Barth syndrome (BTHS; OMIM 302060) is an ultra-rare, life-limiting genetic disorder characterized by cardiomyopathy, skeletal muscle myopathy, neutropenia, gastrointestinal issues, and fatigue. Formal analyses of survival and clinical progression remain limited. Barth Syndrome Foundation has maintained an intake database (n = 502), representing > 80% of the known global population, as well as a patient-inputted registry for a subset of individuals (n = 162) with up to 11 years of longitudinal outcome data. We estimate the survival curve, identify factors associated with mortality, characterize clinical manifestations over time, and evaluate causes of death. Death disproportionately affected young children, with a 59% transplant-free survival rate for those age < 5. The risk of death plateaued between ages 5-25 before rising again. Heart transplantation (HR = 0.316, 95% CI: 0.162-0.619, p < 0.001) and living in a developed country (HR = 0.109, 95% CI: 0.018-0.659, p < 0.05) were associated with reduced risk of death. Clinical manifestations increased with age, with musculoskeletal/fatigue (66%) being most frequent. Top causes of death were cardiac-related complications, with cardiomyopathy/heart failure (51.3%), mostly in young children < 5, and arrhythmia/cardiac arrest (15%). This is the most comprehensive longitudinal assessment of BTHS survival, mortality risk, and clinical manifestation progression. Early childhood is a period of high mortality risk, driven in large part by heart failure. Although risk of death and hospitalizations plateaued between ages 5-25, the clinical burden of BTHS increases throughout the lifespan. Our results may guide clinical care, identify time windows for optimal intervention, and help clinicians better recognize BTHS clinical features.
Barth syndrome (BTHS) is an ultra-rare, X-linked genetic disorder for which there is limited economic data. Because compiling such data that target rare indications is difficult, we assessed real-world data to increase understanding of the cost of BTHS based on disease burden and health care resource utilization (HCRU). A search of the published medical literature identified individual case studies and registry data used to assess the burden of disease and potential costs associated with BTHS, including the potential ability of developing treatments to positively impact those costs. In addition, a claims database analysis was conducted to assess HCRU and associated costs in the United States for patients with BTHS. These real-world data were summarized and compared with registry data. The diagnostic journey for patients with BTHS is difficult, with the majority of affected individuals not receiving a diagnosis until after the development of cardiomyopathy or until a family member is diagnosed, even in those who are symptomatic. Of the living individuals known to have BTHS, a high proportion experience heart failure, with >15% requiring heart transplantation. Data extrapolated during the claims database analysis demonstrated that patients with diagnostic codes linked to BTHS are complex, with a high percentage of complications, necessitating a high level of HCRU and associated costs of care in the inpatient setting. Specifically, National Inpatient Sample hospital cost per claim was $32,702 and the Kids' Inpatient Database hospital cost per claim was $62,596. Health economic evaluations for rare diseases are scarce. With a noteworthy absence of pharmacoeconomic evidence, utilization of combined clinical case report data from the medical literature, along with registry and claims datasets, demonstrate that BTHS is a costly disease associated with high disease burden and excessive HCRU. Forthcoming treatments (e.g. elamipretide) have the potential to reduce the high disease burden/HCRU.
