Notch3/Hes5 Induces Vascular Dysfunction in Hypoxia-Induced Pulmonary Hypertension Through ER Stress and Redox-Sensitive Pathways.

BACKGROUND: Notch3 (neurogenic locus notch homolog protein 3) is implicated in vascular diseases, including pulmonary hypertension (PH)/pulmonary arterial hypertension. However, molecular mechanisms remain elusive. We hypothesized increased Notch3 activation induces oxidative and endoplasmic reticulum (ER) stress and downstream redox signaling, associated with procontractile pulmonary artery state, pulmonary vascular dysfunction, and PH development. METHODS: Studies were performed in TgNotch3R169C mice (harboring gain-of-function [GOF] Notch3 mutation) exposed to chronic hypoxia to induce PH, and examined by hemodynamics. Molecular and cellular studies were performed in pulmonary artery smooth muscle cells from pulmonary arterial hypertension patients and in mouse lung. Notch3-regulated genes/proteins, ER stress, ROCK (Rho-associated kinase) expression/activity, Ca2+ transients and generation of reactive oxygen species, and nitric oxide were measured. Pulmonary vascular reactivity was assessed in the presence of fasudil (ROCK inhibitor) and 4-phenylbutyric acid (ER stress inhibitor). RESULTS: Hypoxia induced a more severe PH phenotype in TgNotch3R169C mice versus controls. TgNotch3R169C mice exhibited enhanced Notch3 activation and expression of Notch3 targets Hes Family BHLH Transcription Factor 5 (Hes5), with increased vascular contraction and impaired vasorelaxation that improved with fasudil/4-phenylbutyric acid. Notch3 mutation was associated with increased pulmonary vessel Ca2+ transients, ROCK activation, ER stress, and increased reactive oxygen species generation, with reduced NO generation and blunted sGC (soluble guanylyl cyclase)/cGMP signaling. These effects were ameliorated by N-acetylcysteine. pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension recapitulated Notch3/Hes5 signaling, ER stress and redox changes observed in PH mice. CONCLUSIONS: Notch3 GOF amplifies vascular dysfunction in hypoxic PH. This involves oxidative and ER stress, and ROCK. We highlight a novel role for Notch3/Hes5-redox signaling and important interplay between ER and oxidative stress in PH.

Exploring Well-Being: Resilience, Stress, and Self-Care in Occupational Therapy Practitioners and Students.

Burnout is increasingly documented in occupational therapy (OT); however, practitioner and student well-being have not been examined to date. The research aim was to explore the relationship between well-being, resilience, stress, and self-care in OT. For this purpose, a cross-sectional survey of practitioners and students was done, including a background survey, World Health Organization-5 Well-Being Index (WHO-5), Brief Resilience Scale (BRS), Perceived Stress Scale (PSS), and Mindful Self-Care Scale (MSCS). Open-ended questions and Visual Analog Scales were used to gather satisfaction and service access. Practitioners (n = 235) and students (n = 200) reported well-being "less than half of the time" on the WHO-5, "moderate" stress on the PSS, and "normal" resilience on the BRS. The BRS, PSS, and MSCS explained a significant proportion of variance on the WHO-5 for practitioners and students. Most participants used at least one self-care strategy and desired additional organizational services. The findings of elevated stress and decreased well-being underscore the importance of reimagining wellness initiatives in OT.

Waning of SARS-CoV-2 Seropositivity among Healthy Young Adults over Seven Months.

