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Rocky Mountain spotted fever (RMSF), a tickbome disease caused by Rickettsia rickettsii, is the leading cause of death from rickettsial infections in the Western Hemisphere (1). The disease can progress [...]

Syphilis transmission remains a public health challenge; [approximately equal to]7.1 million new cases were reported in 2020 (2). Despite its relatively low incidence, if left untreated, syphilis results in substantial [...]

Spotted fever rickettsiosis in solid organ transplant recipients is rarely described, and all reports document disease acquired months to years after the transplant, after recognized tick bites or exposures to [...]

Ocular mpox, caused by monkeypox virus (MPXV), can threaten eyesight and requires prompt ophthalmologic consultation. Understanding of the disease course, treatments, and treatment durations is limited. We describe a case [...]

COVID-19 has caused a significant global disease burden since it was first identified in December 2019; as of May 2024, [greater than or equal to]750 million cases had been confirmed, [...]

Xenotransplantation, the implantation of vascularized organs or viable cells from nonhuman species into humans, is under development to address the shortage of human organs for transplantation. Clinical xenotransplantation from swine [...]

An important concept in managing clozapine's clinical issues and adverse effects is that not all approaches possess the highest levels of evidence from randomized clinical trials (RCTs), leaving clinicians to [...]

BACKGROUND: Overweight and obesity impose a considerable individual and social burden, and the urban environments might encompass factors that contribute to obesity. Nevertheless, there is a scarcity of research that takes into account the simultaneous interaction of multiple environmental factors. OBJECTIVES: Our objective was to perform an exposome-wide association study of body mass index (BMI) in a multicohort setting of 15 studies. METHODS: Studies were affiliated with the Dutch Geoscience and Health Cohort Consortium (GECCO), had different population sizes (688-141,825), and covered the entire Netherlands. Ten studies contained general population samples, others focused on specific populations including people with diabetes or impaired hearing. BMI was calculated from self-reported or measured height and weight. Associations with 69 residential neighborhood environmental factors (air pollution, noise, temperature, neighborhood socioeconomic and demographic factors, food environment, drivability, and walkability) were explored. Random forest (RF) regression addressed potential nonlinear and nonadditive associations. In the absence of formal methods for multimodel inference for RF, a rank aggregation-based meta-analytic strategy was used to summarize the results across the studies. RESULTS: Six exposures were associated with BMI: five indicating neighborhood economic or social environments (average home values, percentage of high-income residents, average income, livability score, share of single residents) and one indicating the physical activity environment (walkability in 5-km buffer area). Living in high-income neighborhoods and neighborhoods with higher livability scores was associated with lower BMI. Nonlinear associations were observed with neighborhood home values in all studies. Lower neighborhood home values were associated with higher BMI scores but only for values up to [euro]300,000. The directions of associations were less consistent for walkability and share of single residents. DISCUSSION: Rank aggregation made it possible to flexibly combine the results from various studies, although between-study heterogeneity could not be estimated quantitatively based on RF models. Neighborhood social, economic, and physical environments had the strongest associations with BMI. https://doi.org/10.1289/EHP13393, Introduction Overweight and obesity impose a considerable individual and social burden, with global rates that have nearly tripled since 1975. (1) This striking rise could be attributed to changes in [...]