Zearalenone (ZEN) is an estrogenic mycotoxin ("mycoestrogen") that contaminates global grain crops leading to detectable concentrations of ZEN and its metabolites, including the synthetic version α-zearalanol (also called zeranol; ZER), in human populations. Despite in vitro and in vivo animal evidence of endocrine disruption by ZEN, there has been limited investigation in humans. To examine markers of fetal growth following prenatal exposure to ZEN and evaluate the role of the placental efflux transporter BCRP/ABCG2 in protecting against ZEN's potential fetoplacental toxicity. Placentas were collected from participants (n=271) in the Understanding Pregnancy Signals and Development cohort (Rochester, New York, USA). Placental ZEN and its metabolites were analyzed from tissue samples using HPLC-MS. Birth weights and placental weights were obtained from medical records and direct measurement, respectively; fetoplacental weight ratio (FPR) was calculated by dividing birth weight by placental weight. Covariate-adjusted generalized linear regression models were used to examine ZEN, ZER, and total mycoestrogens (sum of ZEN, ZER, and their metabolites) in relation to birth length, birth weight, placental weight and FPR. We additionally stratified models by infant sex and ABCG2 C421A (Q141K) genotype. Mycoestrogens were detected in 84% of placentas (median ZEN: 0.010 ng/g) and total mycoestrogens were associated with lower FPR [-0.20; 95% confidence interval (CI): -0.32, -0.08], particularly in female infants (-0.31; 95% CI: -0.52, -0.09). Associations with birth weight were inverse and overall nonsignificant. Among the 17% of participants with the reduced function 421A ABCG2 variant (AA or AC), total mycoestrogens were associated with lower birth weight (-113.5g; 95% CI: -226.5, -0.50), whereas in wild-type individuals, total mycoestrogens were associated with higher placental weight (9.9; 95% CI: 0.57, 19.2) and reduced FPR (-0.19; 95% CI: -0.33, -0.05). Results from this epidemiological study of prenatal mycoestrogen exposure and perinatal health suggest that mycoestrogens may reduce placental efficiency, resulting in lower birth weight, particularly in female and ABCG2 421A infants. https://doi.org/10.1289/EHP14478.
Diego Rivera, an acclaimed Mexican painter active during the first half of the 20th century, painted multiple frescoes in Mexico and the United States. Some include depictions of bacteria, their interactions with human hosts, and processes related to microbiology and public health, including the microbial origin of life, diagnosis of infection, vaccine production, and immunization. Microbiological subjects in Rivera's murals at the Mexican Ministry of Health in Mexico City; the Detroit Institute of Art, Detroit; Rockefeller Center, New York/Palacio de Bellas Artes, Mexico City; Chapultepec Park, Mexico City; and the Institute of Social Security, Mexico City, span almost 25 years, from 1929 to 1953. Illustrating the successes of the application of microbiological discoveries and methods to public health and the prevention and treatment of infectious diseases, they benefited from Rivera's creativity in melding microbiology's unique technological and scientific aspects and public health elements with industrial and political components.
To devise an MRI grading scheme for osseous contusion patterns in elite hockey players for predicting return-to-play (RTP). A retrospective review was performed to identify traumatic lower extremity osseous injuries in professional hockey players. A total of 28 injuries (17 players) were identified over a 10-year period. All had MRIs acquired at ≥ 1.5 T within a mean interval of 2 days from initial injury. MRIs were retrospectively reviewed by 3 musculoskeletal radiologists for osseous contusion pattern, classified as grade 1 (mild), 2 (moderate), or 3 (severe). Grade 3 contusions were further subdivided by the presence or absence of fracture, defined as discrete cortical disruption on MRI or follow-up CT. RTP was calculated from date of injury to next game played based on game log data. Statistical analysis was performed using ANOVA and post hoc unpaired t test. Mean RTP for grade 1, 2, and 3 injuries was 2.8, 4.5, and 20.3 days, respectively. Grade 3 injuries without and with cortical fractures had mean RTP of 18.3 and 21.4 days, respectively. ANOVA analysis between groups achieved statistical significance (p < 0.001). Post hoc t test demonstrated statistically significant differences between grade 3 and grades 1 (p < 0.001) and 2 (p < 0.001) injuries. There was no statistical difference in RTP between grade 3 subgroups without and with fracture (p = 0.327). We propose a novel MRI grading system for assessing severity of osseous contusions and predicting RTP. Clinically, there was no statistically significant difference in RTP between severe osseous contusions and nondisplaced fractures in elite hockey players.