BACKGROUND: We conducted a longitudinal study to estimate immunity produced in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among university students over seven months. METHODS: All participants were attending a public university and resided in Pitt County, North Carolina. University students enrolled weekly for 10 weeks between 26 August 2020 and 28 October 2020, resulting in 136 young adults completing at least one study visit by 17 November 2020. Enrolled students completed an online survey and nasal swab collection at two-week intervals and monthly blood collection between 26 August 2020 and 31 March 2021. RESULTS: Amongst 695 serum samples tested during follow-up, the prevalence of a positive result for anti-nucleocapsid antibodies (N-IgG) was 9.78%. In 22 students with more than one positive N-IgG serum sample, 68.1% of the group lost persistence of N-IgG below the positive threshold over 140 days. Anti-spike IgG antibodies were significantly higher among 11 vaccinated compared to 10 unvaccinated. CONCLUSIONS: In healthy young adults, N-IgG wanes below the detectable threshold within five months. S-IgG titer remained consistently elevated months after infection, and significantly increased after vaccination.

Human papillomavirus vaccine series follow-through: comparison of four clinics in an academic medical center.

OBJECTIVE: The Centers for Disease Control & Prevention (CDC) recommends that the human papillomavirus (HPV) vaccine series be initiated at ages 11-12 years, but many children never follow-through with the series. By examining differences in clinic-specific vaccine series follow-through rates across four clinics, we aimed to identify best practices related to communication around the vaccine and pathways to follow-through. METHODS: We used the electronic medical record (EMR) to retrospectively analyze HPV vaccine follow-through at four clinic settings. We limited the sample to children ages 11-17 who received a dose of the vaccine series at any of the clinics between January 2015 and June 2018. The primary outcome was follow-through of the HPV vaccine series within 18 months of initiation. RESULTS: A total of 3,813 patients were included in this study, 29% of which followed through with the HPV vaccine series. There was significant variability of vaccine follow-through among the clinics (p<0.001), with the Med/Peds clinic having the highest rate of follow-through (32%). After adjusting for confounding variables, multivariable analysis found that Med/Peds and Family Medicine had higher odds of HPV vaccine series follow-through than the Pediatrics clinic. CONCLUSIONS: We found that the likelihood of vaccine series follow-through was highest when the series was started in the Med/Peds and Family Medicine clinics, compared to Pediatrics and Adolescent Medicine. These results suggest that further qualitative research is needed to understand what communication strategies are most effective at facilitating HPV vaccine uptake among adolescents, and how the most effective strategies can be shared among clinics.

Concordance of Data on Children's Unmet Health Care Needs Between 2 National Surveys.

OBJECTIVE: We used public data from 2 national surveys to determine how survey mode and questionnaire wording potentially impact estimated prevalence and predictors of children's unmet health care needs. METHODS: Data from 2016-2017 were obtained for the National Health Interview Survey (NHIS), where interviewers ask caregivers about each type of unmet health care need in person, and the National Survey of Children's Health (NSCH), a self-administered questionnaire asking a general question about any unmet health care needs, with subparts about specific types of unmet needs. Weighted proportions and multivariable logistic regression were used to analyze each data set. RESULTS: The weighted proportion of any unmet health care needs was significantly higher in the NHIS (7.5%; 95% confidence interval [CI], 7.0-8.1; N = 17 723) than in the NSCH (3.3%; 95% CI, 2.9-3.7; N = 65 766). When analyzing specific unmet needs, unmet need for dental care was significantly higher according to the NHIS (4.2% vs 1.9% in the NSCH), as was unmet need for vision care (1.7% vs 0.8%). Conversely, estimates of unmet need for medical care were comparable between the surveys (1.4% and 1.0%). On multivariable analysis, predictors of unmet health care needs, such as being uninsured, had effect sizes of similar magnitude in both surveys. CONCLUSION: The NHIS design, asking about each type of unmet need in person, may have been more conducive to identifying the full range of unmet health care needs among children. However, our results did not indicate that this was a source of bias in multivariable regression analysis.

"Big" Sounds Bigger in More Widely Spoken Languages.

