Resistance and aerobic training increases genome-wide DNA methylation in women with polycystic ovary syndrome.

Physical activity is a first-line treatment for polycystic ovary syndrome (PCOS). Resistance or aerobic exercise improves metabolic complications, reproductive outcomes, and quality of life in PCOS. DNA methylation reprogramming during exercise may be the major modifier behind these changes. We sought to evaluate genome-wide DNA methylation changes after supervised resistance and aerobic exercise in women with PCOS. Exercises were performed in 56 women with PCOS (resistance, n = 30; aerobic, n = 26), for 16 weeks (wks), three times per week, in 50-minute to one-hour sessions. Anthropometric indices and hormonal and metabolic parameters were measured before and after training. Genome-wide leukocyte DNA methylation was analysed by Infinium Human MethylationEPIC 850K BeadChip microarrays (Illumina). Both resistance and aerobic exercise improved anthropometric indices, metabolic dysfunction, and hyperandrogenism in PCOS after the training programme, but no differences were observed between the two exercises. Resistance and aerobic exercise increased genome-wide DNA methylation, although resistance changed every category in the CpG island context (islands, shores, shelve, and open sea), whereas aerobic exercise altered CpG shores and the open sea. Using a stringent FDR (>40), 6 significantly differentially methylated regions (DMRs) were observed in the resistance exercise cohort and 14 DRMs in the aerobic cohort, all of which were hypermethylated. The increase in genome-wide DNA methylation may be related to the metabolic and hormonal changes observed in PCOS after resistance and aerobic exercise. Since the mammalian genome is hypermethylated globally to prevent genomic instability and ageing, resistance and aerobic exercise may promote health and longevity through environmentally induced epigenetic changes.

Characteristics of patients admitted to the ICU with Kaposi sarcoma herpesvirus-associated diseases.

OBJECTIVE: There are four conditions caused by Kaposi sarcoma herpesvirus (KSHV): Kaposi sarcoma, KSHV-associated multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSHV inflammatory cytokine syndrome (KICS). These KSHV-associated disorders (KADs) often occur in people with HIV and can lead to multiorgan dysfunction requiring admission to the ICU. However, little is known about patient outcomes in this setting. METHODS: A retrospective study of patients with KADs admitted to the ICU between 2010 and 2021 was conducted, examining KAD admission diagnoses, HIV characteristics, selected cytokine profiles, and ICU interventions. Primary outcomes were 60-day and median overall survival from ICU admission to death from any cause. RESULTS: Forty-seven patients (all but one with HIV coinfection) were included. At ICU admission, 44 patients (94%) were on antiretroviral therapy with a median CD4 + count of 88 cells/µl and HIV viral load of 23 copies/ml. The most common presentation was respiratory failure alone (19%) or with hypotension (17%). Twenty-two (47%) patients had presumed KICS (with or without Kaposi sarcoma) at admission and an additional KAD was diagnosed in 36% of these patients. IL-6 levels did not vary across KAD subtype. Twenty (43%) patients received KAD-directed therapy in the ICU. Sixty-day survival was 70% and median overall survival was 9 months. CONCLUSION: The majority of patients with HIV and KADs admitted to the ICU had well controlled HIV. Additional KAD were diagnosed during ICU admission in a proportion of patients who presented with presumed KICS. Critical illness did not preclude a subset of patients from receiving KAD-directed therapy in the ICU.

Racial Disparities in Prostate Cancer: Evaluation of Diet, Lifestyle, Family History, and Screening Patterns.

