FKRP directed fibronectin glycosylation: A novel mechanism giving insights into muscular dystrophies?

The recently uncovered role of Fukutin-related protein (FKRP) in fibronectin glycosylation has challenged our understanding of the basis of disease pathogenesis in the muscular dystrophies. FKRP is a Golgi-resident glycosyltransferase implicated in a broad spectrum of muscular dystrophy (MD) pathologies that are not fully attributable to the well-described α-Dystroglycan hypoglycosylation. By revealing a new role for FKRP in the glycosylation of fibronectin, a modification critical for the development of the muscle basement membrane (MBM) and its associated muscle linkages, new possibilities for understanding clinical phenotype arise. This modification involves an interaction between FKRP and myosin-10, a protein involved in the Golgi organization and function. These observations suggest a FKRP nexus exists that controls two critical aspects to muscle fibre integrity, both fibre stability at the MBM and its elastic properties. This review explores the new potential disease axis in the context of our current knowledge of muscular dystrophies.

Smoking Status, Nicotine Medication, Vaccination, and COVID-19 Hospital Outcomes: Findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study.

INTRODUCTION: Available evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown. METHODS: Electronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission. RESULTS: Current (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97). CONCLUSIONS: Former but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers. IMPLICATIONS: Prior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

SARS-CoV-2 outbreak among staff and evacuees at Operation Allies Welcome Safe Havens.

We report on five SARS-CoV-2 congregate setting outbreaks at U.S. Operation Allies Welcome Safe Havens/military facilities. Outbreak data were collected, and attack rates were calculated for various populations. Even in vaccinated populations, there was rapid spread, illustrating the importance of institutional prevention and mitigation policies in congregate settings.

Masking Between Reserved Alarm Sounds of the IEC 60601-1-8 International Medical Alarm Standard: A Systematic, Formal Analysis.

OBJECTIVE: In this work, we systematically evaluated the reserved alarm sounds of the IEC 60601-1-8 international medical alarm standard to determine when and how they can be totally and partially masked. BACKGROUND: IEC 60601-1-8 gives engineers instruction for creating human-perceivable auditory medical alarms. This includes reserved alarm sounds: common types of alarms where each is a tonal melody. Even when this standard is honored, practitioners still fail to hear alarms, causing practitioner nonresponse and, thus, potential patient harm. Simultaneous masking, a condition where one or more alarms is imperceptible in the presence of other concurrently sounding alarms due to limitations of the human sensory system, is partially responsible for this. METHODS: In this research, we use automated proof techniques to determine if masking can occur in a modeled configuration of medical alarms. This allows us to determine when and how reserved alarm sound can mask other reserved alarms and to explore parameters to address discovered problems. RESULTS: We report the minimum number of other alarm sounds it takes to both totally and partially mask each of the high-, medium-, and low-priority alarm sounds from the standard. CONCLUSIONS: Significant masking problems were found for both the total and partial masking of high-, medium-, and low-priority reserved alarm sounds. APPLICATION: We show that discovered problems can be mitigated by setting alarm volumes to standard values based on priority level and by randomizing the timing of alarm tones.

Multifaceted Public Health Response to a COVID-19 Outbreak Among Meat-Processing Workers, Utah, March-June 2020.

