Telemedicine Follow-up After Medication Management of Early Pregnancy Loss.

Objective: Our objective was to evaluate the feasibility of a new protocol for telemedicine follow-up after medication management of early pregnancy loss. Study Design: The study was designed to assess the feasibility of planned telemedicine follow-up after medication management of early pregnancy loss. We compared these follow-up rates with those after planned in-person follow-up of medication management of early pregnancy loss and planned telemedicine follow-up after medication abortion. We conducted a retrospective cohort study, including patients initiating medication management of early pregnancy loss <13w0d gestation and medication abortion ≤10w0d with a combination of mifepristone and misoprostol between April 1, 2020, and March 28, 2021. As part of a new clinical protocol, patients could opt for telemedicine follow-up one week after treatment and a home urine pregnancy test 4 weeks after treatment. Our primary outcome was completed follow-up as per clinical protocol. We also examined outcomes related to complications across telemedicine and in-person follow-up groups. Results: Of patients reviewed, 181 were eligible for inclusion; 75 had medication management of early pregnancy loss, and 106 had medication abortion. Thirty-six out of 75 patients elected for telemedicine follow-up after early pregnancy loss. Of patients scheduled for telemedicine follow-up, 29/36 (81%, 95% CI: 64-92) with early pregnancy loss and 64/69 (93%, 95% CI: 84-98) undergoing medication abortion completed follow-up as per protocol (p = 0.06). Completed follow-up was also similar among patients undergoing medication management of early pregnancy loss who planned for in-person follow-up (p = 0.135). Complications were rare and did not differ across early pregnancy loss and medication abortion groups. Conclusions: Telemedicine follow-up is a feasible alternative to in-person assessment after medication management of early pregnancy loss.

Primary care team perspectives on approaches to engaging patients in treatment for opioid use disorder.

INTRODUCTION: Engagement is a critical component of successful treatment for opioid use disorder (OUD). However, rates of patient engagement in OUD treatment, especially in outpatient settings, are variable and often low. Little is known about the specific strategies members of primary care teams use to initiate and encourage ongoing participation in OUD treatment. In a national cohort of primary care clinics in the U.S., we explored the perspectives of primary care team members on the meaning of and approaches to OUD treatment engagement. METHODS: We conducted semi-structured interviews with 35 providers from multidisciplinary primary care teams in an existing national cohort of 13 clinics across seven states. Teams were delivering OUD treatment via the Collaborative Care Model, a model that combines primary care providers (PCP), behavioral health care managers (BHCM) and consulting psychiatric providers (CPP) in a structured way to provide patient-centered, team-based, and measurement-based care. Interview participants included 14 PCPs, 13 BHCMs, and 8 CPPs. Interviews asked open-ended questions about provider experiences and practices that aided or hindered patient engagement in OUD treatment. Interview transcripts were double-coded by trained qualitative researchers and analyzed using a combination of deductive and inductive approaches to identify themes. RESULTS: Two themes emerged that describe provider perspectives on the meaning of engagement: 1) qualifying engagement by the volume of contact with patients, and 2) the need for more multidimensional measures of engagement. Six themes emerged that characterized provider engagement practices: 1) creating an environment of disclosure, 2) normalizing OUD treatment, 3) offering gentle but persistent outreach, 4) providing human connection and encouragement, 5) tailoring treatment to patient needs, and 6) avoiding stigmatizing responses. Analysis identified multiple replicable strategies that providers used to support these engagement practices. CONCLUSIONS: Providers consistently apply a range of strategies when trying to engage patients in OUD treatment. Specific engagement strategies used embodied compassion and pragmatism, hallmarks of patient-centered care. Further research is needed to understand the impact of scaling engagement approaches across all care settings.

Optimizing Patient Engagement in Treatment for Opioid Use Disorder: Primary Care Team Perspectives on Influencing Factors.

