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9 ± 229.3 versus 929.1 ± 206.7 mg/dl; p less then 0.0001); (b) serum IgG subclasses (IgG1 = 351.4 ± 109.9 versus 464.3 ± 124.1, p less then 0.0001; IgG2 = 259.1 ± 140 versus 330.6 ± 124.9, p less then 0.0001; IgG3 = 50.2 ± 26.7 versus 55.6 ± 28.9 mg/dl, p less then 0.002); (c) annual rate of total infections (5.75 ± 3.87 versus 2.13 ± 1.74, p less then 0.0001), URTI (1.48 ± 3.15 versus 0.69 ± 1.27; p less then 0.005), LRTI (3.89 ± 3.52 versus 1.29 ± 1.37; p less then 0.0001) and hospitalizations (0.37 ± 0.77 versus 0.15 ± 0.5; p less then 0.0002). The improvement persisted after 2 years of IRT. No significant improvement in URTI annual rate was noted in UAD and in patients with bronchiectasis. In conclusion, low-dose IRT can improve clinical outcomes in UAD and IgGSD patients, providing a potential economical advantage over the standard IRT dose.The Epithelial Na+ Channel, ENaC, comprised of 3 subunits (αβγ, or sometimes δβγENaC), plays a critical role in regulating salt and fluid homeostasis in the body. It regulates fluid reabsorption into the blood stream from the kidney to control blood volume and pressure, fluid absorption in the lung to control alveolar fluid clearance at birth and maintenance of normal airway surface liquid throughout life, and fluid absorption in the distal colon and other epithelial tissues. Moreover, recent studies have also revealed a role for sodium movement via ENaC in nonepithelial cells/tissues, such as endothelial cells in blood vessels and neurons. Over the past 25 years, major advances have been made in our understanding of ENaC structure, function, regulation, and role in human disease. These include the recently solved three-dimensional structure of ENaC, ENaC function in various tissues, and mutations in ENaC that cause a hereditary form of hypertension (Liddle syndrome), salt-wasting hypotension (PHA1), or polymorphism in ENaC that contributes to other diseases (such as cystic fibrosis). Moreover, great strides have been made in deciphering the regulation of ENaC by hormones (e.g., the mineralocorticoid aldosterone, glucocorticoids, vasopressin), ions (e.g., Na+ ), proteins (e.g., the ubiquitin-protein ligase NEDD4-2, the kinases SGK1, AKT, AMPK, WNKs & mTORC2, and proteases), and posttranslational modifications [e.g., (de)ubiquitylation, glycosylation, phosphorylation, acetylation, palmitoylation]. Characterization of ENaC structure, function, regulation, and role in human disease, including using animal models, are described in this article, with a special emphasis on recent advances in the field. © 2021 American Physiological Society. Compr Physiol 111-29, 2021.The development and maintenance of differentiation is vital to the function of mature cells. Terminal differentiation is achieved by locking in the expression of genes essential for the function of those cells. Gene expression and its memory through generations of cell division is controlled by transcription factors and a host of epigenetic marks. In type 2 diabetes, β cells have altered gene expression compared to controls, accompanied by altered chromatin marks. Mutations, diet, and environment can all disrupt the implementation and preservation of the distinctive β-cell transcriptional signature. Understanding of the full complement of genomic control in β cells is still nascent. This article describes the known effects of histone marks and variants, DNA methylation, how they are regulated in the β cell, and how they affect cell-fate specification, maintenance, and lineage propagation. © 2021 American Physiological Society. Compr Physiol 111-18, 2021.Successful pregnancy and reproduction are dependent on adequate uterine blood flow, placental perfusion, and vascular responsivity to fetal demands. The ability to support pregnancy centers on systemic adaptation and endometrial preparation through decidualization, embryonic implantation, trophoblast invasion, arterial/arteriolar reactivity, and vascular remodeling. These adaptations occur through responsiveness to endocrine signaling and local uteroplacental mediators. The purpose of this article is to highlight the current knowledge associated with vascular remodeling and responsivity during uterine preparation for and during pregnancy. We focus on maternal cardiovascular systemic and uterine modifications, endometrial decidualization, implantation and invasion, uterine and spiral artery remodeling, local uterine regulatory mechanisms, placentation, and pathological consequences of vascular dysfunction during pregnancy. © 2021 American Physiological Society. Compr Physiol 111-23, 2021.Thyroid hormone is essential for brain development and brain function in the adult. During development, thyroid hormone acts in a spatial and temporal-specific manner to regulate the expression of genes essential for normal neural cell differentiation, migration, and myelination. In the adult brain, thyroid hormone is important for maintaining normal brain function. Thyroid hormone excess, hyperthyroidism, and thyroid hormone deficiency, hypothyroidism, are associated with disordered brain function, including depression, memory loss, impaired cognitive function, irritability, and anxiety. Adequate thyroid hormone levels are required for normal brain function. Thyroid hormone acts through a cascade of signaling components activation and inactivation by deiodinase enzymes, thyroid hormone membrane transporters, and nuclear thyroid hormone receptors. Additionally, the hypothalamic-pituitary-thyroid axis, with negative feedback of thyroid hormone on thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) secretion, regulates serum thyroid hormone levels in a narrow range. Animal and human studies have shown both systemic and local reduction in thyroid hormone availability in neurologic disease and after brain trauma. Treatment with thyroid hormone and selective thyroid hormone analogs has resulted in a reduction in injury and improved recovery. This article will describe the thyroid hormone signal transduction pathway in the brain and the role of thyroid hormone in the aging brain, neurologic diseases, and the protective role when administered after traumatic brain injury. © 2021 American Physiological Society. Compr Physiol 111-21, 2021.

