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Several qualitative features of the ultrastructure of pressure overload and thyrotoxic myocardium are unique markers of the type and quantity of increased work the heart has been required to perform. Furthermore, they are reminiscent of features of normally growing myocytes, implying that the changes in the hypertrophied cell are the consequence of normally present capacities for adaptation to a demand for increased myocardial work. Thyrotoxic myocardium has two features which distinguish it from normal and pressure overloaded hearts: the mitochondria are large and have a peculiar fragile or lacey appearance. Many myocytes show considerable disorganization of sarcomeric myofilaments. Pressure overloaded hearts have smaller and more numerous mitochondria than the normal myocyte. Their sarcomeres have thicker Z bands than controls. Double intercalated discs are also a feature of these myocytes. Several features of hypertrophied myocytes are seen in both types of hypertrophy: RER and ribosomes on the external nuclear membrane. There are polyribosomes aligned along the long axes of thick filaments, presumably involved in myosin synthesis or transformation within the cell. There are areas of sarcomerogenesis both under the sarcolemma and within the cell at the intercalated disc. These are characterized by fragments of myofilaments, polyribosomes and rough endoplasmic reticulum. Quantitatively, myocyte composition is transiently disturbed but, like that of normally growing hearts, returns to control values as the adaptation to stress is negotiated. [ABSTRACT FROM PUBLISHER]

Cardiovascular disease, which kills more US women than all cancers combined, may pose an even greater risk for women than for men. For example, the risk factors, testing modalities, presenting symptoms and the therapeutic choices made for women with coronary artery disease are significantly different from those for men. Low levels of high-density lipoprotein cholesterol (HDL-C), <35 mg/dL in men and <45 mg/dL in women, is associated with a greater risk of coronary artery disease and more progression of angiographically demonstrated disease in women, while increasing HDL-C has a more cardioprotective effect in the female than in the male population. The total cholesterol-to-HDL-C ratio is also more predictive of coronary artery disease in women than in men. Because average HDL-C levels in women are approximately 10 mg/dL higher than in men, target HDL-C should be higher (>45 mg/dL) in women. This is not yet reflected in clinical guidelines. Diabetes is particularly hazardous in women, and low HDL-C levels constitute a disproportionate risk for coronary artery disease in diabetic women compared with diabetic men. Regrettably, although lipid-lowering drugs have been shown to be effective in women, they are more rarely prescribed for women than for men. [ABSTRACT FROM AUTHOR]

Background: Biparametric MRI (bpMRI) has an important role in the diagnosis of prostate cancer (PCa), by reducing the cost and duration of the procedure and adverse reactions. We assess the additional benefit of the ADC map in detecting prostate cancer (PCa). Additionally, we examine whether the ADC value correlates with the presence of clinically significant tumors (csPCa)., Methods: 104 peripheral lesions classified as PI-RADS v2.1 score 3 or 3+1 at the mpMRI underwent transperineal MRI/US fusion-guided targeted biopsy., Results: The lesions were classified as PI-RADS 3 or 3+1; at histopathology, 30 were adenocarcinomas, 21 of which were classified as csPCa. The ADC threshold that maximized the Youden index in order to predict the presence of a tumor was 1103 (95% CI (990, 1243)), with a sensitivity of 0.8 and a specificity of 0.59; both values were greater than those found using the contrast medium, which were 0.5 and 0.54, respectively. Similar results were also found with csPCa, where the optimal ADC threshold was 1096 (95% CI (988, 1096)), with a sensitivity of 0.86 and specificity of 0.59, compared to 0.49 and 0.59 observed in the mpMRI., Conclusions: Our study confirms the possible use of a quantitative parameter (ADC value) in the risk stratification of csPCa, by reducing the number of biopsies and, therefore, the number of unwarranted diagnoses of PCa and the risk of overtreatment.