OBJECTIVE: To identify potential strategies to mitigate COVID-19 transmission in a Utah meat-processing facility and surrounding community. DESIGN/SETTING: During March-June 2020, 502 workers at a Utah meat-processing facility (facility A) tested positive for SARS-CoV-2. Using merged data from the state disease surveillance system and facility A, we analyzed the relationship between SARS-CoV-2 positivity and worker demographics, work section, and geospatial data on worker residence. We analyzed worker survey responses to questions regarding COVID-19 knowledge, beliefs, and behaviors at work and home. PARTICIPANTS: (1) Facility A workers (n = 1373) with specimen collection dates and SARS-CoV-2 RT-PCR test results; (2) residential addresses of all persons (workers and nonworkers) with a SARS-CoV-2 diagnostic test (n = 1036), living within the 3 counties included in the health department catchment area; and (3) facility A workers (n = 64) who agreed to participate in the knowledge, attitudes, and practices survey. MAIN OUTCOME MEASURES: New cases over time, COVID-19 attack rates, worker characteristics by SARS-CoV-2 test results, geospatially clustered cases, space-time proximity of cases among workers and nonworkers; frequency of quantitative responses, crude prevalence ratios, and counts and frequency of coded responses to open-ended questions from the COVID-19 knowledge, attitudes, and practices survey. RESULTS: Statistically significant differences in race (P = .01), linguistic group (P < .001), and work section (P < .001) were found between workers with positive and negative SARS-CoV-2 test results. Geographically, only 6% of cases were within statistically significant spatiotemporal case clusters. Workers reported using handwashing (57%) and social distancing (21%) as mitigation strategies outside work but reported apprehension with taking COVID-19-associated sick leave. CONCLUSIONS: Mitigating COVID-19 outbreaks among workers in congregate settings requires a multifaceted public health response that is tailored to the workforce. IMPLICATIONS FOR POLICY AND PRACTICE: Tailored, multifaceted mitigation strategies are crucial for reducing COVID-19-associated health disparities among disproportionately affected populations.

Disentangling the Role of Religiosity in Human Papillomavirus Vaccination Amidst COVID-19 Pandemic.

Religion is a complex and sociocultural driver of human papillomavirus (HPV) vaccination decisions, but its exact role has been mixed/unclear. We used a cross-sectional study of 342 Christian parents to examine the associations between the three domains of religiosity (organizational, non-organizational, and intrinsic) and the intention to (i) seek HPV information and (ii) receive the HPV vaccine. Organizational religiosity was the only domain that was positively associated with information-seeking intention regardless of the type of covariates included. Mixed findings in the association between religiosity and HPV vaccination decisions may depend on the religiosity domain being assessed.

Coronavirus Disease 2019 (COVID-19) Prevalences Among People Experiencing Homelessness and Homelessness Service Staff During Early Community Transmission in Atlanta, Georgia, April-May 2020.

BACKGROUND: In response to reported coronavirus disease 2019 (COVID-19) outbreaks among people experiencing homelessness (PEH) in other US cities, we conducted multiple, proactive, facility-wide testing events for PEH living sheltered and unsheltered and homelessness service staff in Atlanta, Georgia. We describe the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and associated symptoms, and review shelter infection prevention and control (IPC) policies. METHODS: PEH and staff were tested for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) during 7 April-6 May 2020. A subset of PEH and staff was screened for symptoms. Shelter assessments were conducted concurrently at a convenience sample of shelters using a standardized questionnaire. RESULTS: Overall, 2875 individuals at 24 shelters and 9 unsheltered outreach events underwent SARS-CoV-2 testing, and 2860 (99.5%) had conclusive test results. The SARS-CoV-2 prevalences were 2.1% (36/1684) among PEH living sheltered, 0.5% (3/628) among PEH living unsheltered, and 1.3% (7/548) among staff. Reporting fever, cough, or shortness of breath in the last week during symptom screening was 14% sensitive and 89% specific for identifying COVID-19 cases, compared with RT-PCR. Prevalences by shelter ranged 0-27.6%. Repeat testing 3-4 weeks later at 4 shelters documented decreased SARS-CoV-2 prevalences (0-3.9%). Of 24 shelters, 9 completed shelter assessments and implemented IPC measures as part of the COVID-19 response. CONCLUSIONS: PEH living in shelters experienced a higher SARS-CoV-2 prevalence compared with PEH living unsheltered. Facility-wide testing in congregate settings allowed for the identification and isolation of COVID-19 cases, and is an important strategy to interrupt SARS-CoV-2 transmission.

Implementation of tuberculosis preventive treatment among people living with HIV, South Sudan.