BACKGROUND: Opioid use disorder (OUD) care engagement rates in primary care (PC) settings are often low. Little is known about PC team experiences when delivering OUD treatment and potential factors that influence their capacity to engage patients in treatment. Exploring PC team experiences may inform needed supports that can optimize OUD care delivery and improve outcomes for patients with OUD. OBJECTIVE: We explored multidisciplinary PC team perspectives on barriers and facilitators to engaging patients in OUD treatment. DESIGN: Qualitative study using in-depth interviews. PARTICIPANTS: Primary care clinical teams. APPROACH: We conducted semi-structured interviews (n = 35) with PC team members involved in OUD care delivery, recruited using a combination of criterion and maximal variation sampling. Data collection and analysis were informed by existing theoretical literature about patient engagement, specifically that patient engagement is influenced by factors across individual (patient, provider), interpersonal (patient-provider), and health system domains. Interviews were professionally transcribed and doubled-coded using a coding schema based on the interview guide while allowing for emergent codes. Coding was iteratively reviewed using a constant comparison approach to identify themes and verified with participants and the full study team. KEY RESULTS: Analysis identified five themes that impact PC team ability to engage patients effectively, including limited patient contact (e.g., phone, text) in between visits, varying levels of provider confidence to navigate OUD treatment discussions, structural factors (e.g., schedules, productivity goals) that limited provider time, the role of team-based approaches in lessening discouragement and feelings of burnout, and lack of shared organizational vision for reducing harms from OUD. CONCLUSIONS: While the capacity of PC teams to engage patients in OUD care is influenced across multiple levels, some of the most promising opportunities may involve addressing system-level factors that limit PC team time and collaboration and promoting organizational alignment on goals for OUD treatment.

Chemogenetic activation ofarcuate nucleus NPY and NPY/AgRP neurons increases feeding behaviour in mice.

Neuropeptide Y (NPY) plays a crucial role in controlling energy homeostasis and feeding behaviour. The role of NPY neurons located in the arcuate nucleus of the hypothalamus (Arc) in responding to homeostatic signals has been the focus of much investigation, but most studies have used AgRP promoter-driven models, which do not fully encompass Arc NPY neurons. To directly investigate NPY-expressing versus AgRP-expressing Arc neurons function, we utilised chemogenetic techniques in NPY-Cre and AgRP-Cre animals to activate Arc NPY or AgRP neurons in the presence of food and food-related stimuli. Our findings suggest that chemogenetic activation of the broader population of Arc NPY neurons, including AgRP-positive and AgRP-negative NPY neurons, has equivalent effects on feeding behaviour as activation of Arc AgRP neurons. Our results demonstrate that these Arc NPY neurons respond specifically to caloric signals and do not respond to non-caloric signals, in line with what has been observed in AgRP neurons. Activating Arc NPY neurons significantly increases food consumption and influences macronutrient selection to prefer fat intake.

Receipt of Medications for Alcohol Use Disorder in the Veterans Health Administration: Comparison of Rates at the Intersections of Racialized and Ethnic Identity With Both Sex and Transgender Status.

OBJECTIVES: Medications for alcohol use disorder (MAUDs) are recommended for patients with alcohol use disorder yet are underprescribed. Consistent with Minority Stress and Intersectionality theories, persons with multiple sociodemographically marginalized identities (eg, Black women) often experience greater barriers to care and have poorer health outcomes. We use data from the Veterans Health Administration to assess disparities in Federal Drug Administration (FDA)-approved MAUDs and all effective MAUDs between the following groups: racialized and ethnic identity, sex, transgender status, and their intersections. METHODS: Among all Veterans Health Administration outpatients between August 1, 2015, and July 31, 2017, with documented alcohol screenings and an International Classification of Diseases diagnosis for alcohol use disorder in the 0-365 days prior (N = 308,238), we estimated the prevalence and 95% confidence intervals of receiving FDA-approved MAUDs and any MAUDs in the following year and compared them using χ2 or Fisher's exact test. Analyses are unadjusted to present true prevalence and group differences. RESULTS: The overall prevalence for MAUDs was low (FDA-MAUDs = 8.7%, any MAUDs = 20.0%). Within sex, Black males had the lowest rate of FDA-MAUDs (7.3%, [7.1-7.5]), whereas American Indian/Alaskan Native females had the highest (18.4%, [13.8-23.0]). Among those identified as transgender, Asian and Black transgender persons had the lowest rates of FDA-MAUDs (0%; 4.3%, [1.8-8.5], respectively), whereas American Indian/Alaskan Native transgender patients had the highest (33.3%, [2.5-64.1]). Similar patterns were observed for any MAUDs, with higher rates overall. CONCLUSIONS: Substantial variation exists in MAUD prescribing, with marginalized veterans disproportionately receiving MAUDs at lower and higher rates than average. Implementation and quality improvement efforts are needed to improve MAUD prescribing practices and reduce disparities.