Recreational sedentary screen time (rSST) is the most prevalent sedentary behavior for adults outside of work, school, and sleep, and is strongly linked to poor health. StandUPTV is a mHealth trial that uses the Multiphase Optimization Strategy (MOST) framework to develop and evaluate the efficacy of three theory-based strategies for reducing rSST among adults. This paper describes the preparation and optimization phases of StandUPTV within the MOST framework. We identified three candidate components based on previous literature: (a) rSST electronic lockout (LOCKOUT), which restricts rSST through electronic means; (b) adaptive prompts (TEXT), which provides adaptive prompts based on rSST behaviors; and (c) earning rSST through increased moderate-vigorous physical activity (MVPA) participation (EARN). We also describe the mHealth iterative design process and the selection of an optimization objective. Finally, we describe the protocol of the optimization randomized controlled trial using a 23 factorial experimental design. We will enroll 240 individuals aged 23-64 y who engage in >3 h/day of rSST. All participants will receive a target to reduce rSST by 50% and be randomized to one of 8 combinations representing all components and component levels: LOCKOUT (yes vs. no), TEXT (yes vs. no), and EARN (yes vs. no). Results will support the selection of the components for the intervention package that meet the optimization objective and are acceptable to participants. The optimized intervention will be tested in a future evaluation randomized trial to examine reductions in rSST on health outcomes among adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Biological sex and gender-based constructs contribute significantly to the diversity of disease outcomes and treatment responses across the life course. To promote research considering sex and gender, the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) launched the Specialized Centers of Research Excellence (SCORE) on sex differences program. The Career Enhancement Core (CEC) of the Johns Hopkins SCORE on Sex and Age Differences in Immunity to Influenza (SADII) partnered with the Foundation for Gender-Specific Medicine, which matched NIH funding to support seed grants. Over 3 years we awarded 12 (10 were women faculty) seed grants to early-stage investigators. One year after the award, the seed grant awardees highlighted their progress, including publications, grant applications, and abstracts. All awardees noted challenges with their progress related to the COVID-19 pandemic and supply chain delays and shared suggestions for improving the programming of the CEC. They also highlighted the multiple ways the awards had helped them gain pilot data toward larger grants, build collaborative relationships, and present at the annual SCORE symposium. We describe a model and evidence supporting a private-academic collaboration to support the careers of early-stage investigators conducting research related to sex and gender.

Friedreich ataxia (FRDA) is caused by the reduced expression of the mitochondrial protein frataxin (FXN) due to an intronic GAA trinucleotide repeat expansion in the FXN gene. Although FRDA has no cure and few treatment options, there is research dedicated to finding an agent that can curb disease progression and address symptoms as neurobehavioral deficits, muscle endurance, and heart contractile dysfunctions. Because oxidative stress and mitochondrial dysfunctions are implicated in FRDA, we demonstrated the systemic delivery of catalysts activity of gold cluster superstructures (Au 8 -pXs) to improve cell response to mitochondrial reactive oxygen species and thereby alleviate FRDA-related pathology in mesenchymal stem cells from patients with FRDA. We also found that systemic injection of Au 8 -pXs ameliorated motor function and cardiac contractility of YG8sR mouse model that recapitulates the FRDA phenotype. These effects were associated to long-term improvement of mitochondrial functions and antioxidant cell responses. We related these events to an increased expression of frataxin, which was sustained by reduced autophagy. Overall, these results encourage further optimization of Au 8 -pXs in experimental clinical strategies for the treatment of FRDA., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Muscular dystrophies and inflammatory myopathies are heterogeneous muscular disorders characterized by progressive muscle weakness and mass loss. Despite the high variability of etiology, inflammation and involvement of both innate and adaptive immune response are shared features. The best understood immune mechanisms involved in these pathologies include complement cascade activation, auto-antibodies directed against muscular proteins or de-novo expressed antigens in myofibers, MHC-I overexpression in myofibers, and lymphocytes-mediated cytotoxicity. Intravenous immunoglobulins (IVIGs) administration could represent a suitable immunomodulator with this respect. Here we focus on mechanisms of action of immunoglobulins in muscular dystrophies and inflammatory myopathies highlighting results of IVIGs from pre-clinical and case reports evidences., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Farini, Villa, Tripodi, Legato and Torrente.)

Background: Behavioral weight loss interventions promote clinically significant weight loss over 12 months, but weight regain remains problematic and a substantial proportion of participants do not achieve long-term weight loss maintenance. Novel methods are needed that instill habit strength for sustaining weight control behaviors long term. Virtual reality (VR) has the potential to provide opportunities within behavioral treatment for patients to practice desired weight control behaviors in the frequency and magnitude necessary to build durable habits. A pilot randomized trial was done to test the feasibility integrating virtual reality (VR) into standard behavioral weight loss treatment., Methods: Participants were 15 adults (43 years; 46.7% Hispanic), with overweight or obesity who were randomly assigned to a 4-week Standard Behavioral Weight Loss plus Non-Weight-Related VR app (i.e., Control Group) or Standard Behavioral Weight Loss plus Weight-Related VR app (i.e., Intervention Group). The Intervention's VR tool was designed to enable practice of behavioral skills taught in weekly group meetings, including managing social and home environmental cues for eating and activity., Results: Participants were recruited over 3 months, and retention at the final assessment visit was high (86.6%). The VR footage and resulting app were rated as highly realistic (6.7 on a 10-point scale), and the VR program overall was rated as highly satisfactory (3.6 on a 4-point scale). Adverse effects of eye strain and motion sickness were minimal (~ 2 on a 7-point scale). As expected, the intervention and control groups both lost weight and unadjusted means (SD) averaged 3.4% (2.7) and 2.3% (3.6), respectively, over the 4 weeks. Overall, participants reported preferring a VR approach above traditional weight loss programs (rating of 5 on a 7-point scale)., Conclusions: Future research is needed to develop and test the feasibility of using VR for other weight control skills with a larger sample size and longer evaluation period to determine if VR can improve standard behavioral weight loss outcomes by intensifying practice opportunities and building habit strength for weight loss maintenance., Trial Registration: NCT04534088 ; date of registration: 09/01/2020, retrospectively registered.