Despite the biopsychosocial underpinnings of chronic noncancer pain, relatively little is known about the contribution of psychosocial factors to chronic cancer pain. The authors aimed to characterize associations between biopsychosocial factors and pain and opioid use among individuals with chronic pain and cancer.

The authors conducted a retrospective, cross-sectional study of 700 patients with chronic pain and cancer seeking treatment at an academic tertiary pain clinic. Patients completed demographic questionnaires and validated psychosocial and pain measures. Multivariable, hierarchical linear and logistic regressions assessed the relative contributions of biopsychosocial factors to the primary dependent variables of pain severity, pain interference, and opioid use.

Participants were 62% female and 66% White with a mean age of 59 ± 15 years, and 55% held a college degree or higher. Older age, African American or "other" race, sleep disturbance, and pain catastrophizing were significantly associatedrse pain and use more opioids. Also, individuals who have a bad prognosis for their cancer are more likely to be using opioid pain medications. Although race and cancer are related to chronic pain in patients, psychological well-being is also strongly related to this same pain.

Feeling depressed, worrying about pain, and bad sleep are related to higher pain symptoms in individuals with chronic pain and cancer. Specifically, those who struggle to sleep have worse pain and use more opioids. Also, individuals who have a bad prognosis for their cancer are more likely to be using opioid pain medications. GSK3368715 Although race and cancer are related to chronic pain in patients, psychological well-being is also strongly related to this same pain.

Medical financial burden includes material, behavioral, and psychological hardship and has been underinvestigated among adult survivors of childhood cancer.

A survey from 698 survivors and 210 siblings from the Childhood Cancer Survivor Study was analyzed. The intensity of financial hardship was estimated across 3 domains 1) material, including conditions that arise from medical expenses; 2) behavioral, including coping behaviors to manage medical expenses; and 3) psychological hardship resulting from worries about medical expenses and insurance, as measured by the number of instances of each type of financial hardship (0, 1-2, and ≥3 instances). Multivariable logistic regressions were conducted to examine the clinical and sociodemographic predictors of experiencing financial hardship (0-2 vs ≥3 instances).

The intensity of financial hardship did not significantly differ between survivors and siblings. Survivors reported more instances of material hardship than siblings (1-2 instances 27.2% of survivors vs 22.6% of siblings; ≥3 instances 15.9% of survivors vs 11.4% siblings; overall P = .03). In multivariable regressions, insurance was protective against all domains of financial hardship (behavioral odds ratio [OR], 0.12; 95% confidence interval [CI], 0.06-0.22; material OR, 0.37; 95% CI, 0.19-0.71; psychological OR, 0.10; 95% CI, 0.05-0.21). Survivors who were older at diagnosis, female, and with chronic health conditions generally had higher levels of hardship. Brain radiation and alkylating agents were associated with higher levels of hardship.

Material, behavioral, and psychological financial burden among survivors of childhood cancer is common.

Material, behavioral, and psychological financial burden among survivors of childhood cancer is common.Tensions have always existed between innovation and standardization in family medicine, due to the need for rapid responses to changing health issues while ensuring proficiency. For innovation in residency training to be successful, standardization of milestones and frameworks as well as outcomes of residency education are needed and must be clear and rely on measurable effectiveness standards. Standardization without innovation can cause educational stasis, failure to adapt to change, and/or lack of evidence-guided education. Here, we examine possible options for creating the right balance, review what the evidence shows, and make recommendations for the future, including (1) adoption and study of clear, actionable entrustable professional activities (EPAs) as educational standards for residency graduates; (2) core faculty be required to engage in faculty development that includes competency-based medical education using the EPA framework, advanced curriculum development, program evaluation, objective learner assessments aligned with individualized learning plans, and increased opportunities for program directors to gain additional training in the educational sciences; (3) 30% of protected time for core faculty to design, administer, and assess the educational program; (4) required participation in educational collaboratives that rigorously study innovation; (5) required scholarly work that supports program development both clinically and educationally. Taken together, these recommendations represent a vital interplay between cutting-edge innovation and thoughtful standardization using collaboration to graduate residents ready to provide optimal care in their communities, both now and into the future. All stakeholders in the discipline must undertake strategic and deliberate planning designed to adjust direct and indirect costs of residency training to support these recommendations.