Outbreak of multidrug-resistant Salmonella infections in people linked to pig ear pet treats, United States, 2015-2019: results of a multistate investigation.

Background: International distribution of contaminated foods can be a source of Salmonella infections in people and can contribute to the spread of antimicrobial-resistant bacteria across countries. We report an investigation led by the United States Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), and state governmental officials into a multistate outbreak of salmonellosis linked to pig ear pet treats. Methods: Pig ear treats and companion dogs were tested for Salmonella by state officials and the FDA. Products were traced back to the country of origin when possible. Cases were defined as outbreak illnesses in people associated with one of seven Salmonella serotypes genetically related to samples from pig ear pet treats, with isolation dates from June 2015 to September 2019. Whole genome sequencing (WGS) of isolates was used to predict antimicrobial resistance. Findings: The outbreak included 154 human cases in 34 states. Of these, 107 of 122 (88%) patients reported dog contact, and 65 of 97 (67%) reported contact with pig ear pet treats. Salmonella was isolated from 137 pig ear treats, including some imported from Argentina, Brazil, and Colombia, and from four dogs. WGS predicted 77% (105/137) of human and 43% (58/135) of pig ear treat isolates were resistant to ≥3 antimicrobial classes. Interpretation: This was the first documented United States multistate outbreak of Salmonella infections linked to pig ear pet treats. This multidrug-resistant outbreak highlights the interconnectedness of human health and companion animal ownership and the need for zoonotic pathogen surveillance to prevent human illness resulting from internationally transported pet food products. Funding: Animal Feed Regulatory Program Standards award. Animal and product testing conducted by FDA Vet-LIRN was funded by Vet-LIRN infrastructure grants (PAR-22-063).

Intranasal respiratory syncytial virus vaccine attenuated by codon-pair deoptimization of seven open reading frames is genetically stable and elicits mucosal and systemic immunity and protection against challenge virus replication in hamsters.

Respiratory syncytial virus (RSV) is the most important viral agent of severe pediatric respiratory illness worldwide, but there is no approved pediatric vaccine. Here, we describe the development of the live-attenuated RSV vaccine candidate Min AL as well as engineered derivatives. Min AL was attenuated by codon-pair deoptimization (CPD) of seven of the 11 RSV open reading frames (ORFs) (NS1, NS2, N, P, M, SH and L; 2,073 silent nucleotide substitutions in total). Min AL replicated efficiently in vitro at the permissive temperature of 32°C but was highly temperature sensitive (shut-off temperature of 36°C). When serially passaged at increasing temperatures, Min AL retained greater temperature sensitivity compared to previous candidates with fewer CPD ORFs. However, whole-genome deep-sequencing of passaged Min AL revealed mutations throughout its genome, most commonly missense mutations in the polymerase cofactor P and anti-termination transcription factor M2-1 (the latter was not CPD). Reintroduction of selected mutations into Min AL partially rescued its replication in vitro at temperatures up to 40°C, confirming their compensatory effect. These mutations restored the accumulation of positive-sense RNAs to wild-type (wt) RSV levels, suggesting increased activity by the viral transcriptase, whereas viral protein expression, RNA replication, and virus production were only partly rescued. In hamsters, Min AL and derivatives remained highly restricted in replication in the upper and lower airways, but induced serum IgG and IgA responses to the prefusion form of F (pre F) that were comparable to those induced by wt RSV, as well as robust mucosal and systemic IgG and IgA responses against RSV G. Min AL and derivatives were fully protective against challenge virus replication. The derivatives had increased genetic stability compared to Min AL. Thus, Min AL and derivatives with selected mutations are stable, attenuated, yet highly-immunogenic RSV vaccine candidates that are available for further evaluation.

Prevalence, Patterns, and Predictors of SARS-CoV-2 RNA and Culturable Virus in Tears of a Case-Ascertained Household Cohort.