In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-β and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance.

Duchenne muscular dystrophy (DMD) is a debilitating fatal X-linked muscle disorder. Recent findings indicate that IGFs play a central role in skeletal muscle regeneration and development. Among IGFs, insulinlike growth factor 2 (IGF2) is a key regulator of cell growth, survival, migration and differentiation. The type 2 IGF receptor (IGF2R) modulates circulating and tissue levels of IGF2 by targeting it to lysosomes for degradation. We found that IGF2R and the store-operated Ca 2+ channel CD20 share a common hydrophobic binding motif that stabilizes their association. Silencing CD20 decreased myoblast differentiation, whereas blockade of IGF2R increased proliferation and differentiation in myoblasts via the calmodulin/calcineurin/NFAT pathway. Remarkably, anti-IGF2R induced CD20 phosphorylation, leading to the activation of sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) and removal of intracellular Ca 2+ . Interestingly, we found that IGF2R expression was increased in dystrophic skeletal muscle of human DMD patients and mdx mice. Blockade of IGF2R by neutralizing antibodies stimulated muscle regeneration, induced force recovery and normalized capillary architecture in dystrophic mdx mice representing an encouraging starting point for the development of new biological therapies for DMD., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Internet-based weight loss programs can be effective in promoting weight loss and are less-intensive than traditional face-to-face approaches, which may provide more flexibility for postpartum, low-income women to engage in such programs. Few studies have examined patterns of engagement in internet-based programs for this population. This article used data from the internet-based Fit Moms/ Mamás Activas intervention, a 12-month cluster randomized controlled trial that was effective in promoting postpartum weight loss among low-income, predominantly Hispanic women. The overall objectives of this study were to (1) characterize patterns of engagement with the Fit Moms/ Mamás Activas website among intervention participants and (2) explore associations between engagement and 12-month weight loss outcomes among study completers (87.4%). A number of engagement variables were calculated for each participant, including website logins; time spent on the website; number of posts to the "Discussion Forum;" number of days tracking weight, diet, and physical activity; number of page visits to various website components; and number of in-person visits attended. The average number of logins was 70.74 (approximately once weekly), and average total time spent on the website was 185.35 minutes (approximately 3 hours) over 1 year. Self-monitoring ("Web Diary") and social support ("Discussion Forum") were the most frequently visited components of the website, and more frequent engagement with these components, as well as greater attendance at in-person group sessions, predicted greater percent weight loss at 12 months. Interventions highlighting these features may be particularly effective for weight loss in this population.

Important sex-specific differences in the normal anatomy and physiology of the myocardium exist. It is essential to consider these differences in assessing the meaning of cardiac symptoms in men and women and in constructing strategies for the prevention and treatment of cardiovascular illness.

MMP activity with disruption of structural collagen has been implicated in the pathophysiology of dilated cardiomyopathy. To examine the role of this enzyme in cardiac function, a transgenic mouse was created that constitutively expressed human collagenase (MMP-1) in the heart. At 6 months of age, these animals demonstrated compensatory myocyte hypertrophy with an increase in the cardiac collagen concentration due to elevated transcription of type III collagen. Chronic myocardial expression of MMP-1 produced loss of cardiac interstitial collagen coincident with a marked deterioration of systolic and diastolic function at 12 months of age. This is the first animal model demonstrating that direct disruption of the extracellular matrix in the heart reproduces the changes observed in the progression of human heart failure.

Recent research suggests that the maintenance of emotional well-being is critical to cardiovascular health. People who feel lonely, depressed, and isolated have been found to be significantly more likely to suffer illnesses and to die prematurely of cardiovascular diseases than those who have adequate social support. Consequently, the development of appropriate interventions to improve the emotional health of people with certain psychosocial risk factors has become an important research goal. It is anticipated that such interventions will increase the life expectancy of people at risk and that it may also save millions of dollars in medical care costs. First, however, researchers in this field must identify specific emotional risk factors and must agree upon a working definition of "good emotional health." Such explicit definitions, as well as additional data, are essential to educating physicians and insurers so that consideration of emotional health can be integrated into basic medical care.