OBJECTIVE: To describe an intervention to scale up tuberculosis preventive treatment for people living with human immunodeficiency virus (HIV) in South Sudan, 2017-2020. METHODS: Staff of the health ministry and United States President's Emergency Plan for AIDS Relief designed an intervention targeting the estimated 30 400 people living with HIV on antiretroviral therapy across South Sudan. The intervention comprised: (i) developing sensitization and operational guidance for clinicians to put tuberculosis preventive treatment delivery into clinical practice; (ii) disseminating monitoring and evaluation tools to document scale-up; (iii) implementing a programmatic pilot of tuberculosis preventive treatment; and (iv) identifying a mechanism for procurement and delivery of isoniazid to facilities dispensing tuberculosis preventive treatment. Staff aggregated routine programme data from facility registers on the numbers of people living with HIV who started on tuberculosis preventive treatment across all clinical sites providing this treatment during July 2019-March 2020. FINDINGS: Tuberculosis preventive treatment was implemented in 13 HIV treatment sites during July-October 2019, then in 26 sites during November 2019-March 2020. During July 2019-March 2020, 6503 people living with HIV started tuberculosis preventive treatment. CONCLUSION: Lessons for other low-resource settings may include supplementing national guidelines with health ministry directives, clinician guidance and training, and an implementation pilot. A cadre of field supervisors can rapidly disseminate a standardized approach to implementation and monitoring of tuberculosis preventive treatment, and this approach can be used to strengthen other tuberculosis-HIV services. Procuring a reliable and steady supply of tuberculosis preventive treatment medication is crucial.

Rapid Scale-up of an Antiretroviral Therapy Program Before and During the COVID-19 Pandemic - Nine States, Nigeria, March 31, 2019-September 30, 2020.

In 2018, an estimated 1.8 million persons living in Nigeria had HIV infection (1.3% of the total population), including 1.1 million (64%) who were receiving antiretroviral therapy (ART) (1). Effective ART reduces morbidity and mortality rates among persons with HIV infection and prevents HIV transmission once viral load is suppressed to undetectable levels (2,3). In April 2019, through the U.S. President's Emergency Plan for AIDS Relief (PEPFAR),* CDC launched an 18-month ART Surge program in nine Nigerian states to rapidly increase the number of persons with HIV infection receiving ART. CDC analyzed programmatic data gathered during March 31, 2019-September 30, 2020, to describe the ART Surge program's progress on case finding, ART initiation, patient retention, and ART Surge program growth. Overall, the weekly number of newly identified persons with HIV infection who initiated ART increased approximately eightfold, from 587 (week ending May 4, 2019) to 5,329 (week ending September 26, 2020). The ART Surge program resulted in 208,202 more HIV-infected persons receiving PEPFAR-supported ART despite the COVID-19 pandemic (97,387 more persons during March 31, 2019-March 31, 2020 and an additional 110,815 persons during April 2020-September 2020). Comprehensive, data-guided, locally adapted interventions and the use of incident command structures can help increase the number of persons with HIV infection who receive ART, reducing HIV-related morbidity and mortality as well as decreasing HIV transmission.

Expanding access to HIV services during the COVID-19 pandemic-Nigeria, 2020.

