Guidelines for in vivo models of developmental programming of cardiovascular disease risk.

Research using animals depends on the generation of offspring for use in experiments or for the maintenance of animal colonies. Although not considered by all, several different factors preceding and during pregnancy, as well as during lactation, can program various characteristics in the offspring. Here, we present the most common models of developmental programming of cardiovascular outcomes, important considerations for study design, and provide guidelines for producing and reporting rigorous and reproducible cardiovascular studies in offspring exposed to normal conditions or developmental insult. These guidelines provide considerations for the selection of the appropriate animal model and factors that should be reported to increase rigor and reproducibility while ensuring transparent reporting of methods and results.

Mycobacterium immunogenum acquisition from hospital tap water: a genomic and epidemiologic analysis.

We identified 23 cases of Mycobacterium immunogenum respiratory acquisition linked to a colonized plumbing system at a new hospital addition. We conducted a genomic and epidemiologic investigation to assess for clonal acquisition of M. immunogenum from hospital water sources and improve understanding of genetic distances between M. immunogenum isolates. We performed whole-genome sequencing on 28 M. immunogenum isolates obtained from August 2013 to July 2021 from patients and water sources on four intensive care and intermediate units at an academic hospital. Study hospital isolates were recovered from 23 patients who experienced de novo respiratory isolation of M. immunogenum and from biofilms obtained from five tap water outlets. We also analyzed 10 M. immunogenum genomes from previously sequenced clinical (n = 7) and environmental (n = 3) external control isolates. The 38-isolate cohort clustered into three clades with pairwise single-nucleotide polymorphism (SNP) distances ranging from 0 to 106,697 SNPs. We identified two clusters of study hospital isolates in Clade 1 and one cluster in Clade 2 for which clinical and environmental isolates differed by fewer than 10 SNPs and had less than 0.5% accessory genome variation. A less restrictive combined threshold of 40 SNPs and 5% accessory genes reliably captured additional isolates that met clinical criteria for hospital acquisition, but 12 (4%) of 310 epidemiologically unrelated isolate pairs also met this threshold. Core and accessory genome analyses confirmed respiratory acquisition of multiple clones of M. immunogenum from hospital water sources to patients. When combined with epidemiologic investigation, genomic thresholds accurately distinguished hospital acquisition.

Oil and Gas Extraction industry workers' compensation claims and proposed safety interventions.

OBJECTIVE: This study analyzed Ohio workers' compensation (WC) data to identify potential prevention strategies for common Oil and Gas Extraction industry claims. METHODS: Claim rates for 2001-2018 were calculated per full-time equivalent employee. Descriptive analyses on free-text descriptions of lost-time (LT) claims (>7 days away from work) identified common characteristics among claims and injured workers. RESULTS: Among 3,134 claims, 860 (27%) were LT. The industry group, Drilling contractors, experienced the highest LT claims rate, while the cost from Servicing contractors was highest. Contact with objects and equipment caused the highest LT claims rate. The most frequent LT occupation was Roustabout and LT work activity was Material Handling. Transportation Incidents caused most fatalities and hospitalizations. Over half of LT claims were from short-tenured workers. CONCLUSIONS: Both proven and innovative approaches are needed to reduce severe WC claims in this industry.

Late surgical site infections among solid organ transplant recipients: an unrecognized clinical entity.

This study identified 26 late invasive primary surgical site infection (IP-SSI) within 4-12 months of transplantation among 2073 SOT recipients at Duke University Hospital over the period 2015-2019. Thoracic organ transplants accounted for 25 late IP-SSI. Surveillance for late IP-SSI should be maintained for at least one year following transplant.

Guidelines for assessing maternal cardiovascular physiology during pregnancy and postpartum.

Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the United States. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand disease-related pathology. Significant systemic and cardiovascular physiological changes occur during pregnancy that are essential for supporting the maternal-fetal dyad. The physiological impact of pregnancy on the cardiovascular system has been examined in both experimental animal models and in humans. However, there is a continued need in this field of study to provide increased rigor and reproducibility. Therefore, these guidelines aim to provide information regarding best practices and recommendations to accurately and rigorously measure cardiovascular physiology during normal and cardiovascular disease-complicated pregnancies in human and animal models.

Risk Factors for Invasive Fungal Infection in Lung Transplant Recipients on Universal Antifungal Prophylaxis.

Background: Many centers use universal antifungal prophylaxis after lung transplant, but risk factors for invasive fungal infection (IFI) in this setting are poorly described. Methods: This retrospective, single-center cohort study including 603 lung transplant recipients assessed risk factors for early (within 90 days of transplant) invasive candidiasis (IC) and invasive mold infection (IMI) and late (90-365 days after transplant) IMI using Cox proportional hazard regression. Results: In this cohort, 159 (26.4%) patients had 182 IFIs. Growth of yeast on donor culture (hazard ratio [HR], 3.30; 95% CI, 1.89-5.75) and prolonged length of stay (HR, 1.02; 95% CI, 1.01-1.03) were associated with early IC risk, whereas transplantation in 2016 or 2017 (HR, 0.21; 95% CI, 0.06-0.70; HR, 0.25; 95% CI, 0.08-0.80, respectively) and female recipient sex (HR, 0.53; 95% CI, 0.30-0.93) were associated with reduced risk. Antimold therapy (HR, 0.21; 95% CI, 0.06-0.78) was associated with lower early IMI risk, and female donor sex (HR, 0.40; 95% CI, 0.22-0.72) was associated with lower late IMI risk. Recent rejection was a risk factor for late IMI (HR, 1.73; 95% CI, 1.02-2.95), and renal replacement therapy predisposed to early IC, early IMI, and late IMI (HR, 5.67; 95% CI, 3.01-10.67; HR, 7.54; 95% CI, 1.93-29.45; HR, 5.33; 95% CI, 1.46-19.49, respectively). Conclusions: In lung transplant recipients receiving universal antifungal prophylaxis, risk factors for early IC, early IMI, and late IMI differ.

Risk factors, management, and clinical outcomes of invasive Mycoplasma and Ureaplasma infections after lung transplantation.

Mollicute infections, caused by Mycoplasma and Ureaplasma species, are serious complications after lung transplantation; however, understanding of the epidemiology and outcomes of these infections remains limited. We conducted a single-center retrospective study of 1156 consecutive lung transplants performed from 2010-2019. We used log-binomial regression to identify risk factors for infection and analyzed clinical management and outcomes. In total, 27 (2.3%) recipients developed mollicute infection. Donor characteristics independently associated with recipient infection were age ≤40 years (prevalence rate ratio [PRR] 2.6, 95% CI 1.0-6.9), White race (PRR 3.1, 95% CI 1.1-8.8), and purulent secretions on donor bronchoscopy (PRR 2.3, 95% CI 1.1-5.0). Median time to diagnosis was 16 days posttransplant (IQR: 11-26 days). Mollicute-infected recipients were significantly more likely to require prolonged ventilatory support (66.7% vs 21.4%), undergo dialysis (44.4% vs 6.3%), and remain hospitalized ≥30 days (70.4% vs 27.4%) after transplant. One-year posttransplant mortality in mollicute-infected recipients was 12/27 (44%), compared to 148/1129 (13%) in those without infection (P <.0001). Hyperammonemia syndrome occurred in 5/27 (19%) mollicute-infected recipients, of whom 3 (60%) died within 10 weeks posttransplant. This study highlights the morbidity and mortality associated with mollicute infection after lung transplantation and the need for better screening and management protocols.

A conceptual framework for nomenclatural stability and validity of medically important fungi: a proposed global consensus guideline for fungal name changes supported by ABP, ASM, CLSI, ECMM, ESCMID-EFISG, EUCAST-AFST, FDLC, IDSA, ISHAM, MMSA, and MSGERC.