PURPOSE: To investigate the prevalence, patterns, and predictors of SARS-CoV-2 RNA and culturable virus in tears of a case-ascertained household cohort. DESIGN: Prospective, longitudinal case-ascertained household cohort identified through convenience sampling. METHODS: This analysis was restricted to individuals who were non-hospitalized, symptomatic, and tested positive for SARS-CoV-2 by nasal RT-PCR. Tears and anterior nasal biospecimens were serially collected throughout the acute period. Tears specimens were collected by the study staff using Schirmer test strips, and nasal specimens were self-collected. For both, SARS-CoV-2 RNA was quantified using qRT-PCR, and culturable virus was detected using presence of cytopathic effect (CPE) in tissue culture; positive CPE was confirmed by a qRT-PCR step. A series of cross-sectional unadjusted analyses were performed investigating the relationship between different sociodemographic determinants and biological factors associated with tears RNA positivity. RESULTS: Among the 83 SARS-CoV-2 infected participants, 10 (12%) had at least one RNA-positive tears specimen. Amongst these 10, 5 (50%) had concurrent presence of culturable virus, at a median of 7 days postsymptom onset (IQR: 4-7 days) (absolute range: 4-8 days). CONCLUSIONS: In this longitudinal cohort, we found evidence of culturable virus in the tears of a small proportion of nonhospitalized SARS-CoV-2 infected individuals. Current public health infection precautions do not account for transmission via tears, so these findings may improve our understanding of potential sources of SARS-CoV-2 transmission and contribute to developing future guidelines.

Abnormal p53 expression is associated with poor outcomes in grade I or II, stage I, endometrioid carcinoma: a retrospective single-institute study.

OBJECTIVE: The Cancer Genome Atlas study revealed an association between copy-number high (p53 abnormal) genetic mutation and poor prognosis in endometrial cancer in 2013. This retrospective study investigated outcomes in patients with abnormal p53 expression and stage I, low-grade endometrial endometrioid carcinoma (EEC). METHODS: We enrolled women with stage I, grade 1 or 2 EEC who received comprehensive staging and adjuvant therapy between January 2019 and December 2022 at MacKay Memorial Hospital, Taipei, Taiwan. Pathologists interpreted immunohistochemistry stains of cancerous tissues to detect p53 mutation. We compared recurrence, survival, progression-free survival, and overall survival between p53 abnormal and p53 normal groups. RESULTS: Of the 115 patients included, 26 had pathologically confirmed abnormal p53 expression. Of these 26 patients, five (19.2%) experienced recurrence, and two died due to disease progression. By contrast, no patients in the normal p53 group experienced disease recurrence or died due to disease progression. Significant intergroup differences were discovered in recurrent disease status (19.4% vs. 0%, p<0.001), mortality (7.7% vs. 0%, p<0.001), and progression-free survival (p<0.001). The overall survival (p=0.055) also showed powerful worse trend. CONCLUSION: For patients with stage I, low-grade EEC, abnormal p53 expression may be used as an indicator of poor prognosis. Therefore, we suggest considering aggressive adjuvant therapies for these patients.

Perspectives of clinical stakeholders and patients from four VA liver clinics to tailor practice facilitation for implementing evidence-based alcohol-related care.

BACKGROUND: Unhealthy alcohol use (UAU) is particularly dangerous for people with chronic liver disease. Liver clinics may be an important setting in which to provide effective alcohol-related care by integrating evidence-based strategies, such as brief intervention and medications for alcohol use disorder. We conducted qualitative interviews with clinical stakeholders and patients at liver clinics in four Veterans Health Administration (VA) medical centers to understand barriers and facilitators of integrating alcohol-related care and to support tailoring of a practice facilitation implementation intervention. METHODS: Data collection and analysis were guided by the Consolidated Framework for Implementation Research (CFIR). Interviews were transcribed and qualitatively analyzed using a Rapid Assessment Process (RAP) guided by the CFIR. RESULTS: We interviewed 46 clinical stakeholders and 41 patient participants and analyzed findings based on the CFIR. Clinical stakeholders described barriers and facilitators that ranged from operations/clinic resource-based (e.g., time and capacity, desire for additional provider types, referral processes) to individual perspective and preference-based (e.g., supportiveness of leadership, individual experiences/beliefs). Patient participants shared barriers and facilitators that ranged from relationship-based (e.g., trusting the provider and feeling judged) to resource and education-based (e.g., connection to a range of treatment options, education about impact of alcohol). Many barriers and facilitators to integrating alcohol-related care in liver clinics were similar to those identified in other clinical settings (e.g., time, resources, role clarity, stigmatizing beliefs). However, some barriers (e.g., fellow-led care and lack of integration of liver clinics with addictions specialists) and facilitators (e.g., presence of quality improvement staff in clinics and integrated pharmacists and behavioral health specialists) were more unique to liver clinics. CONCLUSIONS: These findings support the possibility of integrating alcohol-related care into liver clinics but highlight the importance of tailoring efforts to account for variation in provider beliefs and experiences and clinic resources. The barriers and facilitators identified in these interviews were used to tailor a practice facilitation implementation intervention in each clinic setting.