BACKGROUND: To accelerate progress toward the UNAIDS 90-90-90 targets, US Centers for Disease Control and Prevention Nigeria country office (CDC Nigeria) initiated an Antiretroviral Treatment (ART) Surge in 2019 to identify and link 340,000 people living with HIV/AIDS (PLHIV) to ART. Coronavirus disease 2019 (COVID-19) threatened to interrupt ART Surge progress following the detection of the first case in Nigeria in February 2020. To overcome this disruption, CDC Nigeria designed and implemented adapted ART Surge strategies during February-September 2020. METHODS: Adapted ART Surge strategies focused on continuing expansion of HIV services while mitigating COVID-19 transmission. Key strategies included an intensified focus on community-based, rather than facility-based, HIV case-finding; immediate initiation of newly-diagnosed PLHIV on 3-month ART starter packs (first ART dispense of 3 months of ART); expansion of ART distribution through community refill sites; and broadened access to multi-month dispensing (MMD) (3-6 months ART) among PLHIV established in care. State-level weekly data reporting through an Excel-based dashboard and individual PLHIV-level data from the Nigeria National Data Repository facilitated program monitoring. RESULTS: During February-September 2020, the reported number of PLHIV initiating ART per month increased from 11,407 to 25,560, with the proportion found in the community increasing from 59 to 75%. The percentage of newly-identified PLHIV initiating ART with a 3-month ART starter pack increased from 60 to 98%. The percentage of on-time ART refill pick-ups increased from 89 to 100%. The percentage of PLHIV established in care receiving at least 3-month MMD increased from 77 to 93%. Among PLHIV initiating ART, 6-month retention increased from 74 to 92%. CONCLUSIONS: A rapid and flexible HIV program response, focused on reducing facility-based interactions while ensuring delivery of lifesaving ART, was critical in overcoming COVID-19-related service disruptions to expand access to HIV services in Nigeria during the first eight months of the pandemic. High retention on ART among PLHIV initiating treatment indicates immediate MMD in this population may be a sustainable practice. HIV program infrastructure can be leveraged and adapted to respond to the COVID-19 pandemic.

Role of EphA4 in Mediating Motor Neuron Death in MND.

Motor neuron disease (MND) comprises a group of fatal neurodegenerative diseases with no effective cure. As progressive motor neuron cell death is one of pathological characteristics of MND, molecules which protect these cells are attractive therapeutic targets. Accumulating evidence indicates that EphA4 activation is involved in MND pathogenesis, and inhibition of EphA4 improves functional outcomes. However, the underlying mechanism of EphA4's function in MND is unclear. In this review, we first present results to demonstrate that EphA4 signalling acts directly on motor neurons to cause cell death. We then review the three most likely mechanisms underlying this effect.

Establishment of Isolation and Noncongregate Hotels During COVID-19 and Symptom Evolution Among People Experiencing Homelessness-Atlanta, Georgia, 2020.

CONTEXT: Local agencies across the United States have identified public health isolation sites for individuals with coronavirus disease 2019 (COVID-19) who are not able to isolate in residence. PROGRAM: We describe logistics of establishing and operating isolation and noncongregate hotels for COVID-19 mitigation and use the isolation hotel as an opportunity to understand COVID-19 symptom evolution among people experiencing homelessness (PEH). IMPLEMENTATION: Multiple agencies in Atlanta, Georgia, established an isolation hotel for PEH with COVID-19 and noncongregate hotel for PEH without COVID-19 but at risk of severe illness. PEH were referred to the isolation hotel through proactive, community-based testing and hospital-based testing. Daily symptoms were recorded prospectively. Disposition location was recorded for all clients. EVALUATION: During April 10 to September 1, 2020, 181 isolation hotel clients (77 community referrals; 104 hospital referrals) were admitted a median 3 days after testing. Overall, 32% of community referrals and 7% of hospital referrals became symptomatic after testing positive; 83% of isolation hotel clients reported symptoms at some point; 93% completed isolation. Among 302 noncongregate hotel clients, median stay was 18 weeks; 61% were discharged to permanent housing or had a permanent housing discharge plan. DISCUSSION: Overall, a high proportion of PEH completed isolation at the hotel, suggesting a high level of acceptability. Many PEH with COVID-19 diagnosed in the community developed symptoms after testing, indicating that proactive, community-based testing can facilitate early isolation. Noncongregate hotels can be a useful COVID-19 community mitigation strategy by bridging PEH at risk of severe illness to permanent housing.

EphA4 Regulates Hippocampal Neural Precursor Proliferation in the Adult Mouse Brain by d-Serine Modulation of N-Methyl-d-Aspartate Receptor Signaling.

