The role of native cysteine residues in the oligomerization of KCNQ1 channels.

KCNQ1, the major component of the slow-delayed rectifier potassium channel, is responsible for repolarization of cardiac action potential. Mutations in this channel can lead to a variety of diseases, most notably long QT syndrome. It is currently unknown how many of these mutations change channel function and structure on a molecular level. Since tetramerization is key to proper function and structure of the channel, it is likely that mutations modify the stability of KCNQ1 oligomers. Presently, the C-terminal domain of KCNQ1 has been noted as the driving force for oligomer formation. However, truncated versions of this protein lacking the C-terminal domain still tetramerize. Therefore, we explored the role of native cysteine residues in a truncated construct of human KCNQ1, amino acids 100-370, by blocking potential interactions of cysteines with a nitroxide based spin label. Mobility of the spin labels was investigated with continuous wave electron paramagnetic resonance (CW-EPR) spectroscopy. The oligomerization state was examined by gel electrophoresis. The data provide information on tetramerization of human KCNQ1 without the C-terminal domain. Specifically, how blocking the side chains of native cysteines residues reduces oligomerization. A better understanding of tetramer formation could provide improved understanding of the molecular etiology of long QT syndrome and other diseases related to KCNQ1.

Barriers to colonoscopy in UK colorectal cancer screening programmes: Qualitative interviews with ethnic minority groups.

OBJECTIVE: People from ethnic minority backgrounds are less likely to attend colonoscopy, following faecal immunochemical test screening, and are more likely to be diagnosed with colorectal cancer at an advanced stage as a result. The aim of this research was to explore the barriers and facilitators to attending colonoscopy, perceived by ethnic minority groups living in the United Kingdom. METHODS: Semi-structured online and telephone interviews were conducted with thirty men and women of Black-African (n = 5), Black-Caribbean (n = 5), South Asian (n = 10) and White British (n = 10) descent. Participants were eligible for screening, but had not necessarily been invited for colonoscopy. All interviews were conducted in the participant's first language and were assessed using Framework-analysis, in line with a conceptual framework developed from previous interviews with healthcare professionals. RESULTS: Five thematic groups of barriers and facilitators were developed: 'Locus of control', 'Cultural attitudes and beliefs', 'Individual beliefs, knowledge and personal experiences with colonoscopy and cancer', 'Reliance on family and friends' and 'Health concerns'. Differences were observed, between ethnic groups, for: 'Locus of control', 'Cultural attitudes and beliefs' and 'Reliance on family and friends'. Black and South Asian participants frequently described the decision to attend colonoscopy as lying with 'God' (Muslims, specifically), 'the doctor', or 'family' (Locus of control). Black and South Asian participants also reported relying on friends and family for 'language, transport and emotional support' (Reliance on family and friends). Black-African participants, specifically, described cancer as 'socially taboo' (Cultural attitudes and beliefs). CONCLUSIONS: The results highlight several targets for culturally-tailored interventions to make colonoscopy more equitable.

Increased Breast and Colorectal Cancer Risk in Type 2 Diabetes: Awareness Among Adults With and Without Diabetes and Information Provision on Diabetes Websites.

BACKGROUND: People with type 2 diabetes mellitus (T2DM) have a higher risk of developing breast and bowel cancers but are less likely to participate in cancer screening. PURPOSE: Two interlinked studies examined public awareness of the fact that T2DM increases breast and bowel cancer risk, and provision of this information on diabetes websites. METHODS: Study-1: phase-1 surveyed awareness of T2DM-increased cancer risk in a nationally-representative British sample aged 50-74 (N = 1,458) and compared respondents with and without T2DM (n = 125 vs. n = 1,305); phase-2 surveyed an additional exclusively T2DM sample (N = 319). Study-2: High-ranking diabetes websites (N = 25) were reviewed to determine the rate of inclusion of cancer risk and cancer screening information in evident sections about diabetes-related health conditions. RESULTS: A low proportion of respondents were aware that T2DM increases risk of breast (13.7%) and bowel (27.6%) cancers, compared to much higher awareness of other diabetes-related conditions such as sight loss (82.2%) and foot problems (81.8%). Respondents with T2DM were significantly more likely than those without T2DM to be aware of all the surveyed diabetes-related health conditions (e.g., sight loss, OR: 3.14, 95%CI: 1.61-6.15; foot problems, OR: 2.58, 95%CI: 1.38-4.81), except breast (OR: 0.82, 95%CI: 0.46-1.45) and bowel (OR: 0.95, 95%CI: 0.63-1.45) cancer, for which awareness was equally low among people with and without T2DM. Few diabetes websites with a section on diabetes-related health conditions included cancer in this section (n = 4/19), and fewer still included cancer screening among any noted cancer-protective behaviors (n = 2/4). CONCLUSIONS: There is low public awareness that T2DM increases the risk of developing breast and bowel cancers, even among people with T2DM, which may be partly due to limited information provision regarding T2DM-increased cancer risk from diabetes care providers and organizations.