Pain Care Disparities and the Use of Virtual Care Among Racial-Ethnic Minority Groups During COVID-19.

BACKGROUND AND OBJECTIVE: COVID-19 led to an unprecedented reliance on virtual modalities to maintain care continuity for patients living with chronic pain. We examined whether there were disparities in virtual specialty pain care for racial-ethnic minority groups during COVID-19. DESIGN AND PARTICIPANTS: This was a retrospective national cohort study with two comparison groups: primary care patients with chronic pain seen immediately prior to COVID-19 (3/1/19-2/29/20) (N = 1,649,053) and a cohort of patients seen in the year prior (3/1/18-2/28-19; n = 1,536,954). MAIN MEASURES: We assessed use of telehealth (telephone or video) specialty pain care, in-person care specialty pain care, and any specialty pain care for both groups at 6 months following cohort inclusion. We used quasi-Poisson regressions to test associations between patient race and ethnicity and receipt of care. KEY RESULTS: Prior to COVID-19, there were Black-White (RR = 0.64, 95% CI [0.62, 0.67]) and Asian-White (RR = 0.63, 95% CI [0.54, 0.75]) disparities in telehealth use, and these lessened during COVID-19 (Black-White: RR = 0.75, 95% CI [0.73, 0.77], Asian-White: RR = 0.81, 95% CI [0.74, 0.89]) but did not disappear. Individuals identifying as American Indian/Alaska Native used telehealth less than White individuals during early COVID-19 (RR = 0.98, 95% CI [0.85, 1.13] to RR = 0.87, 95% CI [0.79, 0.96]). Hispanic/Latinx individuals were less likely than non-Hispanic/Latinx individuals to use telehealth prior to COVID-19 but more likely during early COVID-19 (RR = 0.70, 95% CI [0.66, 0.75] to RR = 1.06, 95% CI [1.02, 1.09]). Disparities in virtual pain care occurred over the backdrop of overall decreased specialty pain care during the early phase of the pandemic (raw decrease of n = 17,481 specialty care encounters overall from pre-COVID to COVID-era), including increased disparities in any VA specialty pain care for Black (RR = 0.81, 95% CI [0.80, 0.83] to RR = 0.79, 95% CI [0.77, 0.80]) and Asian (RR = 0.91, 95% CI [0.86, 0.97] to RR = 0.88, 95% CI [0.82, 0.94]) individuals. CONCLUSIONS: Disparities in virtual specialty pain care were smaller during the early phases of the COVID-19 pandemic than prior to the pandemic but did not disappear entirely, despite the rapid growth in telehealth. Targeted efforts to increase access to specialty pain care need to be concentrated among racial-ethnic minority groups.

Inguinal nodal metastatic squamous cell carcinoma of unknown primary (CUP) detected 7 years before the diagnosis of vulvar squamous cell carcinoma: A case report.

OBJECTIVE: Metastatic squamous cell carcinoma (SCC) of inguinal lymph node region with unknown origin is a rare condition. A patient was diagnosed to have vulvar SCC 7 years after the initial diagnosis of inguinal nodal metastatic SCC of unknown primary. CASE REPORT: A 59-year-old woman with metastatic SCC of unknown origin in the right inguinal lymph node underwent tumor resection and no evidence of residual disease or possible tumor origin was detected after the surgery and a comprehensive work-up. Seven years later, she was diagnosed to have invasive right vulvar SCC with right pelvic lymph node metastasis. We performed a series of tests to evaluate the relationship between these two events. CONCLUSION: According to our investigation, the possible relationship between the two events could not be ruled out. This case emphasizes the possibility of late recurrence and the importance of long-term follow up for patients with isolated nodal CUP.

