK346294A and GSK448459A) are structurally similar, but have unique kinase activity profiles and exhibited differential biologic effects on TNBC cells, specifically on epithelial-to-mesenchymal transition (EMT). Here, we further interrogate these effects and compare activity of these inhibitors on transwell migration, gene (qRT-PCR) and protein (western blot) expressions, and cancer stem cell-like behavior. We incorporated translational patient-derived xenograft models in these studies, and we focused on the lead inhibitor hit, GSK346294A, to demonstrate the utility of our comparative analysis as a screening modality to identify novel kinase targets and signaling pathways to pursue in TNBC. This study introduces a new method for discovering novel kinase targets that reverse the EMT phenotype; this screening approach can be applied to all cancer types and is not limited to breast cancer.

Background: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown., Methods: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network)., Results: Two hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies ( P =5.63×10 -12 ). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P =5.33×10 -04 ) and longer times to final extubation (hazard ratio, 0.74; P =0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival ( P =0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P =0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P =1.61×10 -05 ) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation., Conclusions: In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Background: Facial feminization surgery entails a series of surgical procedures that help the transwoman pass as their affirmed gender. Although virtual surgical planning, with intraoperative cutting guides, and custom plates have been shown to be helpful for craniomaxillofacial reconstruction, they have not yet been studied for facial feminization surgery. The authors used cadaveric analysis for morphologic typing and to demonstrate the utility of virtual surgical planning in facial feminization surgery procedures., Methods: Male cadaveric heads underwent morphologic typing analysis of the frontal brow, lateral brow, mandibular angle, and chin regions (n = 50). Subsequently, the cadavers were split into two groups: (1) virtual surgical planning intraoperative cutting guides and (2) no preoperative planning. Both groups underwent (1) anterior frontal sinus wall setback, (2) lateral supraorbital recontouring, (3) mandibular angle reduction, and (4) osseous genioplasty narrowing. Efficiency (measured as operative time), safety (determined by dural or nerve injury), and accuracy (scored with three-dimensional computed tomographic preoperative plan versus postoperative result) were compared between groups, with significance being p < 0.05., Results: For frontal brow and lateral lower face, morphologic type 3 (severe) predominated; for lateral brow and chin, type 2 (moderate) predominated. For frontal sinus wall setback, virtual surgical planning improved efficiency (19 minutes versus 44 minutes; p < 0.05), safety (100 percent versus 88 percent; p < 0.05; less intracranial entry), and accuracy (97 percent versus 79 percent; p < 0.05) compared with no preoperative planning. For mandibular angle reduction, virtual surgical planning improved safety (100 percent versus 88 percent; p < 0.05; less inferior alveolar nerve injury) and accuracy (95 percent versus 58 percent; p < 0.05)., Conclusions: Preoperative planning for facial feminization surgery is helpful to determine morphologic typing. Virtual surgical planning with the use of cutting guides/custom plates improved efficiency, safety, and accuracy when performing four key craniofacial techniques for facial feminization.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Complications in pediatric regional anesthesia are rare, so a large sample size is necessary to quantify risk. The Pediatric Regional Anesthesia Network contains data on more than 100,000 blocks administered at more than 20 children's hospitals. This study analyzed the risk of major complications associated with regional anesthesia in children., Methods: This is a prospective, observational study of routine clinical practice. Data were collected on every regional block placed by an anesthesiologist at participating institutions and were uploaded to a secure database. The data were audited at multiple points for accuracy., Results: There were no permanent neurologic deficits reported (95% CI, 0 to 0.4:10,000). The risk of transient neurologic deficit was 2.4:10,000 (95% CI, 1.6 to 3.6:10,000) and was not different between peripheral and neuraxial blocks. The risk of severe local anesthetic systemic toxicity was 0.76:10,000 (95% CI, 0.3 to 1.6:10,000); the majority of cases occurred in infants. There was one epidural abscess reported (0.76:10,000, 95% CI, 0 to 4.8:10,000). The incidence of cutaneous infections was 0.5% (53:10,000, 95% CI, 43 to 64:10,000). There were no hematomas associated with neuraxial catheters (95% CI, 0 to 3.5:10,000), but one epidural hematoma occurred with a paravertebral catheter. No additional risk was observed with placing blocks under general anesthesia. The most common adverse events were benign catheter-related failures (4%)., Conclusions: The data from this study demonstrate a level of safety in pediatric regional anesthesia that is comparable to adult practice and confirms the safety of placing blocks under general anesthesia in children.

Objectives: Objectives were to ( a ) advance point-of-care (POC) education, international exchange, and culture; ( b ) report needs assessment survey results from Thua Thien Hue Province, Central Vietnam; ( c ) determine diagnostic capabilities in regional health care districts of the small-world network of Hue University Medical Center; and ( d ) recommend Spatial Care Paths that accelerate the care of acute myocardial infarction (AMI) patients., Methods: We organized progressively focused, intensive, and interactive lectures, workshops, and investigative teamwork over a 2-year period. We surveyed hospital staff in person to determine the status of diagnostic testing at 15 hospitals in 7 districts. Questions focused on cardiac rapid response, prediabetes/diabetes, infectious diseases, and other serious challenges, including epidemic preparedness., Results: Educational exchange revealed a nationwide shortage of POC coordinators. Throughout the province, ambulances transfer patients primarily between hospitals, rarely picking up from homes. No helicopter rescue was available. Ambulance travel times from distant sites to referral hospitals were excessive, longer in costal and mountainous areas. Most hospitals (92.3%) used electrocardiogram and creatine phosphokinase-MB isoenzyme to diagnose AMI. Cardiac troponin I/T testing was performed only at large referral hospitals., Conclusions: Central Vietnam must improve rapid diagnosis and treatment of AMI patients. Early upstream POC cardiac troponin testing on Spatial Care Paths will expedite transfers directly to hospitals capable of intervening, improving outcomes following coronary occlusion. Point-of-care coordinator certification and financial support will enhance standards of care cost-effectively. Training young physicians pivots on high-value evidence-based learning when POC cardiac troponin T/cardiac troponin I biomarkers are in place for rapid decision making, especially in emergency rooms., Competing Interests: The authors declare no conflict of interest.