People with type 2 diabetes (T2D) have a higher risk of developing breast and bowel cancers. Despite this, they are less likely to participate in cancer screening, which can improve survival from cancer. We addressed two questions. Are people aware that T2D increases the risk of breast and bowel cancer? Are people being told about this by diabetes care providers and organizations? We surveyed a large representative sample of the British public (aged 50­74). We also reviewed key information about diabetes-related health problems provided on 25 top-ranking diabetes websites. There were three main findings. (1) Relatively few people knew that T2D increases the risk of breast and bowel cancer. In contrast, many people knew that T2D increases the risk of other conditions like sight loss, foot problems, and heart disease. (2) Awareness of higher cancer risk was equally low among people with T2D and those without. In contrast, knowledge of other diabetes-related conditions (e.g., sight loss, foot problems) was higher among people with T2D than those without. (3) Few websites included cancer in their key information about diabetes-related health problems. In contrast, nearly all the diabetes websites listed the more well-known risks of sight loss, foot problems, and heart disease.

"It's hard to feel a part of something when you've never met people": defining "learning community" in an online era.

Feeling part of a community of learners has been shown to foster students' engagement and sense of belonging, leading to higher retention and achievement of learning outcomes. The pivot to online teaching caused by the COVID-19 pandemic has prompted a reappraisal of all aspects of the student experience, including students' capacity and opportunity to engage in meaningful learning communities online. There has been some emergent literature which considers how to facilitate online learning communities in the emergency remote teaching context prompted by COVID-19. However, there is a notable lack of literature which considers how learning communities are defined, understood, and negotiated by students in this unique teaching context. Given how students' perceptions of learning communities contributes to Higher Education policy (e.g. through the National Student Survey), this is important to understand. In the present study (N = 309), we qualitatively investigated students' understanding and definition of the term "learning community" during a time of emergency pivot to online teaching and learning. A reflexive thematic analysis of students' first-hand responses generated three dominant themes: "Feeling connected: Bridging the gap whilst physically distanced", "Feeling included: Visible and valued", and "Feeling together: Mutuality and the shared experience". We discuss the implications for these conceptualisations of an online learning community and suggest ways forward for Higher Education pedagogy.

Barriers to flexible sigmoidoscopy colorectal cancer screening in low uptake socio-demographic groups: A systematic review.

OBJECTIVE: To synthesise qualitative evidence related to barriers and facilitators of flexible sigmoidoscopy screening (FSS) intention and uptake, particularly within low socio-demographic uptake groups. FSS uptake is lower amongst women, lower socio-economic status (SES), and Asian ethnic groups within the United Kingdom (UK) and United States of America. METHODS: A total of 12 168 articles were identified from searches of four databases: EMBASE, MEDLINE, PsycINFO and Web of Science. Eligibility criteria included: individuals eligible to attend FSS and empirical peer-reviewed studies that analysed qualitative data. The Critical Appraisal Skills Program tool evaluated the methodological quality of included studies, and thematic synthesis was used to analyse the data. RESULTS: Ten qualitative studies met the inclusion criteria. Key barriers to FSS intention and uptake centred upon procedural anxieties. Women, including UK Asian women, reported shame and embarrassment, anticipated pain, perforation risk, and test preparation difficulties to elevate anxiety levels. Religious and cultural-influenced health beliefs amongst UK Asian groups were reported to inhibit FSS intention and uptake. Competing priorities, such as caring commitments, particularly impeded women's ability to attend certain FSS appointments. The review identified a knowledge gap concerning factors especially associated with FSS participation amongst lower SES groups. CONCLUSIONS: Studies mostly focussed on barriers and facilitators of intention to participate in FSS, particularly within UK Asian groups. To determine the barriers associated with FSS uptake, and further understand how screening intention translates to behaviour, it is important that future qualitative research is equally directed towards factors associated with screening behaviour.