Multistate nontyphoidal Salmonella and Shiga toxin-producing Escherichia coli outbreaks linked to international travel-United States, 2017-2020.

Enteric bacterial infections are common among people who travel internationally. During 2017-2020, the Centers for Disease Control and Prevention investigated 41 multistate outbreaks of nontyphoidal Salmonella and Shiga toxin-producing Escherichia coli linked to international travel. Resistance to one or more antimicrobial agents was detected in at least 10% of isolates in 16 of 30 (53%) nontyphoidal Salmonella outbreaks and 8 of 11 (73%) Shiga toxin-producing E. coli outbreaks evaluated by the National Antimicrobial Resistance Monitoring System. At least 10% of the isolates in 14 nontyphoidal Salmonella outbreaks conferred resistance to one or more of the clinically significant antimicrobials used in human medicine. This report describes the epidemiology and antimicrobial resistance patterns of these travel-associated multistate outbreaks. Investigating illnesses among returned travellers and collaboration with international partners could result in the implementation of public health interventions to improve hygiene practices and food safety standards and to prevent illness and spread of multidrug-resistant organisms domestically and internationally.

High tumor infiltrating lymphocytes are significantly associated with pathological complete response in triple negative breast cancer treated with neoadjuvant KEYNOTE-522 chemoimmunotherapy.

INTRODUCTION: For patients with locally advanced triple negative breast cancer (TNBC), the standard of care is to administer the KEYNOTE-522 (K522) regimen, including chemotherapy and immunotherapy (pembrolizumab) given in the neoadjuvant setting. Pathological complete response (pCR) is more likely in patients who receive the K522 regimen than in patients who receive standard chemotherapy. Studies have shown that pCR is a strong predictor of long-term disease-free survival. However, factors predicting pCR to K522 are not well understood and require further study in real-world populations. METHODS: We evaluated 76 patients who were treated with the K522 regimen at our institution. Twenty-nine pre-treatment biopsy slides were available for pathology review. Nuclear grade, Nottingham histologic grade, Ki-67, lymphovascular invasion, and tumor infiltrating lymphocytes (TIL) were evaluated in these 29 cases. For the cases that did not have available slides for review from pre-treatment biopsies, these variables were retrieved from available pathology reports. In addition, clinical staging, race, and BMI at the time of biopsy were retrieved from all 76 patients' charts. Binary logistic regression models were used to correlate these variables with pCR. RESULTS: At the current time, 64 of 76 patients have undergone surgery at our institution following completion of K522 and 31 (48.4%) of these achieved pCR. In univariate analysis, only TIL was significantly associated with pCR (p = 0.014) and this finding was also confirmed in multivariate analysis, whereas other variables including age, race, nuclear grade, Nottingham grade, Ki-67, lymphovascular invasion, BMI, pre-treatment tumor size, and lymph node status were not associated with pCR (p > 0.1). CONCLUSION: Our real-world data demonstrates high TIL is significantly associated with pCR rate in the K522 regimen and may potentially serve as a biomarker to select optimal treatment. The pCR rate of 48.4% in our study is lower than that reported in K522, potentially due to the smaller size of our study; however, this may also indicate differences between real-world data and clinical trial results. Larger studies are warranted to further investigate the role of immune cells in TNBC response to K522 and other treatment regimens.

Antimicrobial resistance in multistate outbreaks of nontyphoidal Salmonella infections linked to animal contact-United States, 2015-2018.