There is increasing interest in measuring metals concentrations in human placentas to better understand physiology, disease, and toxic and diagnostic exposures. For these purposes, formalin-fixed paraffin embedded (FFPE) tissues obtained at clinical pathology examination represent a valuable potential store of well-characterized tissues for analysis. However, the limited data that exist comparing metal concentrations in FFPE tissue to recently collected frozen tissues paints a confusing picture, and there is no published data directly comparing frozen and FFPE placental villus tissues. Paired samples of fresh frozen and FFPE tissue from 22 rapidly processed human singleton placentae were weighed and digested using standard clean laboratory procedures and subsequently analyzed for a suite of 13 metals using a PerkinElmer DRC II ICP-MS. The analytical results were compared using either a paired t-test or a sign test depending on data normality. Concentrations of metals (aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), gadolinium (Gd), mercury (Hg), manganese (Mn), lead (Pb), strontium (Sr), and zinc (Zn)) measured in both types of tissue preparations (frozen and FFPE) displayed a consistent range with other studies and did not display significantly different values from each of the paired specimens for any of the 13 specific metals analyzed. Within placentae, metals concentrations of measured trace, toxic and diagnostic elements (Al, As, Ba, Cd, Cr, Cu, Fe, Gd, Hg, Mn, Pb, Sr, and Zn) are consistent between FFPE and fresh placental villus tissue, without indications of systematic element loss or bias. FFPE from archived pathology specimens may offer an important and convenient alternative for measuring trace metals in human frozen placental tissues.
Barth syndrome (BTHS) is a rare X-linked genetic disease that affects multiple systems and leads to complex clinical manifestations. Although a considerable amount of research has focused on the physical aspects of the disease, less has focused on the psychosocial impact and quality of life (QoL) in BTHS. The current study investigated caregiver- (n = 10) and self-reported (n = 16) psychological well-being and QoL in a cohort of BTHS-affected patients and families. Participants completed the depression and anxiety components of the Patient-Reported Outcomes Information System (PROMIS) Short Form 8A and Health-related quality of life (HRQoL) surveys at enrollment and again during a follow-up period ranging from 6 to 36 months after baseline. Quality of life changed significantly over time and the various domains with some improvement and some decline. Among the available caregiver-patient dyad data, there was a trend toward discordance between caregiver and self-reported outcomes. Most notably, patients reported improvement in HRQoL, while caregivers reported declines. This suggests that there may be differences in perceived quality of life between the patients and parents, though our study is limited by small sample size. Our study provides valuable insights into the impacts of psychosocial and mental health aspects of BTHS. Implications of these findings include incorporating longitudinal assessment of QoL and screening for psychological symptoms in BTHS care to identify interventions that may drastically impact health status and the course of the disease.
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A retrospective single-center study was performed to assess the performance of ultrasound image-based texture analysis in differentiating angiomyolipoma (AML) from renal cell carcinoma (RCC) on incidental hyperechoic renal lesions. Ultrasound reports of patients from 2012 to 2017 were queried, and those with a hyperechoic renal mass <5 cm in diameter with further imaging characterization and/or pathological correlation were included. Quantitative texture analysis was performed using a model including 18 texture features. Univariate logistic regression was used to identify texture variables differing significantly between AML and RCC, and the performance of the model was measured using the area under the receiver operating characteristic (ROC) curve. One hundred thirty hyperechoic renal masses in 127 patients characterized as RCCs (25 [19%]) and AMLs (105 [81%]) were included. Size (odds ratio [OR] = 0.12, 95% confidence interval [CI]: 0.04-0.43, p < 0.001) and 4 of 18 texture features, including entropy (OR = 0.09, 95% CI: 0.01-0.81, p = 0.03), gray-level non-uniformity (OR = 0.12, 95% CI: 0.02-0.72, p = 0.02), long-run emphasis (OR = 0.49, 95% CI: 0.27-0.91, p = 0.02) and run-length non-uniformity (OR = 2.18, 95% CI: 1.14-4.16, p = 0.02) were able to differentiate AMLs from RCCs. The area under the ROC curve for the performance of the model, including texture features and size, was 0.945 (p < 0.001). Ultrasound image-based textural analysis enables differentiation of hyperechoic RCCs from AMLs with high accuracy, which improves further when combined with tumor size.