The hippocampal dentate gyrus (DG) is a major region of the adult rodent brain in which neurogenesis occurs throughout life. The EphA4 receptor, which regulates neurogenesis and boundary formation in the developing brain, is also expressed in the adult DG, but whether it regulates adult hippocampal neurogenesis is not known. Here, we show that, in the adult mouse brain, EphA4 inhibits hippocampal precursor cell proliferation but does not affect precursor differentiation or survival. Genetic deletion or pharmacological inhibition of EphA4 significantly increased hippocampal precursor proliferation in vivo and in vitro, by blocking EphA4 forward signaling. EphA4 was expressed by mature hippocampal DG neurons but not neural precursor cells, and an EphA4 antagonist, EphA4-Fc, did not activate clonal cultures of precursors until they were co-cultured with non-precursor cells, indicating an indirect effect of EphA4 on the regulation of precursor activity. Supplementation with d-serine blocked the increased precursor proliferation induced by EphA4 inhibition, whereas blocking the interaction between d-serine and N-methyl-d-aspartate receptors (NMDARs) promoted precursor activity, even at the clonal level. Collectively, these findings demonstrate that EphA4 indirectly regulates adult hippocampal precursor proliferation and thus plays a role in neurogenesis via d-serine-regulated NMDAR signaling.

Addressing advanced HIV disease and mortality in global HIV programming.

INTRODUCTION: The US President's Emergency Plan for AIDS Relief (PEPFAR) was launched to increase access to antiretroviral treatment (ART) among people living with HIV (PLHIV) and to prevent new HIV infections globally. As new infections have decreased in many PEPFAR-supported countries, PEPFAR is increasingly focusing on understanding and decreasing mortality among PLHIV, specifically by addressing advanced HIV disease (AHD) and its attendant opportunistic infections (OIs). Several developments in identifying AHD, in preventing, diagnosing, and treating selected OIs, and in PEPFAR's support for mortality surveillance make this an opportune moment for PEPFAR to address HIV-related mortality. DISCUSSION: AHD upon diagnosis or re-engagement in HIV care is not uncommon, and it substantially increases risk of death from OIs. The World Health Organization provides evidence-based guidelines for a package of interventions for preventing, diagnosing, and treating common OIs, including tuberculosis (TB), cryptococcal meningitis, and severe bacterial infections. PEPFAR facilitates implementation of these guidelines. To identify PLHIV with low CD4, PEPFAR plans to support expanded access to CD4 testing, including a point-of-care assay that differentiates CD4 cell count as a binary of greater than or less than 200 cells/µL. To prevent AHD-related mortality, PEPFAR supports rapid ART initiation with integrase inhibitor-based regimens and implementation and documentation of TB preventive treatment. To diagnose selected OIs, PEPFAR is implementing urine lateral flow lipoarabinomannan use to identify TB among PLHIV who have a CD4 cell count < 200 cells/µL. To treat selected OIs, PEPFAR has focused on improving patient-centered care in TB/HIV co-infection services and scaling up implementation of new drug regimens for cryptococcal meningitis. To better understand mortality, PEPFAR has introduced an indicator, TX_ML, to routinely and systematically categorize outcomes, including deaths, among PLHIV on ART. CONCLUSIONS: PEPFAR is increasing its efforts to identify AHD; to prevent, diagnose, and treat OIs; and to track mortality in its programs. These ongoing efforts, done in collaboration with other stakeholders, seek to decrease mortality among PLHIV.

An Experimental Validation of Masking in IEC 60601-1-8:2006-Compliant Alarm Sounds.

OBJECTIVE: This research investigated whether the psychoacoustics of simultaneous masking, which are integral to a model-checking-based method, previously developed for detecting perceivability problems in alarm configurations, could predict when IEC 60601-1-8-compliant medical alarm sounds are audible. BACKGROUND: The tonal nature of sounds prescribed by IEC 60601-1-8 makes them potentially susceptible to simultaneous masking: where concurrent sounds render one or more inaudible due to human sensory limitations. No work has experimentally assessed whether the psychoacoustics of simultaneous masking accurately predict IEC 60601-1-8 alarm perceivability. METHOD: In two signal detection experiments, 28 nursing students judged whether alarm sounds were present in collections of concurrently sounding standard-compliant tones. The first experiment used alarm sounds with single-frequency (primary harmonic) tones. The second experiment's sounds included the additional, standard-required frequencies (often called subharmonics). T tests compared miss, false alarm, sensitivity, and bias measures between masking and nonmasking conditions and between the two experiments. RESULTS: Miss rates were significantly higher and sensitivity was significantly lower for the masking condition than for the nonmasking one. There were no significant differences between the measures of the two experiments. CONCLUSION: These results validate the predictions of the psychoacoustics of simultaneous masking for medical alarms and the masking detection capabilities of our method that relies on them. The results also show that masking of an alarm's primary harmonic is sufficient to make an alarm sound indistinguishable. APPLICATION: Findings have profound implications for medical alarm design, the international standard, and masking detection methods.