BACKGROUND: Racial disparities in prostate cancer incidence and mortality rates are considerable. We previously found in the Health Professionals Follow-up Study (HPFS) that African-American men had an 80% higher prostate cancer risk than White men. With 21 additional years of follow-up and four-fold increase in cases, we undertook a contemporary analysis of racial differences in prostate cancer incidence and mortality in HPFS. METHODS: For 47,679 men, we estimated HRs and 95% confidence intervals (CI) for the association between race and risk of prostate cancer through 2016 using Cox proportional hazards regression. Multivariable models (mHR) were adjusted for lifestyle, diet, family history, and PSA screening collected on biennial questionnaires. RESULTS: 6,909 prostate cancer cases were diagnosed in White, 89 in African-American, and 90 in Asian-American men. African-Americans had higher prostate cancer incidence (mHR = 1.31; 95% CI, 1.06-1.62) and mortality (mHR = 1.67; 95% CI, 1.00-2.78), and lower PSA screening prevalence than White men. The excess risk was greater in the pre-PSA screening era (HR = 1.68; 95% CI, 1.14-2.48) than the PSA screening era (HR = 1.20; 95% CI, 0.93-1.56). Asian-Americans had lower prostate cancer risk (mHR = 0.74; 95% CI, 0.60-0.92), but similar risk of fatal disease compared with white men. CONCLUSIONS: Racial differences in prostate cancer incidence and mortality in HPFS are not fully explained by differences in lifestyle, diet, family history, or PSA screening. IMPACT: Additional research is necessary to address the disproportionately higher rates of prostate cancer in African-American men.

Diagnostic and Therapeutic Challenges of Vasculitis.

Systemic vasculitis can be a challenge to differentiate from other forms of vasculopathy. Because treatment for systemic vasculitis is disparate from that for other forms of vasculopathy, clinicians should strive for high diagnostic certainty. This review article aims to highlight the clinical, radiographic, and histologic clues to distinguish systemic vasculitis from mimics. Vasculitis should be considered in patients with preexisting conditions including autoimmune connective tissue diseases, multisystem manifestations, unexplained ischemic events, unusual radiographic findings, or signs of systemic inflammation. A multidisciplinary approach can be used among rheumatologists, vascular cardiologists, radiologists, and vascular interventionalists to raise diagnostic certainty in cases with large- and/or medium-vessel involvement. Recognition of cardiac manifestations, including myocarditis seen in forms of small-vessel vasculitis (eg, eosinophilic granulomatosis with polyangiitis) or coronary arteritis seen in forms of medium-vessel vasculitis (eg, polyarteritis nodosa and Kawasaki disease) is important owing to the associated mortality. Clinical phenotype, radiographic features, laboratory tests, and histology can help to differentiate vasculitis from noninflammatory vasculopathies and define the etiology of the vasculitis to help guide appropriate treatment. Various modalities of imaging can give clues to aid in diagnosis of vasculitis and can be considered in the context of physician preference and patient comorbidity. While conventional angiography can give important details regarding luminal anatomy and pressure gradients in medium- and large-vessel vasculitis, noninvasive imaging modalities such as computed tomographic angiography, magnetic resonance angiography, color Doppler ultrasound, and positron emission tomography/computed tomography are commonly used for both diagnosis and follow-up. Treatment for systemic vasculitis should be coordinated with an experienced rheumatologist.

Experimental validation of acoustic and thermal modeling in heterogeneous phantoms using the hybrid angular spectrum method.

PURPOSE: The aim was to quantitatively validate the hybrid angular spectrum (HAS) algorithm, a rapid wave propagation technique for heterogeneous media, with both pressure and temperature measurements. METHODS: Heterogeneous tissue-mimicking phantoms were used to evaluate the accuracy of the HAS acoustic modeling algorithm in predicting pressure and thermal patterns. Acoustic properties of the phantom components were measured by a through-transmission technique while thermal properties were measured with a commercial probe. Numerical models of each heterogeneous phantom were segmented from 3D MR images. Cylindrical phantoms 30-mm thick were placed in the pre-focal field of a focused ultrasound beam and 2D pressure measurements obtained with a scanning hydrophone. Peak pressure, full width at half maximum, and normalized root mean squared difference (RMSDn) between the measured and simulated patterns were compared. MR-guided sonications were performed on 150-mm phantoms to obtain MR temperature measurements. Using HAS-predicted power density patterns, temperature simulations were performed. Experimental and simulated temperature patterns were directly compared using peak and mean temperature plots, RMSDn metrics, and accuracy of heating localization. RESULTS: The average difference between simulated and hydrophone-measured peak pressures was 9.0% with an RMSDn of 11.4%. Comparison of the experimental MRI-derived and simulated temperature patterns showed RMSDn values of 10.2% and 11.1% and distance differences between the centers of thermal mass of 2.0 and 2.2 mm. CONCLUSIONS: These results show that the computationally rapid hybrid angular spectrum method can predict pressure and temperature patterns in heterogeneous models, including uncertainties in property values and other parameters, to within approximately 10%.