Clinical outcomes of total hip arthroplasty for fractured neck of femur in patients over 75 years.

To date, there has been little research into the clinical outcomes of total hip arthroplasty (THA) for intracapsular neck of femur (NOF) fracture in the very elderly. 44 patients over 75years underwent THA for an intracapsular NOF fracture over a two year period. Oxford Hip Scores were obtained from 37 patients with a mean score of 39.7 (range 11-47). Katz Index Scores were collected from 36 patients with a mean pre-operative score of 5.9 and post operative score of 5.7. THA in this population gives patients the best opportunity to return to premorbid function. When complications occur there is a catastrophic effect on independence. Therefore it is important to select these patients' appropriately and to optimise their medical condition peri-operatively.

Effects of a modified invitation letter to follow-up colonoscopy for bowel cancer detection.

OBJECTIVE: To investigate whether modifications made to the current National Health Service (NHS) invitation letter for follow-up colonoscopy examination affect participant state anxiety and behavioural intentions to attend. METHODS: Five hundred and thirty-eight adults of bowel cancer-eligible screening age (56-74) were randomized to receive the current NHS invitation letter or the modified version of the letter as a hypothetical scenario. Modifications to the letter included fewer uses of the term cancer and awareness of alternative screening options. The history of the colonoscopy invitation, anticipated state anxiety, behavioural intention to attend the nurse appointment, and colonoscopy concerns upon reading the letter were measured. RESULTS: Behavioural intentions were high in both conditions; however, participants reading the current letter reported significantly higher behavioural intentions compared to the modified letter. There was no main effect of previous invite status or interaction between previous invite status and letter condition on behavioural intentions. However, the effect of the letter on levels of anxiety depended on the participant's invitation history. Those never invited for a colonoscopy were more anxious when reading the modified letter compared to the current letter. Conversely, previous colonoscopy invitees were less anxious following reading the modified letter than those reading the current letter. Those never invited for a colonoscopy were more concerned about embarrassment and test invasiveness. All findings remained the same when controlling for age and education. CONCLUSION: Modifications to the invitation letter were not beneficial to levels of screening intention or anxiety.

Effects of a self-affirmation intervention on responses to bowel cancer screening information.

OBJECTIVE: To investigate the effect of two brief self-affirmation interventions, immediately prior to reading standard information about bowel cancer screening, on state anxiety, message acceptance and behavioural intention to screen for bowel cancer. METHODS: 242 adults aged 49 were randomised to one of two self-affirmation interventions (health or values) or one of two control conditions, before reading an NHS England bowel cancer screening leaflet. Participant friend and family history of bowel cancer, state anxiety, message acceptance, behavioural intention to screen, trait self-esteem and spontaneous self-affirmation were measured. Data were analysed using between-participants analysis of variance, planned contrasts and moderated regression. RESULTS: No main effects of experimental condition on levels of state anxiety, message acceptance and behavioural intention were found. However, planned contrasts showed participants who self-affirmed about their health or values (conditions-collapsed) were significantly less anxious and reported significantly higher behavioural intentions compared to participants in the controls (conditions-collapsed). Irrespective of condition, higher levels of spontaneous self-affirmation and trait self-esteem were correlated with lower anxiety, higher intentions, and message acceptance. CONCLUSION: There was some evidence of the effect of health-based self-affirmation on lowering anxiety; however, further research is needed to explore the effectiveness of different self-affirmation interventions in larger samples.

Advancing Salary Equity in Schools of Medicine in the United States.