BACKGROUND: Maternal cigarette smoking during pregnancy (MSDP) is associated with numerous adverse health outcomes in infants and children with potential lifelong consequences. Negative effects of MSDP on placental DNA methylation (DNAm), placental structure, and function are well established. OBJECTIVE: Our aim was to develop biomarkers of MSDP using DNAm measured in placentas (N =96), collected as part of the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function double-blind, placebo-controlled randomized clinical trial conducted between 2012 and 2016. We also aimed to develop a digital polymerase chain reaction (PCR) assay for the top ranking cytosine--guanine dinucleotide (CpG) so that large numbers of samples can be screened for exposure at low cost. METHODS: We compared the ability of four machine learning methods [logistic least absolute shrinkage and selection operator (LASSO) regression, logistic elastic net regression, random forest, and gradient boosting machine] to classify MSDP based on placental DNAm signatures. We developed separate models using the complete EPIC array dataset and on the subset of probes also found on the 450K array so that models exist for both platforms. For comparison, we developed a model using CpGs previously associated with MSDP in placenta. For each final model, we used model coefficients and normalized beta values to calculate placental smoking index (PSI) scores for each sample. Final models were validated in two external datasets: the Extremely Low Gestational Age Newborn observational study, N = 426; and the Rhode Island Children's Health Study, N = 237. RESULTS: Logistic LASSO regression demonstrated the highest performance in cross-validation testing with the lowest number of input CpGs. Accuracy was greatest in external datasets when using models developed for the same platform. PSI scores in smokers only (n = 72) were moderately correlated with maternal plasma cotinine levels. One CpG (cg27402634), with the largest coefficient in two models, was measured accurately by digital PCR compared with measurement by EPIC array ([R.sup.2] = 0.98). DISCUSSION: To our knowledge, we have developed the first placental DNAm-based biomarkers of MSDP with broad utility to studies of prenatal disease origins. https://doi.org/10.1289/EHP13838, Introduction Maternal cigarette smoking during pregnancy (MSDP) is associated with increased risk of low birth weight, prematurity, and perinatal mortality. (1-4) MSDP is also associated with greater risk of cardiovascular, [...]

Background: Inguinal lymphadenectomy (ILND) has historically been associated with substantial morbidity. The objective of this study was to obtain contemporary ILND morbidity rates and to identify potentially preventable risk factors. Methods: We carried out a retrospective review of medical records for all superficial, deep, and combination groin dissections performed at a single, high-volume academic centre between January 2007 and December 2020. We collected data points for patient, disease, and surgery characteristics, and cancer outcomes. The outcome of interest was any complication within 30 days of surgery. Complications included wound infection, wound necrosis or disruption, seroma, drainage procedure, hematoma, and lymphedema. We performed multivariate logistic regression using SAS version 9.4. Results: We identified 139 patients having undergone 89 superficial, 12 deep, and 38 combined dissection types, respectively. Melanoma accounted for 84.9% of cases. Of these patients, 56.1% had an adverse postoperative event within 30 days. Increasing age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.01-1.07, p < 0.01) and number of positive lymph nodes harvested (OR 1.22, 95% CI 1.00-1.50, p = 0.05) were associated with more complications. Patients with deep dissection showed a lower likelihood of complications than those with superficial dissection (OR 0.15, 95% CI 0.03-0.84, p < 0.05). Conclusion: Complication rates after ILND remain high. We identified a number of risk factors, providing opportunities for better selection and prevention. Contexte : La lymphad nectomie inguinale (LI) a toujours t associ e une morbidit importante. Cette tude avait pour but de mesurer les taux de morbidit actuellement associ s la LI et d'en identifer les facteurs de risque potentiellement vitables. M thodes : Nous avons proc d une revue r trospective des dossiers m dicaux de tous les cas de curage inguinal superficiel, profond et complet effectu s dans un seul centre hospitalier universitaire achaland entre janvier 2007 et d cembre 2020. Nous avons recueilli des donn es relatives aux caract ristiques des malades, des maladies et des chirurgies, de m me que l'issue des cancers. Le param tre principal tait toute complication survenant dans les 30 jours suivant la chirurgie. Les complications incluaient infection, n crose ou d hiscence de la plaie, s rome, pose de drain, h matome et lymphoed me. Nous avons proc d une analyse de r gression logistique multivari e l'aide du logiciel SAS Enterprise 9.4. R sultats : Nous avons recens 139 personnes ayant subi un curage inguinal : 89 superficiels, 12 profonds et 38 complets. Un m lanome justifiait l'intervention dans 84,9% des cas. Parmi ces malades, 56,1% ont eu une complication postop ratoire dans les 30 jours suivants l'intervention. Un ge avanc (rapport des cotes [RC] 1,04, intervalle de confiance [IC] de 95% 1,01-1,07, p < 0,01) et le nombre de ganglions lymphatiques positifs r s qu s (RC 1,22, IC de 95% 1,00-1,50, p = 0,05) ont t associ s plus de complications. Les curages profonds ont t associ s une probabilit moindre de complications comparativement aux curages superficiels (RC 0,15, IC de 95% 0,03-0,84, p < 0,05). Conclusion : Les taux de complications suivant la lymphad nectomie inguinale restent lev s. Nous avons identif certains facteurs de risque qui sont autant d'occasions de mieux s lectionner les malades et d'am liorer la pr vention., Inguinal lymphadenectomy (ILND) is a surgical proced ure used for the management of regionally advanced or recurrent malignancies such as melanoma. (1,2) It is classified into different types, based on [...]