Larger communities face more communication barriers. We propose that languages spoken by larger communities adapt and overcome these greater barriers by increasing their reliance on sound symbolism, as sound symbolism can facilitate communication. To test whether widely spoken languages are more sound symbolic, participants listened to recordings of the words big and small in widely spoken and less common languages and guessed their meanings. Accuracy was higher for words from widely spoken languages providing evidence that widely spoken languages harbor more sound symbolism. Preliminary results also suggest that widely spoken languages rely on different sound symbolic patterns than less common languages. Community size can thus shape linguistic forms and influence the tools that languages use to facilitate communication.

Does a Medical Home Buffer the Association between Child Poverty and Poor Health?

OBJECTIVE: To evaluate effects of the medical home on health status and health care use among children living in poverty compared with children not living in poverty. METHODS: Data from the 2016-2017 National Survey of Children's Health were used to examine the associations of having a medical home with health outcomes of interest, among children living in poverty and among children not living in poverty. RESULTS: Among 69,039 children ages 0-17 years, children living in poverty had lower medical home access (31%) compared with those not living in poverty (50%). Medical home access was favorably associated with health outcomes, but the strength of these association did not vary according to poverty status. CONCLUSIONS: Notwithstanding the efficacy of the medical home at promoting child health, children living in poverty did not have greater health benefits associated with medical home access compared with children not living in poverty.

Outpatient Follow-up Care After Hospital Discharge of Children With Complex Chronic Conditions at a Rural Tertiary Care Hospital.

OBJECTIVE: To determine factors associated with completion of recommended outpatient follow-up visits in children with complex chronic conditions (CCCs) following hospital discharge. METHODS: We retrospectively identified children aged 1 to 17 years diagnosed with a CCC who were discharged from our rural tertiary care children's hospital between 2017 and 2018 with a diagnosis meeting published CCC criteria. Patients discharged from the neonatal intensive care unit and patients enrolled in a care coordination program for technology-dependent children were excluded. RESULTS: Of 113 eligible patients, 77 (68%) had outpatient follow-up consistent with discharge instructions. Intensive care unit (ICU) admission (P = .020) and prolonged length of stay (P = .004) were associated with decreased likelihood of completing recommended follow-up. CONCLUSIONS: Among children with CCCs who were not already enrolled in a care coordination program, ICU admission was associated with increased risk of not completing recommended outpatient follow-up. This population could be targeted for expanded care coordination efforts.

Which Children Use School-Based Health Services as a Primary Source of Care?

BACKGROUND: School-based health centers (SBHCs) offer primary and preventive health care for children and adolescents. Using nationally representative data, we aimed to examine which child and family characteristics are associated with using school-based health care providers as the primary source of health care, and whether care received from these providers met the criteria for a medical home. METHODS: Using data from the 2016-2018 National Survey of Children's Health (NSCH), we analyzed children's usual source of care (school-based provider, doctor's office or clinic, other location, or none), and whether they received care meeting medical home criteria. RESULTS: Based on a sample of 64,710 children, 0.5% identified school-based providers as their primary source of health care. Children who were older, uninsured, or living in the Northeast were significantly more likely to report school-based providers as their usual source of care. Children whose usual source of care was a school-based provider were less likely to receive care meeting medical home criteria than children who usually received care at a doctor's office. CONCLUSIONS: While SBHCs improve access to care, our findings indicate potential challenges with establishing a medical home for children who usually receive health care from a school-based provider.

Dissemination of Quality Improvement Project Results After Local Presentation.

Among quality improvement (QI) projects submitted for local presentation, the authors sought to understand how often project results were eventually disseminated through national/international presentation or peer-reviewed journal publication. Projects submitted for local presentation from 2016 to 2019 were linked to resulting publications or national/international conference presentations. Submitting authors were surveyed about their intentions, experience, and satisfaction with the process of disseminating their project results. Of 83 projects, 5 were published and another 10 were presented nationally/internationally. External dissemination was more likely with fewer project cycles and cost-focused outcomes. Survey responses indicated that most project leaders wanted to see their results published but held mixed opinions about resources and encouragement available to reach this goal. Few QI projects submitted for local presentation resulted in wider dissemination of project results. Sharing results and lessons learned beyond the local institution requires long-term planning, education, and support beginning early in the QI process.