Equity, in broad terms, is a critical issue and has been identified as an area that needs particular attention in academic medicine. Gender equity, as a subset of overall equity, has equally been shown to be lacking in academic medicine, and most medical schools and academic health systems are involved in substantive journeys to improve all dimensions of equity, diversity, and inclusion. This Invited Commentary calls for including gender-based salary equity as a foundational accomplishment for institutions seeking to achieve overall equity. In addition, the authors provide evidence and recommendations to guide institutions toward best practices in achieving salary equity. They propose 4 areas of consideration: (1) prioritization by leadership; (2) prioritization of resources to ensure success; (3) development of corrective action plans which are "automatic" and based on clear guidelines; and (4) transparency of methodology, data, and results.

Barriers and facilitators to colonoscopy for cancer detection: patient and practitioner perspectives.

OBJECTIVE: To further understand the barriers and facilitators to attending colonoscopy examination following a positive routinely offered stool test result, from the perspective of patients and Specialist Screening Practitioners (SSPs). METHODS: Qualitative semi-structured interviews were conducted. Participants (N = 32) were patients (n = 20) who, as part of the Bowel Cancer Screening Programme (BCSP) in England, were invited to attend a colonoscopy examination, and SSPs (n = 12), who worked for the BCSP in England. Framework analysis included inductive and deductive coding. RESULTS: Anxiety was as a key barrier cited by patients and SSPs, arising from the moment the patient received the invitation letter. Notably, procedural-related anxieties centred upon the fear of pain and discomfort and test invasiveness. The role of family, friends and the SSP were recognised by patients and SSPs to facilitate participation. Many patients, yet not SSPs, emphasised an obligation to attend all medical test invitations. CONCLUSION: Practically orientated strategies suggested by patients and SSPs address the patient barriers identified. These include earlier information to patients on the option of sedation for pain relief, earlier notification of potential financial support for patients unable to fund their own travel costs, and fewer uses of the term cancer within written materials.

Barriers and facilitators to colonoscopy following fecal immunochemical test screening for colorectal cancer: A key informant interview study.

OBJECTIVES: People who are referred for colonoscopy, following an abnormal colorectal cancer (CRC) screening result, are at increased risk of CRC. Despite this, many individuals decline the procedure. The aim of this study was to investigate why. METHODS: As little is currently known about non-attendance at follow-up colonoscopy, and follow-up of abnormal screening results is a nurse-led process, we decided to conduct key informant interviews with Specialist Screening Practitioners ([SSPs] nurses working in the English Bowel Cancer Screening Program). Interviews were conducted online. Transcripts were assessed using inductive and deductive coding techniques. RESULTS: 21 SSPs participated in an interview. Five main types of barriers and facilitators to colonoscopy were described, namely: Sociocultural, Practical, Psychological, Health-related and COVID-related. Key psychological and sociocultural factors included: 'Fear of pain and discomfort associated with the procedure' and 'Lack of support from family and friends'. Key practical, health-related and COVID-related factors included: 'Family and work commitments', 'Existing health conditions as competing priorities' and 'Fear of getting COVID-19 at the hospital'. CONCLUSIONS: A range of barriers and facilitators to follow-up colonoscopy exist. Future studies conducted with patients are needed to further explore barriers to colonoscopy. PRACTICE IMPLICATIONS: Strategies to reduce non-attendance should adopt a multifaceted approach.

Community Forum Identifies Opportunities to Engage with Eastern Kentucky Community Leaders about Chronic Disease and Environmental Pollution.

The NIEHS-sponsored Appalachian Health & Well-Being Community Forum held in Eastern Kentucky brought various community members together to communicate and establish better coordination of efforts to improve health and address regional environmental issues. The two-hour forum discussion provided bi-directional feedback about the needs and interests of community members. Top concerns of community members included obesity and obesity-related diseases and environmental pollution. Healthful lifestyles were identified as part of the remedy to protect health from potential adverse health effects associated with environmental pollution. This study highlights opportunities to engage with Appalachian communities around topics related to health and environmental pollution.

Haemophilus influenzae lysate induces aspects of the chronic obstructive pulmonary disease phenotype.