Objective: To delineate the natural history, diagnosis, and treatment response of Parkinson disease (PD) in individuals with 22q11.2 deletion syndrome (22q11.2DS), and to determine if these patients differ from those with idiopathic PD., Methods: In this international observational study, we characterized the clinical and neuroimaging features of 45 individuals with 22q11.2DS and PD (mean follow-up 7.5 ± 4.1 years)., Results: 22q11.2DS PD had a typical male excess (32 male, 71.1%), presentation and progression of hallmark motor symptoms, reduced striatal dopamine transporter binding with molecular imaging, and initial positive response to levodopa (93.3%). Mean age at motor symptom onset was relatively young (39.5 ± 8.5 years); 71.4% of cases had early-onset PD (<45 years). Despite having a similar age at onset, the diagnosis of PD was delayed in patients with a history of antipsychotic treatment compared with antipsychotic-naive patients (median 5 vs 1 year, p = 0.001). Preexisting psychotic disorders (24.5%) and mood or anxiety disorders (31.1%) were common, as were early dystonia (19.4%) and a history of seizures (33.3%)., Conclusions: Major clinical characteristics and response to standard treatments appear comparable in 22q11.2DS-associated PD to those in idiopathic PD, although the average age at onset is earlier. Importantly, treatment of preexisting psychotic illness may delay diagnosis of PD in 22q11.DS patients. An index of suspicion and vigilance for complex comorbidity may assist in identifying patients to prioritize for genetic testing., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Rationale: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis., Objective: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise., Methods and Results: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity., Conclusions: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease., (© 2017 American Heart Association, Inc.)

Objective: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP., Methods: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission., Results: Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time., Conclusions: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.

Elevated CD8 counts with combination antiretroviral therapy (cART) initiation may be an early warning indicator for future treatment failure. Thus, we investigated whether elevated CD8 counts were associated with virological failure (VF) in the first 4 years of cART in Asian HIV-infected patients in a multicenter regional cohort.We included patients from the TREAT Asia HIV Observational Database (TAHOD). Patients were included in the analysis if they started cART between 1996 and 2013 with at least one CD8 measurement within 6 months prior to cART initiation and at least one CD8 and viral load (VL) measurement beyond 6 months after starting cART. We defined VF as VL ≥400 copies/mL after 6 months on cART. Elevated CD8 was defined as CD8 ≥1200 cells/μL. Time to VF was modeled using Cox regression analysis, stratified by site.In total, 2475 patients from 19 sites were included in this analysis, of whom 665 (27%) experienced VF in the first 4 years of cART. The overall rate of VF was 12.95 per 100 person-years. In the multivariate model, the most recent elevated CD8 was significantly associated with a greater hazard of VF (HR = 1.35, 95% CI 1.14-1.61; P = 0.001). However, the sensitivity analysis showed that time-lagged CD8 measured at least 6 months prior to our virological endpoint was not statistically significant (P = 0.420).This study indicates that the relationship between the most recent CD8 count and VF was possibly due to the CD8 cells reacting to the increase in VL rather than causing the VL increase itself. However, CD8 levels may be a useful indicator for VF in HIV-infected patients after starting cART.

Background and Purpose: Ischemic stroke of undetermined cause is a major health issue because of its high frequency and clinical relevance. Histopathologic analysis of human thrombi, retrieved from stroke patients with large-vessel occlusion during mechanical thrombectomy, may provide information about underlying pathologies. This study examines the relationship between stroke causes and histological clot composition to identify specific patterns that might help to distinguish causes of cryptogenic stroke., Methods: Thrombi of 145 consecutive stroke patients with large-vessel occlusion were collected during intracranial mechanical recanalization. The hematoxylin and eosin-stained specimens were quantitatively analyzed in terms of the relative fractions of the main constituents (red and white blood cells and fibrin/platelets). These data, along with additional clinical and interventional parameters, were compared for different stroke subtypes, as defined by the international Trial of Org 10172 in Acute Stroke Treatment criteria., Results: The composition of thrombi from cardioembolic and noncardioembolic stroke patients differed significantly for all main thrombus components. Cardioembolic thrombi had higher proportions of fibrin/platelets (P=0.009), less erythrocytes (P=0.003), and more leucocytes (P=0.035) than noncardioembolic thrombi. Cryptogenic strokes showed strong overlap with cardioembolic strokes but not with noncardioembolic strokes, in terms of both thrombus histology and interventional and clinical outcome parameters., Conclusions: Quantitative evaluation of thrombus composition may help to distinguish between different stroke causes. Our findings support the notion that the majority of cryptogenic strokes are cardioembolic., (© 2016 American Heart Association, Inc.)