Animal contact is an established risk factor for nontyphoidal Salmonella infections and outbreaks. During 2015-2018, the U.S. Centers for Disease Control and Prevention (CDC) and other U.S. public health laboratories began implementing whole-genome sequencing (WGS) of Salmonella isolates. WGS was used to supplement the traditional methods of pulsed-field gel electrophoresis for isolate subtyping, outbreak detection, and antimicrobial susceptibility testing (AST) for the detection of resistance. We characterized the epidemiology and antimicrobial resistance (AMR) of multistate salmonellosis outbreaks linked to animal contact during this time period. An isolate was considered resistant if AST yielded a resistant (or intermediate, for ciprofloxacin) interpretation to any antimicrobial tested by the CDC or if WGS showed a resistance determinant in its genome for one of these agents. We identified 31 outbreaks linked to contact with poultry (n = 23), reptiles (n = 6), dairy calves (n = 1), and guinea pigs (n = 1). Of the 26 outbreaks with resistance data available, we identified antimicrobial resistance in at least one isolate from 20 outbreaks (77%). Of 1,309 isolates with resistance information, 247 (19%) were resistant to ≥1 antimicrobial, and 134 (10%) were multidrug-resistant to antimicrobials from ≥3 antimicrobial classes. The use of resistance data predicted from WGS increased the number of isolates with resistance information available fivefold compared with AST, and 28 of 43 total resistance patterns were identified exclusively by WGS; concordance was high (>99%) for resistance determined by AST and WGS. The use of predicted resistance from WGS enhanced the characterization of the resistance profiles of outbreaks linked to animal contact by providing resistance information for more isolates.

Military Sexual Trauma As a Risk Factor for Treatment Non-Response from an Online, Self-Management Posttraumatic Stress Disorder Treatment for Women Veterans.

Women veterans are exposed to high rates of trauma, including military sexual trauma (MST), and face unique barriers to posttraumatic stress disorder (PTSD) treatment. Telehealth interventions that are tailored to women veterans' unique lived experiences may improve treatment engagement and outcomes. It is important to ascertain how beneficial new telehealth interventions are in the context of different patient characteristics and trauma types, particularly for lower-intensity telehealth interventions (e.g., web-based programs or apps). This secondary analysis of a randomized clinical trial conducted in a sample of 102 women veterans examines predictors of treatment response to a self-management, telehealth intervention for PTSD: Delivery of Self Training and Education for Stressful Situations-Women Veterans (DESTRESS-WV). In the trial, women veterans with PTSD received either an online cognitive behavioral intervention with phone coaching, or phone monitoring alone. We examined associations between baseline patient characteristics (demographics, trauma types, and clinical symptoms) and treatment outcome at post-treatment, 3 months, and 6 months, focusing on the association between treatment outcome and MST. Our primary outcomes were changes in PTSD (PTSD Symptom Checklist, Version 5, PCL-5) and depression (8-item Patient Health Questionnaire, PHQ-8) in the full sample, adjusting for treatment condition. Women veterans who identified MST as the primary trauma for which they were seeking PTSD treatment experienced a nearly nine-point lesser improvement on the PCL-5 than those seeking PTSD treatment for other trauma types (e.g., childhood abuse, combat trauma; p = .0073). Similar patterns were found for depression symptoms. To our knowledge, this is the first study to examine the association between trauma type and treatment outcomes within the context of a self-management, telehealth treatment for PTSD. While the study was not powered to examine differential treatment response for patient subgroups, our exploratory findings suggest that gaps remain in providing effective PTSD care for women veterans who experienced MST.Trial registration: The trial and analysis plan were preregistered in ClinicalTrials.gov (Identifier: NCT02917447).

Expression of m6A Regulator Genes can Facilitate the Diagnosis of Chronic Heart Failure.

BACKGROUND: RNA N6-methyladenosine (m6A) is the most common type of modification in eukaryotic mRNA. The relationship between m6A modification and disease has been studied extensively, but there have been few studies on chronic heart failure (CHF). This study investigated a possible role for m6A in the diagnosis of CHF. METHODS: Seven candidate m6A regulators (writers: WTAP and ZC3H13; readers: YTHDF3, FMR1, IGFBP1, and ELAVL1; eraser: FTO) were identified using a random forest (RF) model and the GSE5406 dataset from the Gene Expression Omnibus database. A nomogram model was developed to predict the risk of CHF, while consensus clustering methodology assigned CHF samples into two m6A patterns (cluster A and cluster B) according to the 7 candidate m6A regulators. Principal component analysis was used to calculate an m6A score for each sample and to quantify m6A patterns. RESULTS: Decision curve analysis and the nomogram model were used to obtain predictions that may be of clinical use. Patients in cluster B had higher m6A scores than patients in cluster A. Cluster B patients also had higher expression levels (ELs) of IL-4, IL-5, IL-10 and IL-13 than patients in cluster A, whereas cluster A patients had a higher EL for IL-33. The m6A cluster B pattern likely represents the ischemic heart failure (HF) disease group. CONCLUSION: m6A regulators are important in the pathogenesis of CHF associated with ischemic and idiopathic dilated cardiomyopathy, and may prove useful for the diagnosis and treatment of CHF.