Peripheral arteriopathy caused by Notch3 gain-of-function mutation involves ER and oxidative stress and blunting of NO/sGC/cGMP pathway.

Notch3 mutations cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), which predisposes to stroke and dementia. CADASIL is characterised by vascular dysfunction and granular osmiophilic material (GOM) accumulation in cerebral small vessels. Systemic vessels may also be impacted by Notch3 mutations. However vascular characteristics and pathophysiological processes remain elusive. We investigated mechanisms underlying the peripheral vasculopathy mediated by CADASIL-causing Notch3 gain-of-function mutation. We studied: (i) small arteries and vascular smooth muscle cells (VSMCs) from TgNotch3R169C mice (CADASIL model), (ii) VSMCs from peripheral arteries from CADASIL patients, and (iii) post-mortem brains from CADASIL individuals. TgNotch3R169C vessels exhibited GOM deposits, increased vasoreactivity and impaired vasorelaxation. Hypercontractile responses were normalised by fasudil (Rho kinase inhibitor) and 4-phenylbutyrate (4-PBA; endoplasmic-reticulum (ER) stress inhibitor). Ca2+ transients and Ca2+ channel expression were increased in CADASIL VSMCs, with increased expression of Rho guanine nucleotide-exchange factors (GEFs) and ER stress proteins. Vasorelaxation mechanisms were impaired in CADASIL, evidenced by decreased endothelial nitric oxide synthase (eNOS) phosphorylation and reduced cyclic guanosine 3',5'-monophosphate (cGMP) levels, with associated increased soluble guanylate cyclase (sGC) oxidation, decreased sGC activity and reduced levels of the vasodilator hydrogen peroxide (H2O2). In VSMCs from CADASIL patients, sGC oxidation was increased and cGMP levels decreased, effects normalised by fasudil and 4-PBA. Cerebral vessels in CADASIL patients exhibited significant oxidative damage. In conclusion, peripheral vascular dysfunction in CADASIL is associated with altered Ca2+ homoeostasis, oxidative stress and blunted eNOS/sGC/cGMP signaling, processes involving Rho kinase and ER stress. We identify novel pathways underlying the peripheral arteriopathy induced by Notch3 gain-of-function mutation, phenomena that may also be important in cerebral vessels.

Bone remodeling and cyclical loading in maxillae of New Zealand white rabbits (Oryctolagus cuniculus).

Mammalian feeding behaviors are altered when mechanically challenging (e.g., tough, stiff) foods require large bite forces or prolonged mastication. Bony responses to high bite forces are well-documented for the mammalian skull, but osteogenesis due to cyclical loading, caused by repetitive chewing, is more poorly understood. Previous studies demonstrate that cyclical loading results in greater bone formation in the rabbit masticatory apparatus and in substantial Haversian remodeling in primate postcrania. Here we assess the relationship between cyclical loading and remodeling in the rabbit maxilla. Twenty male New Zealand white rabbits (Oryctolagus cuniculus) were raised on either an overuse or control diet (10 per group) for 48 weeks, beginning at weaning onset. The control group was raised on a diet of rabbit pellets (E = 29 MPa, R = 1031 J/m2 ), whereas the overuse group ate rabbit pellets and hay, which has high stiffness (E = 3336 MPa) and toughness (R = 2760 J/m2 ) properties. Hay requires greater chewing investment (475 chews/g) and longer chewing durations (568 s/g) than pellets (161 chews/g and 173 s/g), therefore causing cyclical loading of the jaws. Remodeling was measured as osteon population density (OPD), percent Haversian bone (%HAV), and osteon cross-sectional area (On.Ar). The only significant difference found was greater On.Ar in the alveolar region of the maxilla (p < 0.001) in the overuse group. The hypothesis that cyclical loading engenders Haversian remodeling in the developing maxilla is not supported. The continuation of modeling throughout the experimental duration may negate the need for remodeling as newly laid bone tends to be more compliant and resistant to crack propagation.