The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way.

Real-world Experiences in the Transplantation of Hepatitis C-NAAT-positive Organs.

Background: Hepatitis C virus (HCV) nucleic acid amplification test (NAAT)-positive donors have increased the organ pool. Direct-acting antivirals (DAAs) have led to high rates of treatment success and sustained virologic response (SVR) in recipients with donor-derived HCV infection without significant adverse effects, although variability remains in the timing and duration of antivirals. Methods: This retrospective study analyzed all adult HCV-NAAT-negative transplant recipients who received an organ from HCV-NAAT-positive donors from November 24, 2018, to March 31, 2022, at Duke University Medical Center with protocolized delay of DAA initiation until after hospital discharge, with at least 180-d follow-up on all patients. Transplant and HCV-related outcomes were analyzed. Results: Two hundred eleven transplants (111 kidneys, 41 livers, 34 hearts, and 25 lungs) were performed from HCV-NAAT-positive donors to HCV-NAAT-negative recipients. Ninety percent of recipients became viremic within 7 d posttransplant. Ninety-nine percent of recipients were initiated on pangenotypic DAAs in the outpatient setting a median of 52 d posttransplant, most commonly with 12-wk courses of sofosbuvir-velpatasvir (lungs) and glecaprevir-pibrentasvir (heart, kidney, and liver). Ninety-seven percent of recipients had SVR after a first-line DAA; all ultimately achieved SVR at 12 wk after subsequent treatment courses. The median peak HCV RNA for all organ systems was 2 436 512 IU/mL; the median time from antiviral to undetectable RNA was 48 d, although differences were noted between organ groups. No patient deaths or graft losses were directly attributable to HCV infection. Conclusions: One hundred percent of transplant recipients of HCV-NAAT-positive organs ultimately developed SVR without significant adverse effects when HCV antivirals were initiated in the outpatient setting after transplant hospitalization, suggesting that this real-world treatment pathway is a viable option.

Prevalence of Undiagnosed Monkeypox Virus Infections during Global Mpox Outbreak, United States, June-September 2022.

Since May 2022, mpox has been identified in 108 countries without endemic disease; most cases have been in gay, bisexual, or other men who have sex with men. To determine number of missed cases, we conducted 2 studies during June-September 2022: a prospective serologic survey detecting orthopoxvirus antibodies among men who have sex with men in San Francisco, California, and a retrospective monkeypox virus PCR testing of swab specimens submitted for other infectious disease testing among all patients across the United States. The serosurvey of 225 participants (median age 34 years) detected 18 (8.0%) who were orthopoxvirus IgG positive and 3 (1.3%) who were also orthopoxvirus IgM positive. The retrospective PCR study of 1,196 patients (median age 30 years; 54.8% male) detected 67 (5.6%) specimens positive for monkeypox virus. There are likely few undiagnosed cases of mpox in regions where sexual healthcare is accessible and patient and clinician awareness about mpox is increased.

Real-world Use of Mold-Active Triazole Prophylaxis in the Prevention of Invasive Fungal Diseases: Results From a Subgroup Analysis of a Multicenter National Registry.