Practice Consolidation Among U.S. Radiation Oncologists Over Time.

PURPOSE: Health care practices across the United States have been consolidating in response to various market forces. The degree of practice consolidation varies widely across specialties but has not been well studied within radiation oncology. This study used Medicare data to characterize the extent of practice consolidation among radiation oncologists and to investigate associated market factors. METHODS AND MATERIALS: We utilized Medicare Provider Enrollment, Chain, and Ownership System data to assess the practice size and billing patterns of U.S. radiation oncologists in 2013 and again in 2017. Individual practices were categorized by the number of radiation oncologists practicing together: solo practices had 1 radiation oncologist, small practices 2 to 10, and large practices 11 or more. Market consolidation within each hospital referral region (HRR) across the country was quantified using the Herfindahl-Hirschman Index. Hospital and market level data were obtained for each HRR, and factors associated with the growth of radiation oncology practices over time were calculated via multivariable linear regression. RESULTS: Across the United States, radiation oncology practices appear to be highly consolidated. The mean Herfindahl-Hirschman Index was 0.4711 in 2013-indicating high levels of consolidation at baseline-and increased further to 0.4865 by 2017. Between 2013 and 2017, the number of practices with radiation oncologists in the United States decreased 3.8%, from 1679 to 1615, whereas the number of practicing radiation oncologists increased 9.4%, from 4948 to 5415. Over the study period, the number of solo practices fell 11% (from 708 in 2013 to 627 in 2017), whereas the number of large practices (those with 11 or more radiation oncologists) increased 50% (from 60 to 90). Large practices likewise grew to employ a greater share of all radiation oncologists (23.9%-32.4%) and accounted for a larger proportion of total Medicare billing (21%-26%). Two market factors were predictive for increases in the mean radiation oncology practice size. HRRs with greater hospital market consolidation and those with lower levels of baseline radiation oncology consolidation were more likely to experience higher levels of growth over the study period. CONCLUSIONS: Radiation oncologists are increasingly working in larger practices. By 2017, nearly one-third of all practicing radiation oncologists in the United States were employed by just the 90 largest practices. Radiation oncology, as a field, is highly concentrated, and represents one of the most consolidated specialties across the country. The implications of practice consolidation among radiation oncologists warrants further investigation.

Use of hemoglobin A1c to identify dysglycemia in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) leads to pancreatic endocrine dysfunction with progressive glycemic disturbance. Approximately 30%-50% of people with CF eventually develop CF-related diabetes (CFRD). Pre-CFRD states progress from indeterminant glycemia (INDET) to impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Screening guidelines recommend inconvenient annual 2-hour oral glucose tolerance tests (OGTTs), beginning at age 10 years. More efficient methods, such as hemoglobin A1C (HbA1c), have been evaluated, but only limited, relatively small studies have evaluated the association between HbA1c and pre-CFRD dysglycemic states. OBJECTIVE: To determine whether HbA1c is an appropriate screening tool for identifying patients with pre-CFRD dysglycemia to minimize the burden of annual OGTTs. METHODS: This retrospective review evaluated medical records data of all University of Massachusetts Memorial Health System CF patients with an HbA1c result within 90 days of an OGTT between 1997 and 2019. Exclusion criteria were uncertain CF diagnosis, other forms of diabetes, or incomplete OGTT. In total, 56 patients were included and categorized according to OGTT results (American Diabetes Association criteria): normal glucose tolerance, INDET, IFG, or IGT. Associations were evaluated between HbA1c and OGTT results and between HbA1c and pre-CFRD dysglycemic states. RESULTS: Mean HbA1c was not significantly different between patients with normal glucose tolerance and those in the INDET (p = 0.987), IFG (p = 0.690), and IGT (p = 0.874) groups. Analysis of variance confirmed the lack of association between HbA1c and glycemia, as mean HbA1c was not significantly different amongst the four categories (p = 0.250). CONCLUSION: There is increasing awareness of the impact of pre-CFRD states, including reduced pulmonary function and nutritional status. Unfortunately, our results do not support using HbA1c as a screening tool for pre-CFRD dysglycemia, specifically INDET, IFG, and IGT. Further studies are warranted to evaluate more efficient screening methods to reduce the burden of annual OGTTs.