Sex Differences in Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) occurs in women more than men whereas survival in men is worse than in women. In recent years, much research has been carried out to understand these sex differences in PAH. This article discusses clinical and preclinical studies that have investigated the influences of sex, serotonin, obesity, estrogen, estrogen synthesis, and estrogen metabolism on bone morphogenetic protein receptor type II signaling, the pulmonary circulation and right ventricle in both heritable and idiopathic pulmonary hypertension.

The Impact of Medical Financial Hardship on Children's Health.

Objective. To determine whether living in a family with medical financial hardship decreases children's access to health care. Methods. We identified children aged 4 to 17 years from the 2013 to 2018 National Health Interview Surveys. Medical financial hardship was defined as living in a family where one or more family members had problems paying medical bills in the past 12 months. Results. Of 53 483 children in the analysis, 19% were exposed to medical financial hardship. This was adversely associated with children's health status and health care use, especially greater odds of delaying care (odds ratio [OR] = 5.28; 95% confidence interval [CI] = 4.51-6.19) and having unmet health care needs (OR = 4.43; 95% CI = 4.00-4.91). Conclusions. One fifth of children live in families experiencing medical financial hardship, and this exposure is adversely correlated with child health outcomes even controlling for established measures of socioeconomic status, such as family income, health insurance coverage, and need-based program participation.

Peer pressure and alcohol consumption in adults living in the UK: a systematic qualitative review.

BACKGROUND: Peer pressure to drink alcohol may influence excessive alcohol consumption, which can have adverse impacts on health and wellbeing. While peer pressure to drink alcohol is extensively studied among youth, less examination exists among adults. This systematic review examined qualitative research studies which explored the role and concept of peer pressure within the context of alcohol consumption in adults living in the UK. METHODS: Qualitative studies which explored peer pressure within the context of alcohol consumption or alcohol related behaviours and views in adults (age range approximately 18-52 years) living in the UK were included. Systematic searches conducted in Medline, PsycINFO and Web of Science identified 1462 references, of which 13 studies met inclusion criteria. Thematic analysis was conducted. RESULTS: Five overarching themes were identified. Four of these themes directly address aspects of peer pressure, including: experiences of peer pressure; consequences of peer pressure; strategies to deal with peer pressure; and conditions perceived to affect peer pressure. The fifth overarching theme explains the wider social context influencing peer pressure. Pressure to drink alcohol affects individuals across the life span and can be experienced as overt and aggressive, or subtle and friendly. Those consuming little or no alcohol are more likely to feel overt forms of peer pressure. Some developed strategies to cope with pressure from drinkers. Peer pressure can result in feelings of social isolation, or giving in by consuming alcohol against ones wishes. CONCLUSION: Peer pressure to drink alcohol is a complex and multifaceted phenomenon experienced across adulthood requiring better understanding to support initiatives to decrease the impact of pressure-inducing environments and develop strategies to deal with perceived pressure conditions. TRIAL REGISTRATION: The protocol for this review is registered with PROSPERO ( CRD42019122201 ). Registered 11 February 2019.

Don't be fooled by the fat: A rare case of renal cell carcinoma with intratumoural fat.

Angiomyolipoma (AML) is a benign renal tumour composed of fat, smooth muscle and blood vessels. Radiologic evidence of macroscopic fat within a solid renal lesion on computed tomography was historically thought to be pathognomonic for this condition. Herein, we report a case of an incidental solid renal cell mass with multiple foci of intra-tumoral fat, which was shown to be a clear cell renal cell carcinoma (RCC) at nephrectomy. Macroscopic fat within solid renal lesions does not exclude malignancy, evaluation of other radiologic features is necessary when RCC is suspected.