Background: Antifungal prophylaxis can prevent invasive fungal diseases (IFDs) in high-risk, immunocompromised patients. This study assessed the real-world use of mold-active triazoles (MATs) for the prevention of IFDs. Methods: This subgroup analysis of a multicenter, observational, prospective registry in the United States from March 2017 to April 2020 included patients who received MATs for prophylaxis (isavuconazole, posaconazole, and voriconazole) at study index/enrollment. The primary objective was to describe patient characteristics and patterns of MAT use. Exploratory assessments included the frequency of breakthrough IFDs and MAT-related adverse drug reactions (ADRs). Results: A total of 1177 patients (256 isavuconazole, 397 posaconazole, 272 voriconazole, and 252 multiple/sequenced MATs at/after index/enrollment) were included in the prophylaxis subgroup analysis. Patient characteristics were similar across MAT groups, but risk factors varied. Hematological malignancy predominated (76.5%) across all groups. Breakthrough IFDs occurred in 7.1% (73/1030) of patients with an investigator's assessment (5.0% [11/221] isavuconazole; 5.3% [20/374] posaconazole; 4.0% [9/226] voriconazole; and 15.8% [33/209] multiple/sequenced MATs). Aspergillus (29.5% [18/61]) and Candida (36.1% [22/61]) species were the most common breakthrough pathogens recovered. ADRs were reported in 14.1% of patients, and discontinuation of MATs due to ADRs was reported in 11.1% of patients (2.0% [5/245] isavuconazole; 8.2% [30/368] posaconazole; and 10.1% [27/267] voriconazole). Conclusions: Breakthrough IFDs were uncommon in patients who received MATs for prophylaxis. Candida and Aspergillus species were the most commonly reported breakthrough pathogens. The discontinuation of MATs due to ADRs was infrequent. These findings support prophylactic strategies with isavuconazole, posaconazole, and voriconazole in high-risk patients.

Insights Into the Cardiomodulatory Effects of Sex Hormones: Implications in Transgender Care.

Transgender individuals that undergo gender-affirming hormone therapy may experience discrimination in the health care setting with a lack of access to medical personnel competent in transgender medicine. Recent evidence suggests that gender-affirming hormone therapy is associated with an increased risk of cardiovascular diseases and cardiovascular risk factors. A recent statement from the American Heart Association reinforces the importance of cardiovascular-focused clinical management and the necessity for more research into the impact of gender-affirming hormone therapy. With this in mind, this review will highlight the known cardiovascular risk factors associated with gender-affirming hormone therapy and identify potential molecular mechanisms determined from the limited animal studies that explore the role of cross-sex steroids on cardiovascular risk. The lack of data in this understudied population requires future clinical and basic research studies to inform and educate clinicians and their transgender patient population to promote precision medicine for their care to improve their quality of life.

Use of Letermovir for Primary and Secondary Cytomegalovirus Prophylaxis in Abdominal Organ Transplantation: A Single Center Experience.

BACKGROUND: Cytomegalovirus (CMV) infection after abdominal organ transplantation is associated with increased morbidity and mortality. The use of valganciclovir for CMV prophylaxis is limited by drug-induced myelosuppression and potential emergence of resistance. Letermovir is approved for primary CMV prophylaxis in CMV seropositive allogeneic hematopoietic cell transplant recipients. However, it is increasingly used off-label for prophylaxis in solid organ transplant (SOT) recipients. METHODS: Based on pharmacy records, we examined retrospectively the use of letermovir for CMV prophylaxis in abdominal transplant recipients initiated on therapy at our center from January 1, 2018 through October 15, 2020. Data were summarized using descriptive statistics. RESULTS: Twelve episodes of letermovir prophylaxis occurred in ten patients. Four patients received primary and 6 patients received secondary prophylaxis during the study period, with 1 patient receiving letermovir secondary prophylaxis on 3 separate occasions. All patients receiving letermovir for primary prophylaxis had successful outcomes. However, letermovir secondary prophylaxis was unsuccessful in 5 of the 8 episodes (62.5%) due to breakthrough CMV DNAemia and/or disease. Only 1 patient discontinued therapy due to adverse effects. CONCLUSION: Although letermovir was generally well tolerated, the high rate of failure when used as secondary prophylaxis was noteworthy. Additional controlled clinical trials assessing the safety and efficacy of letermovir prophylaxis in SOT recipients are warranted.

C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection.

Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.

Epidemiology, management, and clinical outcomes of extrapulmonary Mycobacterium abscessus complex infections in heart transplant and ventricular assist device recipients.