Social work contact in a UK cohort study: Under-reporting, predictors of contact and the emotional and behavioural problems of children.

BACKGROUND: There is little evidence on the degree of underreporting of social work contact in survey studies. There are also few studies about the emotional and behavioural problems of children in families who have contact with social workers, despite the adversities they face. OBJECTIVE: We examine underreporting of social work contact; the predictors of social work contact with families; and links between social work contact and emotional and behavioural outcomes for children. PARTICIPANTS AND SETTING: The Avon Longitudinal Study of Parents and Children follows the health and development of 14,062 children born in 1991-2 to women living in and around the City of Bristol. The study includes self-reported information about mothers' contact with social workers and children's emotional and behavioural outcomes using the Strengths and Difficulties Questionnaire (SDQ). METHODS: Self-reporting of social work contact in ALSPAC is compared with administrative data from the child protection register to examine rates of underreporting. We use a fixed-effects model to account for measurement error in estimating the association between social work contact and potential predictors, namely gender of the child and maternal factors: marital status, trouble with law, hospitalisation, cannabis and alcohol use, employment, financial difficulty and experience of cruelty from a partner. SDQ scores are explored using linear regression with lagged indicators of social work contact. RESULTS: The probability of a false negative for self-report of social work contact ranged from 22% to 34% across three survey waves. Mothers who married within the last 12 months were less likely to receive social work contact (OR: 0.13, CI95%: 0.01-1.34). Those who had either been hospitalised (OR: 1.52, CI95%: 1.01 - 2.28) or increased their rate of alcohol consumption (OR: 2.14, CI95%: 0.91 - 5.07) within the last 12 months were more likely to receive such contact. Overall children whose mothers report social work contact were much more likely to have emotional and behavioural problems within the first seven years of their lives (p < 0.01). CONCLUSION: There is potentially a high degree of underreporting of social work contact in social surveys and cohort studies. Researchers should adopt methods to account for this issue in the future. The risk of emotional and behavioural problems is greater among children whose mothers have had contact with social workers compared to other children with seemingly similar adversities.

The dystroglycan receptor maintains glioma stem cells in the vascular niche.

Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the perivascular niche. Glycosylated αDG is highly expressed and functional on the most aggressive mesenchymal-like (MES-like) GBM tumour compartment. Furthermore, we found that DG acts to maintain an MES-like state via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation in MES-like GBM, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor, not only as a structural element, but also as a critical factor promoting MES-like GBM and the maintenance of GSCs residing in the perivascular niche.

Patient-centered design in developing a mobile application for oral anticancer medications.