The Purinome and the preBötzinger Complex - A Ménage of Unexplored Mechanisms That May Modulate/Shape the Hypoxic Ventilatory Response.

Exploration of purinergic signaling in brainstem homeostatic control processes is challenging the traditional view that the biphasic hypoxic ventilatory response, which comprises a rapid initial increase in breathing followed by a slower secondary depression, reflects the interaction between peripheral chemoreceptor-mediated excitation and central inhibition. While controversial, accumulating evidence supports that in addition to peripheral excitation, interactions between central excitatory and inhibitory purinergic mechanisms shape this key homeostatic reflex. The objective of this review is to present our working model of how purinergic signaling modulates the glutamatergic inspiratory synapse in the preBötzinger Complex (key site of inspiratory rhythm generation) to shape the hypoxic ventilatory response. It is based on the perspective that has emerged from decades of analysis of glutamatergic synapses in the hippocampus, where the actions of extracellular ATP are determined by a complex signaling system, the purinome. The purinome involves not only the actions of ATP and adenosine at P2 and P1 receptors, respectively, but diverse families of enzymes and transporters that collectively determine the rate of ATP degradation, adenosine accumulation and adenosine clearance. We summarize current knowledge of the roles played by these different purinergic elements in the hypoxic ventilatory response, often drawing on examples from other brain regions, and look ahead to many unanswered questions and remaining challenges.

Failure of a Best Practice Alert to Reduce Antibiotic Prescribing Rates for Acute Sinusitis Across an Integrated Health System in the Midwest.

BACKGROUND: Antimicrobial resistance is a growing concern, and in recent years, there has been increased interest in ambulatory antimicrobial stewardship. Acute rhinosinusitis (ARS) is one of the most common outpatient diagnoses that results in an antibiotic prescription. OBJECTIVE: To determine if a best practice alert (BPA) will affect the percentage of oral antibiotic prescriptions for adults with ARS. METHODS: A prospective, pre/post study was initiated to evaluate the percentage of oral antibiotic prescriptions for ARS in 117 primary care clinics in the Midwest. Included in the study results were 16,570 adults who had an office visit for ARS: 8,106 patients from December 1, 2015, to February 28, 2016, were in the pre-intervention group without an active BPA, and 8,464 patients from December 1, 2016, to February 28, 2017, were in the post-intervention group when the BPA was active. The primary outcome was the number of oral antibiotic prescriptions for ARS compared with the number of office visits for ARS in the pre- and postintervention groups. RESULTS: The percentage of oral antibiotics prescribed for the pre- and postintervention groups were 94.8% and 94.3%, respectively (P = 0.152). The BPA displayed for 7,780 visits, prompting discontinuation of an antibiotic for 10 (0.1%) visits in the postintervention group. CONCLUSIONS: This study suggests that, although an electronic alert may be attractive to facilitate antimicrobial stewardship, it may be ineffective. These results warrant alternative measures to facilitate ambulatory antimicrobial stewardship. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to declare. Study concept and design were contributed by Hansen, D. Leedahl, and N. Leedahl. Hansen and N. Leedahl took the lead in data collection, with assistance from Carson and D. Leedahl. Data interpretation was performed by all the authors. The manuscript was written by Hansen, along with the other authors, and revised by all the authors.

Comparison of NIRS, serum biomarkers, and muscle damage in a porcine balloon compression model of acute compartment syndrome.