Nontuberculous mycobacteria are emerging pathogens, yet data on the epidemiology and management of extrapulmonary nontuberculous mycobacteria infections in orthotopic heart transplantation (OHT) and ventricular assist device (VAD) recipients are scarce. We retrospectively reviewed records of OHT and VAD recipients who underwent cardiac surgery at our hospital and developed Mycobacterium abscessus complex (MABC) infection from 2013 to 2016 during a hospital outbreak of MABC linked to heater-cooler units. We analyzed patient characteristics, medical and surgical management, and long-term outcomes. Ten OHT patients and 7 patients with VAD developed extrapulmonary M. abscessus subspecies abscessus infection. The median time from presumed inoculation during cardiac surgery to the first positive culture was 106 days in OHT and 29 days in VAD recipients. The most common sites of positive cultures were blood (n = 12), sternum/mediastinum (n = 8), and the VAD driveline exit site (n = 7). The 14 patients diagnosed when alive received combination antimicrobial therapy for a median of 21 weeks, developed 28 antibiotic-related adverse events, and underwent 27 surgeries. Only 8 (47%) patients survived longer than 12 weeks after diagnosis, including 2 patients with VAD who experienced long-term survival after an explantation of infected VADs and OHT. Despite aggressive medical and surgical management, OHT and VAD patients with MABC infection experienced substantial morbidity and mortality.

Growth Restriction in Preeclampsia: Lessons from Animal Models.

Preeclampsia remains a major health concern for mother and child. Yet, treatment options remain limited to early delivery. Placental dysfunction in preeclampsia occurs in response to an increase in oxidative stress and inflammatory cytokines with vasoactive and anti-angiogenic factors contributing to impaired maternal and fetal health. Moreover, recent studies indicate a potential role for epigenetic mediators in the pathophysiology of placental ischemia. Numerous animal models are utilized to explore the pathogenesis of preeclampsia and fetal growth restriction. This review provides a brief overview of recent progress in preclinical studies regarding potential therapeutic targets for the treatment and prevention of preeclampsia with an emphasis on fetal growth restriction and the fetal programming of increased cardiovascular risk.

Appraising the Preclinical Evidence of the Role of the Renin-Angiotensin-Aldosterone System in Antenatal Programming of Maternal and Offspring Cardiovascular Health Across the Life Course: Moving the Field Forward: A Scientific Statement From the American Heart Association.

There is increasing interest in the long-term cardiovascular health of women with complicated pregnancies and their affected offspring. Emerging antenatal risk factors such as preeclampsia appear to increase the risk of hypertension and cardiovascular disease across the life course in both the offspring and women after pregnancy. However, the antenatal programming mechanisms responsible are complex and incompletely understood, with roots in alterations in the development, structure, and function of the kidney, heart, vasculature, and brain. The renin-angiotensin-aldosterone system is a major regulator of maternal-fetal health through the placental interface, as well as kidney and cardiovascular tissue development and function. Renin-angiotensin-aldosterone system dysregulation plays a critical role in the development of pregnancy complications such as preeclampsia and programming of long-term adverse cardiovascular health in both the mother and the offspring. An improved understanding of antenatal renin-angiotensin-aldosterone system programming is crucial to identify at-risk individuals and to facilitate development of novel therapies to prevent and treat disease across the life course. Given the inherent complexities of the renin-angiotensin-aldosterone system, it is imperative that preclinical and translational research studies adhere to best practices to accurately and rigorously measure components of the renin-angiotensin-aldosterone system. This comprehensive synthesis of preclinical and translational scientific evidence of the mechanistic role of the renin-angiotensin-aldosterone system in antenatal programming of hypertension and cardiovascular disease will help (1) to ensure that future research uses best research practices, (2) to identify pressing needs, and (3) to guide future investigations to maximize potential outcomes. This will facilitate more rapid and efficient translation to clinical care and improve health outcomes.