Evaluation of whole and core genome multilocus sequence typing allele schemes for Salmonella enterica outbreak detection in a national surveillance network, PulseNet USA.

Salmonella enterica is a leading cause of bacterial foodborne and zoonotic illnesses in the United States. For this study, we applied four different whole genome sequencing (WGS)-based subtyping methods: high quality single-nucleotide polymorphism (hqSNP) analysis, whole genome multilocus sequence typing using either all loci [wgMLST (all loci)] and only chromosome-associated loci [wgMLST (chrom)], and core genome multilocus sequence typing (cgMLST) to a dataset of isolate sequences from 9 well-characterized Salmonella outbreaks. For each outbreak, we evaluated the genomic and epidemiologic concordance between hqSNP and allele-based methods. We first compared pairwise genomic differences using all four methods. We observed discrepancies in allele difference ranges when using wgMLST (all loci), likely caused by inflated genetic variation due to loci found on plasmids and/or other mobile genetic elements in the accessory genome. Therefore, we excluded wgMLST (all loci) results from any further comparisons in the study. Then, we created linear regression models and phylogenetic tanglegrams using the remaining three methods. K-means analysis using the silhouette method was applied to compare the ability of the three methods to partition outbreak and sporadic isolate sequences. Our results showed that pairwise hqSNP differences had high concordance with cgMLST and wgMLST (chrom) allele differences. The slopes of the regressions for hqSNP vs. allele pairwise differences were 0.58 (cgMLST) and 0.74 [wgMLST (chrom)], and the slope of the regression was 0.77 for cgMLST vs. wgMLST (chrom) pairwise differences. Tanglegrams showed high clustering concordance between methods using two statistical measures, the Baker's gamma index (BGI) and cophenetic correlation coefficient (CCC), where 9/9 (100%) of outbreaks yielded BGI values ≥ 0.60 and CCCs were ≥ 0.97 across all nine outbreaks and all three methods. K-means analysis showed separation of outbreak and sporadic isolate groups with average silhouette widths ≥ 0.87 for outbreak groups and ≥ 0.16 for sporadic groups. This study demonstrates that Salmonella isolates clustered in concordance with epidemiologic data using three WGS-based subtyping methods and supports using cgMLST as the primary method for national surveillance of Salmonella outbreak clusters.

Overcoming Soluble Target Interference in Measurement of Total Bispecific Therapeutic Antibody Concentrations.

The measurement of therapeutic drug concentrations is used to assess drug exposure and the relationship between therapeutic pharmacokinetics (PK) and pharmacodynamics (PD), which help determine the optimal dose for patients. Ligand binding assays (LBAs) are often the method of choice for evaluation of drug concentration and use either the therapeutic target protein or antibodies to the therapeutic as capture and/or detection reagents. Due to the bivalency of antibody therapeutics, heterogeneous states of the drug/target complex can exist in the presence of soluble targets which can complicate measurement of unbound drug. In the case of bispecific antibodies, measurement of drug can be even more complicated and depend upon the levels of both targets to each arm. Measuring the total drug allows for PKPD modeling prediction of human dose projections in addition to overcoming challenges associated with measuring free drug for bispecific antibodies. Here, we present a study in which a sandwich ELISA format was used to measure total anti-KLK5/KLK7 antibody concentrations. This assay utilized a non-blocking anti-idiotype (ID) antibody to one arm of the antibody for capture and an antibody to target bound to the other arm of the antibody for detection. Our qualified assay showed acceptable precision, accuracy, dilutional linearity, and reproducibility and enabled detection of a total bispecific antibody at high levels of two targets. To confirm that our assay was detecting total drug, a subset of samples was evaluated in a generic total LC-MS/MS assay.