Hantaviruses are a large group of rodentborne single-stranded RNA viruses that cause clinical illness of varying severity in humans. Austria, and especially its southernmost federal states (Styria, Carinthia, and Burgenland), [...]

Human parainfluenza virus (HPIV) is a major cause of acute respiratory tract infections, such as croup in children and pneumonia in immunocompromised patients (1). HPIV is a single-stranded, enveloped RNA [...]

Researchers have reported a rising prevalence of food sensitivities, or adverse reactions to food that are mediated by the immune system. These reactions include food allergies (1) and celiac disease [...]

Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic mutation AF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have dramatically increased the lifespan of patients with this mutation. This development has led to major changes in the field and has pushed research beyond the ion transport nature of cystic fibrosis and toward multiorgan physiological reprogramming. In this issue of the JCI, Bae, Kim, and colleagues utilized a large animal pig model prior to the onset of disease. They revealed metabolic reprogramming and organ crosstalk that occurred prior to disease progression. These findings provide paradigm-shifting insight into this complex disease., Trikafta propels a new era in CFTR research Cystic fibrosis (CF) is a genetic condition that affects the cystic fibrosis transmembrane conductance regulator (CFTR) protein (1, 2). Patients with CF [...]

Multiple approaches have targeted voltage-gated sodium (Nav) channels for analgesia. In this issue of the JCI, Shin et al. identified a peptide aptamer, [Na.sub.V]iPA1, carrying a short polybasic motif flanked by serine residues in a structurally disordered region of loop 1 in tetrodotoxin-sensitive (TTX-S) but not tetrodotoxin-resistant (TTX-R) channels. [Na.sub.V]iPA1h inhibited TTX-S [Na.sub.V] channels and attenuated excitability of sensory neurons. Delivery of [Na.sub.V]iPA1 in vivo via adeno-associated virions restricted its expression to peripheral sensory neurons and induced analgesia in rats. Targeting of short linear motifs in this manner may provide a gene therapy modality, with minimal side effects due to its peripherally-restricted biodistribution, which opens up a therapeutic strategy for hyperexcitability disorders, including pain., [Na.sub.V] channels as targets for pain disorders Voltage-gated sodium ([Na.sub.V]) channels are obligate components of the electrogenic machinery that underlie action potential electrogenesis (1). Nine members of the pore-forming a-subunit [...]

Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell- targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases., Introduction Autoantibodies have been identified in a wide range of autoimmune diseases (1-4). In many cases these autoantibodies are directly pathogenic (5-10), while in others they amplify or support T [...]

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. [NAD.sup.+] supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies., Introduction The primary cilium is a solitary, immobile microtubule-based structure present on the apical surface of many cell types, especially in sensory organs such as the eye and nose. The [...]

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfsl (mitochondrial Rieske iron- sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in a-ketoglutarate (required for TET-mediated demethylation) and an increase in 5-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation., Introduction Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), but they also participate in diverse biological functions that include redox signaling (1), metabolite signaling (2), calcium signaling (3), and the generation [...]