We tested the hypothesis that the fetal-placental relationship scales allometrically and identified modifying factors of that relationship. Among women delivering after 34 weeks but prior to 43 weeks' gestation, 24,601 participants in the Collaborative Perinatal Project (CPP) had complete data for placental gross proportion measures, specifically, placental weight (PW), disk shape, larger and smaller disk diameters and thickness, and umbilical cord length. The allometric metabolic equation was solved for alpha and beta by rewriting PW = alpha(BW)beta as ln(PW) = ln alpha + beta[ln(BW)]. alpha(iota) was then the dependent variable in regressions with p < 0.05 significant. Mean beta was 0.78 + 0.02 (range 0.66, 0.89), which is consistent with the scaling exponent 0.75 predicted by Kleiber's Law. Gestational age, maternal age, maternal BMI, parity, smoking, socioeconomic status, infant sex, and changes in placental proportions each had independent and significant effects on alpha. We find an allometric scaling relation between the placental weight and the birthweight in the CPP cohort with an exponent approximately equal to 0.75, as predicted by Kleiber's Law. This implies that: (1) placental weight is a justifiable proxy for fetal metabolic rate when other measures of fetal metabolic rate are not available; and (2) the allometric relationship between placental and birthweight is consistent with the hypothesis that the fetal-placental unit functions as a fractal supply limited system. Furthermore, our data suggest that the maternal and fetal variables we examined have at least part of their effects on the normal balance between placental weight and birth weight via effects on gross placental growth dimensions.
Infants born below 2500 g are classified as low birth weight. Excess in utero exposure to cortisol has been linked to restricted fetal growth. Placental production of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol before passage into the fetus. The present study tested the hypothesis that placental 11β-HSD2 expression is positively correlated with an individualized birth weight centile and raw birth weight, and examines the relationship between metal concentrations in placental tissue and 11β-HSD2 expression. Placentae from 191 births were collected and samples preserved to maintain mRNA profile. Placental 11β-HSD2 expression was measured via qRT-PCR. Addition samples were collected from placental tissues and uniformly dried in order to quantify 18 metals via ICP-MS (n = 160). A significant, positive correlation between 11β-HSD2 expression and individualized birth weight centile (p = 0.0321) and birth weight (p = 0.0243) was found. Additionally, maternal age and gestational age were positivity correlated with each other (p = 0.0321). Birth weight was significantly different with race, marital status, education and maternal tobacco use. Four metals (Co, Mn, Ni, Zn) demonstrated significant positive correlations (p < 0.05) with 11β-HSD2 expression. Sex specific differences were found; Co, Cu, Fe, Zn, and Ni were positively correlated with 11β-HSD2 expression in males only, no significant correlations were found in the female only sample. These data indicate that the growth potential of a fetus is related to the 11β-HSD2 expression in the placenta, and that 11β-HSD2 expression is related to the trace metals status of the mother.
The deleterious effect of HIV on the immune system begins at the time of infection. At seroconversion the virologic and immunologic factors that ultimately will dictate the rate of disease progression are believed to be already in place. The concept developed in this paper implies that, to impact significantly on the progression of disease, anti-HIV therapies should be initiated as early as possible in asymptomatic individuals. Published results have shown that combination drug therapies are potent in reducing HIV-1 RNA load in plasma in asymptomatic individuals, and that some HIV-1 immune-based therapies have a positive impact on immunological markers of disease progression, including HIV-1 cell-mediated immunity (CMI) and CD4 percent. The strategy discussed is to test a combination of antiretroviral therapy with HIV-1 immune-based therapy, such as the inactivated HIV-1 immunogen preparation, in asymptomatic individuals. The goal of this combination approach is to overcome the limitations of each therapy alone. Preliminary data suggest that antiretroviral therapy and the HIV-1 Immunogen can be combined with no noticeable interference and/or added toxicity in a broad range of HIV-1-infected individuals. Combining both therapies may enhance and expand the impact on key surrogate markers of disease progression, although they likely achieve this impact through different mechanisms. Thus, the primary question remains: Can these effects be synergistic?