OBJECTIVES: To develop and test the usability and feasibility of a customizable mobile application (app) designed to help educate patients about their oral anticancer medications (OAMs) and regimens. SETTING: Outpatient cancer center and oncology pharmacy for urban, Midwestern academic health system. PRACTICE DESCRIPTION: Clinically-supervised educational intervention to support patients learning about OAMs. PRACTICE INNOVATION: With input from patient partners, our interdisciplinary team designed the first known tablet-based educational app that can interface with a patient's electronic medical record. The app is based on learning style and adherence theories and is customizable for individually prescribed OAMs. The app can accommodate multiple learning styles through text at 6th-grade reading level, pictures, animations, and audio voiceovers. Functionalities include interactive educational modules on 11 OAMs and case-based patient stories on common barriers to OAM adherence. EVALUATION: Early phase testing provided the opportunity to observe the user interface with the app and app functionality. Data were summarized descriptively from observations and comments of patient subjects. RESULTS: Thirty patient subjects provided input-19 in phase 1 usability testing and 11 in phase 2 feasibility testing. Comments provided by patient subjects during usability testing were largely positive. Responses included self-identification with patient stories, usefulness of drug information, preferences for text messages, and app limitations (e.g., perceived generational digital divide in technology use and potential patient inability to receive text messages). Using their feedback, modifications were made to the prototype app. Responses in feasibility testing demonstrated the app's usefulness across a wide range of ages. Highest opinion ratings on app usefulness were stated by patients who were newer to OAM therapy. CONCLUSION: User feedback suggests the potential benefit of the app as a tool to help patients with cancer, particularly after the first months for those starting new OAM regimens. Processes and lessons learned are transferable to other settings.

ATM inhibition prevents interleukin-6 from contributing to the proliferation of glioblastoma cells after ionizing radiation.

Glioblastoma (GBM) is a highly fatal disease with a 5 year survival rate of less than 22%. One of the most effective treatment regimens to date is the use of radiotherapy which induces lethal DNA double-strand breaks to prevent tumour growth. However, recurrence occurs in the majority of patients and is in-part a result of robust radioresistance mechanisms. In this study, we demonstrate that the multifunctional cytokine, interleukin-6 (IL-6), confers a growth advantage in GBM cells but does not have the same effect on normal neural progenitor cells. Further analysis showed IL-6 can promote radioresistance in GBM cells when exposed to ionising radiation. Ablation of the Ataxia-telangiectasia mutated serine/threonine kinase that is recruited and activated by DNA double-strand breaks reverses the effect of radioresistance and re-sensitised GBM to DNA damage thus leading to increase cell death. Our finding suggests targeting the signaling cascade of DNA damage response is a potential therapeutic approach to circumvent IL-6 from promoting radioresistance in GBM.

The Improving Global Health fellowship: a qualitative analysis of innovative leadership development for NHS healthcare professionals.

BACKGROUND: The importance of leadership development in the early stages of careers in the NHS has been highlighted in recent years and many programmes have been implemented which seek to develop leadership skills in healthcare professionals. The Improving Global Health (IGH) Fellowship scheme is one such programme, it provides a unique leadership development opportunity through an overseas placement with a focus on quality improvement work. This evaluation examines the impact of completing an IGH Fellowship on the career and leadership development of participants, who are referred to as Fellows. METHODS: Fellows who had returned from overseas placement between August 2008 and February 2015 were invited to complete an anonymised online questionnaire, which collected information on: demographic details, motivations for applying to the programme, leadership development and the impact of the IGH Fellowship on their career. Fifteen semi-structured interviews were conducted to further explore the impact of the programme on Fellows' leadership development and career progression. Interview transcripts were manually coded and underwent thematic content analysis. RESULTS: The questionnaire had a 67% (74/111) response rate. The number of fellows who self-identified as a leader more than doubled on completion of the IGH Fellowship (24/74 pre-fellowship versus 58/74 post-fellowship). 74% (55/74) reported that the IGH Fellowship had an impact upon their career, 35 of which reported that the impact was "substantial". The themes that emerged from the interviews revealed a personal development cycle that consolidated the fellows' interests and values whilst enhancing their self-efficacy and subsequently impacted positively upon their career choices. Three interviewees expressed frustration at the lack of opportunity to utilise their new skills on returning to the United Kingdom (UK). CONCLUSIONS: The IGH Fellowship successfully empowered healthcare professionals to self-identify as leaders. Of the 45/74 respondents who commented on the impact of the IGH Fellowship on their career, 41/45 comments were positive. The fellows described a process of experiential learning, reflection and evolving cultural intelligence, which consolidated their interests and values. The resultant increase in self-efficacy empowered these returned fellows in their choice of career.