Nontypeable Haemophilus influenzae (NTHi) commonly colonizes the lower airways of patients with chronic obstructive pulmonary disease (COPD). Whether it contributes to COPD progression is unknown. Here, we determined which aspects of the COPD phenotype can be induced by repetitive exposure to NTHi products. Mice were exposed weekly to an aerosolized NTHi lysate, and inflammation was evaluated by measurement of cells and cytokines in bronchoalveolar lavage fluid (BALF) and immunohistochemical staining; structural changes were evaluated histochemically by periodic acid fluorescent Schiff's reagent, Masson's trichrome, and Picrosirius red staining; mucin gene expression was measured by quantitative RT-PCR; and the role of TNF-alpha was examined by transgenic airway overexpression and use of an inhibitory antibody. NTHi lysate induced rapid activation of NF-kappaB in airway cells and increases of inflammatory cytokines and neutrophils in BALF. Repetitive exposure induced infiltration of macrophages, CD8+ T cells, and B cells around airways and blood vessels, and collagen deposition in airway and alveolar walls, but airway mucin staining and gel-forming mucin transcripts were not increased. Transgenic overexpression of TNF-alpha caused BALF neutrophilia and inflammatory cell infiltration around airways, but not fibrosis, and TNF-alpha neutralization did not reduce BALF neutrophilia in response to NTHi lysate. In conclusion, NTHi products elicit airway inflammation in mice with a cellular and cytokine profile similar to that in COPD, and cause airway wall fibrosis but not mucous metaplasia. TNF-alpha is neither required for inflammatory cell recruitment nor sufficient for airway fibrosis. Colonization by NTHi may contribute to the pathogenesis of small airways disease in patients with COPD.

Rationale and Models for Career Advancement Sponsorship in Academic Medicine: The Time Is Here; the Time Is Now.

The business community has honed the concept of sponsorship and promulgated its utility for harnessing the talent of high-performing women and minorities whose contributions often go unrecognized within organizations. In recent years, academic medicine has begun to do the same. Whereas mentorship often centers on personal and professional development (e.g., skill building and goal setting), sponsorship focuses on enhancing the visibility, credibility, and professional networks of talented individuals. For upward career mobility, mentorship is limited in scope. Sponsorship, on the other hand, directly targets career advancement and is anchored in the sponsor's awareness of organizational structures and critical professional opportunities for junior faculty. Men are more likely to garner sponsors informally, and these sponsors tend to be male. Existing disparities between male and female medical faculty in achievement of academic rank and leadership roles, compensation, and research support suggest that high-performing women have a visibility gap. Such systemic inequity reflects a suboptimal business model that limits organizational potential. Formal sponsorship programs that match women with senior leaders facilitate access to beneficial relationships and institutionalize the value of equal opportunity. In this Perspective, the authors describe two successful sponsorship models that exist within academic medicine, the Society of General Internal Medicine's Career Advising Program and MD Anderson Cancer Center's Leaders' Sponsorship Program. They issue a call to action for much broader implementation of sponsorship programming to cultivate the advancement of all talented medical faculty and provide recommendations for such endeavors.

It Is Time for Zero Tolerance for Sexual Harassment in Academic Medicine.

While more women are in leadership positions in academic medicine now than ever before in U.S. history, evidence from recent surveys of women and graduating medical students demonstrates that sexual harassment continues in academic health centers. Academic medicine's ability to change its culture is hampered by victims' fear of reporting episodes of harassment, which is largely due to fear of retaliation. In this Perspective, the authors describe efforts in scientific societies to address the issue of sexual harassment and to begin to establish safe environments at national meetings. The authors contend that each institution must work to make it safe for individuals to come forward, to provide training for victims and for bystanders, and to abolish "locker room" talk that is demeaning to women.

Genetic susceptibility to late normal tissue injury.

The outcome of all cancer therapies, including radiation, has greatly improved in the last 25 years, resulting in a doubling of the number of long-term cancer survivors. However, a subset of these survivors incurs adverse chronic side effects in unavoidably irradiated normal tissues, persisting long after treatment and compromising the quality of life of these patients. Interpatient variability in normal tissue radiation response is well documented and suggested to be under genetic control. Fibrosis, a clinically significant late effect in many irradiated tissues that results in tissue remodeling and loss of function, is a complex genetic trait making identification of the underlying genes difficult. Current clinical and animal studies are providing information on the genetics and molecular basis of late normal tissue injury in the radiation therapy setting, bringing us closer to our dual goal of individualizing treatment by genetic profiling and improving the quality of life of long-term survivors.