Barth Syndrome (BTHS) is a rare, X-linked disease characterized by cardioskeletal myopathy and neutropenia. Comparative outcomes after heart transplantation have not been reported. We identified BTHS recipients across 3 registries (Pediatric Heart Transplant Study Registry [PHTS], Barth Syndrome Research Registry and Repository, and Scientific Registry of Transplant Recipient-Pediatric Health Information System) and matched them 1:4 to non-BTHS, male heart transplant (HT) recipients listed with dilated cardiomyopathy in PHTS. Demographics and survival data were analyzed for all recipients, whereas post-HT infection, malignancy, allograft vasculopathy, and acute rejection were only available for analysis for individuals with PHTS data. Forty-seven BTHS individuals with 51 listings and 43 HTs (including 2 re-transplants) were identified. Age at primary HT was 1.7 years (IQR: 0.6-4.5). Mechanical circulatory support at HT was common (ventricular assist device 29%, extracorporeal membrane oxygenation 5%). Over a median follow-up of 4.5 years (IQR 2.7-9.1), survival for BTHS HT recipients was no different than non-BTHS HT recipients (HR 0.91, 95% CI 0.40-2.12, p = 0.85). Among those with PHTS data (n = 28), BTHS HT recipients showed no difference in freedom from infection (HR 0.64, 0.34-1.22; p = 0.18), malignancy (HR 0.22, 0.02-2.01, p = 0.18), and allograft vasculopathy (HR 0.58, 0.16-2.1, p = 0.41). Freedom from acute rejection (HR 0.39, 0.17-0.86, p = 0.02) was greater for BTHS HT recipients despite similar use of induction (61 vs 73%, p = 0.20), steroids at 30-days (75 vs 62%, p = 0.27), and dual/triple drug immunosuppression at 1-year (80 vs 84%, p = 0.55). In this largest cohort yet reported, individuals with BTHS have equivalent survival with less acute rejection and no difference in infection or malignancy after HT. When indicated, HT for individuals with BTHS is appropriate.
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This article provides recollections and commentary regarding the lifelong achievements of the founding editor of Preventive Medicine.
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Variability in placental chorionic surface vessel networks (PCSVNs) may mark developmental and functional changes in fetal health. Here we report a protocol of manually tracing PCSVNs from digital 2D images of post-delivery placentas and its validation by a shape matching method to compare the similarity between paint-injected and unmanipulated (uninjected and deflated vessels) tracings of PCSVNs. We show that tracings of unmanipulated vessels produce networks that are very comparable to the networks obtained by tracing paint-injected PCSVNs. We suggest that manual tracings of unmanipulated PCSVNs can extract features of PCSVN growth and structure that may impact fetal wellbeing.
The COVID-19 pandemic had the potential to severely disrupt the delivery of methadone and buprenorphine, as social distancing and other public health regulations made in-person services difficult to maintain. Federal and state regulators changed requirements regarding the dispensing of medication and in-person counseling at opioid treatment programs. Understanding staff and patient reactions to these changes can help determine whether they should be maintained. We interviewed 25 directors of OTP programs located throughout the United States. Note takers wrote summaries of each interview which were coded for topics and themes covered in the interview guide, including changes to clinic practices, take-home medications, telehealth, patient and staff reactions to new COVID-related protocols, and financial concerns for programs. Most programs rapidly incorporated new regulatory requirements, and directors were generally positive about the impact of increased take-home doses of medication and increased reliance on telehealth. Some directors voiced concerns about these changes, and some reported that patients missed the daily clinical contact with staff. Directors also suggested that more time was needed to assess the full impact of these changes. Financial impacts varied, although many directors were quick to point out that the ongoing opioid epidemic has delivered a steady stream of new patients, thus offsetting potential financial losses. Overall, this study demonstrated the generally positive view of OTP directors to the regulatory changes necessitated by the COVID-19 pandemic. More time is needed to fully evaluate the impact of these changes on clinical outcomes.