Epilepsy-specific patient-reported outcome measures of children's health-related quality of life: A systematic review of measurement properties.

OBJECTIVE: To identify and appraise published evidence of the measurement properties for epilepsy-specific patient-reported outcome measures (PROMs) of children's health-related quality of life (HRQoL). METHODS: We searched multiple databases for studies evaluating the measurement properties of English-language epilepsy-specific PROMs of children's HRQoL. We assessed the methodological quality using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidance. We extracted data about the content validity, construct validity, internal consistency, test-retest reliability, proxy reliability, responsiveness, and precision, and assessed the measurement properties with reference to standardized criteria. RESULTS: We identified 27 papers that evaluated 11 PROMs. Methodological quality was variable. Construct validity, test-retest reliability, and internal consistency were more commonly assessed. Quality of Life in Childhood Epilepsy (QoLCE) questionnaires are parent-reported and evaluated more than other PROMs; QoLCE-55 has good and replicated evidence for structural and construct validity and internal consistency. Health-Related Quality of Life Measure for Children with Epilepsy (CHEQoL) has both child and parent-reported versions and good evidence of content, structural, and construct validity. SIGNIFICANCE: This review identified two leading candidate epilepsy-specific PROMs for measuring health-related quality of life in children. Establishing evidence of the responsiveness of PROMs is a priority to help the interpretation of meaningful change scores.

Don't be fooled by the fat: A rare case of renal cell carcinoma with intratumoural fat.

Angiomyolipoma (AML) is a benign renal tumour composed of fat, smooth muscle and blood vessels. Radiologic evidence of macroscopic fat within a solid renal lesion on computed tomography was historically thought to be pathognomonic for this condition. Herein, we report a case of an incidental solid renal cell mass with multiple foci of intra-tumoral fat, which was shown to be a clear cell renal cell carcinoma (RCC) at nephrectomy. Macroscopic fat within solid renal lesions does not exclude malignancy, evaluation of other radiologic features is necessary when RCC is suspected.

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension.

Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1-4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH.

Estrous cycle-induced sex differences in medium spiny neuron excitatory synaptic transmission and intrinsic excitability in adult rat nucleus accumbens core.

Naturally occurring hormone cycles in adult female humans and rodents create a dynamic neuroendocrine environment. These cycles include the menstrual cycle in humans and its counterpart in rodents, the estrous cycle. These hormone fluctuations induce sex differences in the phenotypes of many behaviors, including those related to motivation, and associated disorders such as depression and addiction. This suggests that the neural substrate instrumental for these behaviors, including the nucleus accumbens core (AcbC), likewise differs between estrous cycle phases. It is unknown whether the electrophysiological properties of AcbC output neurons, medium spiny neurons (MSNs), change between estrous cycle phases. This is a critical knowledge gap given that MSN electrophysiological properties are instrumental for determining AcbC output to efferent targets. Here we test whether the intrinsic electrophysiological properties of adult rat AcbC MSNs differ across female estrous cycle phases and from males. We recorded MSNs with whole cell patch-clamp technique in two experiments, the first using gonad-intact adult males and females in differing phases of the estrous cycle and the second using gonadectomized males and females in which the estrous cycle was eliminated. MSN intrinsic electrophysiological and excitatory synaptic input properties robustly changed between female estrous cycle phases and males. Sex differences in MSN electrophysiology disappeared when the estrous cycle was eliminated. These novel findings indicate that AcbC MSN electrophysiological properties change across the estrous cycle, providing a new framework for understanding how biological sex and hormone cyclicity regulate motivated behaviors and other AcbC functions and disorders. NEW & NOTEWORTHY This research is the first demonstration that medium spiny neuron electrophysiological properties change across adult female hormone cycle phases in any striatal region. This influence of estrous cycle engenders sex differences in electrophysiological properties that are eliminated by gonadectomy. Broadly, these findings indicate that adult female hormone cycles are an important factor for neurophysiology.