Reduction of pulmonary compliance found with high-resolution computed tomography in irradiated mice.

PURPOSE: To demonstrate that high-resolution computed tomography (CT) can be used to quantify loss of pulmonary compliance in irradiated mice. METHODS AND MATERIALS: Computed tomography images of three nonirradiated (controls) and three irradiated mice were obtained 200 days after a single dose of 16-Gy Co (60) thoracic irradiation. While intubated, each animal was imaged at static breath-hold pressures of 2, 10, and 18 cm H2O. A deformable image registration algorithm was used to calculate changes in air volume between adjacent-pressure CT image pairs (e.g., 2 and 10 cm H2O), and functional images of pulmonary compliance were generated. The mass-specific compliance was calculated as the change in volume divided by the pressure difference between the 2 image sets and the mass of lung tissue. RESULTS: For the irradiated mice, the lung parenchyma mean CT values ranged from -314 (+/- 11) Hounsfield units (HU) to -378 (+/- 11) HU. For the control mice, the mean CT values ranged from -549 (+/- 11) HU to -633 (+/- 11) HU. Irradiated mice had a 60% (45, 74%; 95% confidence interval) lower mass-specific compliance than did the controls (0.039 [+/- 0.0038] vs. 0.106 [+/- 0.0038] mL air per cm H2O per g lung) from the 2-cm to 10-cm H2O CT image pair. The difference in compliance between groups was less pronounced at the higher distending pressures. CONCLUSION: High-resolution CT was used to quantify a reduction in mass-specific compliance following whole lung irradiation in mice. This small animal radiation injury model and assay may be useful in the study of lung injury.

Quantification of bleomycin-induced murine lung damage in vivo with micro-computed tomography.

RATIONALE AND OBJECTIVES: We explored noninvasive, in vivo cone-beam microcomputed tomography (micro-CT) to visualize and quantify fibrotic and inflammatory damage over the entire lung volume of mice. MATERIALS AND METHODS: We used bleomycin to induce pulmonary damage in vivo and compared the results from micro-CT with histologic measurements. Ten C57BL/6 mice were given 5 U/kg bleomycin intratracheally. Seven surviving mice were scanned with micro-CT before administration of bleomycin, and again before sacrifice. The resulting images were analyzed for lung volume measurements. After the final scan, all lungs were examined histologically and pulmonary damage was quantified. Damaged lung tissue regions were matched between micro-CT images and histologic sections for each mouse. RESULTS: The percent lung damage calculated from micro-CT and histology were correlated (r(2) = 0.49, r = 0.64 with P = 0.12), and the means of their respective distributions were not different (P > 0.05). CONCLUSION: This study shows that micro-CT is a promising alternative to predicting lung damage caused by bleomycin. CT image volumes of the thorax allow for global tissue sampling, which may be useful when following nonuniform lung damage that can occur from intratracheal administration of bleomycin.

H2-Ea deficiency is a risk factor for bleomycin-induced lung fibrosis in mice.

Pulmonary fibrosis is a significant complication in cancer patients when treated by radiation, e.g., thoracic malignant diseases, or chemotherapeutic agents. Bleomycin is one of the primary drugs used to treat testicular cancer, but the incidence of significant pulmonary fibrosis limits the dose. It is known that susceptibility to bleomycin-induced pulmonary fibrosis is a heritable trait controlled by multiple genes, none of which, however, are yet known. In this study, we used expression profiling and genetic analysis in mouse models of bleomycin-induced pulmonary fibrosis and identified MHC class II antigen Ealpha (H2-Ea) as a risk factor for this disease. We found that a loss-of-function deletion in the H2-Ea gene was linked to susceptibility. A functional test of H2-Ea in transgenic mice showed 100% survival in the transgenic mice compared with 53% in C57BL/10J mice and significantly decreased pulmonary fibrosis from 16.42% (C57BL/10J) to 5.76% (transgenic; P = 1.20e(-8)). These results show that H2-Ea expression protects mice from bleomycin-induced pulmonary fibrosis, which implicates H2-Ea as a candidate susceptibility gene for pulmonary fibrosis.