BACKGROUND: Near-infrared spectroscopy (NIRS) has been shown to aid in the diagnosis of extremity acute compartment syndrome (ACS), offering continuous real-time capability to monitor perfusion in extremities. Porcine models of ACS have been developed to attempt to aid in the understanding of the development of ACS and provide better methods of diagnosing ACS. The objective of the present study was to assess and correlate NIRS, tibial intracompartmental pressure (TICP), tibial intracompartmental perfusion pressure (TIPP), serum markers of inflammation and muscle injury in a balloon compression model of ACS. METHODS: Six swine were used. Balloon catheters were inflated below the cranial tibial muscle. Systolic, diastolic, and mean arterial pressures; compartmental pressures; and oximetry were measured before, during, and after balloon inflation/deflation. Cranial tibial muscle was collected for muscle damage scoring. Serum creatine kinase, myoglobin, tumor necrosis factor α, IL-1ß, and IL-6 were measured. Data analysis included comparing differences in TICP, NIRS, and TIPP measurements as well as creatine kinase, myoglobin, tumor necrosis factor α, IL-1ß, and IL-6 levels between time points. Pearson correlations were calculated for muscle degeneration and edema and NIRS. RESULTS: Increases in TICP and decreases in TIPP were found. Near-infrared spectroscopy detected significant changes in tissue oxygenation at all the same time points. Myoglobin significantly increased from 45.7 ± 13.0 ng/mL (baseline) to 219.5 ± 57.3-ng/mL (balloon deflation) and continued to increase over the duration of the study. Creatine kinase significantly increased 2 hours after balloon deflation. Cranial tibial muscle degeneration, necrosis, and edema scores were higher in the test than the control legs. CONCLUSIONS: Near-infrared spectroscopy of the compartment provided a reliable, sensitive measure of both an increase and decrease in TICP and TIPP in this porcine balloon model of ACS. Creatine kinase and myoglobin significantly increased following balloon removal. Significant correlations between muscle degeneration, edema, hemorrhage, and NIRS were found.

Serine protease inhibition attenuates rIL-12-induced GZMA activity and proinflammatory events by modulating the Th2 profile from estrogen-treated mice.

Estrogen has potent immunomodulatory effects on proinflammatory responses, which can be mediated by serine proteases. We now demonstrate that estrogen increased the extracellular expression and IL-12-induced activity of a critical member of serine protease family Granzyme A, which has been shown to possess a novel inflammatory persona. The inhibition of serine protease activity with inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride significantly diminished enhanced production of proinflammatory interferon-γ, IL-1ß, IL-1α, and Granzyme A activity even in the presence of a Th1-inducing cytokine, IL-12 from splenocytes from in vivo estrogen-treated mice. Inhibition of serine protease activity selectively promoted secretion of Th2-specific IL-4, nuclear phosphorylated STAT6A, signal transducer and activator of transcription (STAT)6A translocation, and STAT6A DNA binding in IL-12-stimulated splenocytes from estrogen-treated mice. Inhibition with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride reversed the down-regulation of Th2 transcription factors, GATA3 and c-Maf in splenocytes from estrogen-exposed mice. Although serine protease inactivation enhanced the expression of Th2-polarizing factors, it did not reverse estrogen-modulated decrease of phosphorylated STAT5, a key factor in Th2 development. Collectively, data suggest that serine protease inactivity augments the skew toward a Th2-like profile while down-regulating IL-12-induced proinflammatory Th1 biomolecules upon in vivo estrogen exposure, which implies serine proteases as potential regulators of inflammation. Thus, these studies may provide a potential mechanism underlying the immunomodulatory effect of estrogen and insight into new therapeutic strategies for proinflammatory and female-predominant autoimmune diseases.

Analysis of a challenging subset of World Anti-Doping Agency-banned steroids and antiestrogens by LC-MS-MS.

A qualitative liquid chromatography-tandem mass spectrometry method for the analysis of 22 sporting federation-banned anabolic agents (or their metabolite markers) and anti-estrogens in urine that are refractory to analysis by gas chromatography-mass spectrometry is presented. In addition, a quantitative method built around World Anti-Doping Agency (WADA) guidelines for the confirmatory analysis of 19-norandrosterone, the primary metabolite of nandrolone with a WADA-specified minimum required performance limit of 1 ng/mL, is included. Hydrolysis of glucuronide conjugates, liquid-liquid extraction, no clean-up derivatization with Girard's Reagent P, and analysis by quadrupole-time-of-flight mass spectrometry provide sensitivity and selectivity well beyond that required by the WADA.