The enzymological characterization of the Inositol Phosphatase Synaptojanin

Synaptojanin is unique in that it is the only mammalian inositol phosphatase to contain more than one catalytic domain; a CX5R Suppressor of Actin (Sac) domain and an Inositol Polyphosphate Phosphatase Catalytic (IPPc) domain. The enzyme has been shown to play a crucial role in synaptic vesicle recycling and its functioning has been implicated in the onset of Alzheimer’s disease. Many domains and sub-units in bi- and multi-functional enzymes are found to operate in a co-dependent manner. In this work, the possibility that the functioning of the Sac and IPPc domains in Synaptojanin are co-dependent was investigated. The kinetic parameters of the IPPc domain were assessed in a double Sac/IPPc phosphatase and compared to that in both a double phosphatase where the Sac activity had been rendered inactive and a single IPPc phosphatase. It was found that the VMax activity of the IPPc domain towards its lipid substrate PI(4,5)P2 is significantly lower when the Sac domain is not present or functional. Likewise, it was found that the VMax activity of the Sac domain towards PI(4)P is reduced when the IPPc domain is removed or its activity rendered inactive. Interfacial recognition and substrate channelling were investigated as mechanisms to explain the domain dependency. However, they were found not to contribute to the observed differences in VMax. Instead, it seems likely that protein-lipid interactions induce the dependency. In summary, this thesis presents the first evidence that the catalytic domains in Synaptojanin act in a co-operative manner and probes the mechanism by which the domains interact

Innovation and Collaboration: Creating a Transdisciplinary Childhood Obesity Prevention Graduate Certificate Program

Preparing future professionals to work in transdisciplinary settings with a skill set to effectively foster collaborations and sustainable change requires a thoughtful and concerted interprofessional educational approach. Through an inter-university partnership in 2010 with name of university and the name of university, a group of faculty convened to propose the Transdisciplinary Obesity Prevention (TOP) graduate certificate program. With funding supported by a United States (US) Department of Agriculture (USDA) National Institute of Food and Agriculture grant in 2011, a team of faculty from name of university and name of university representing various disciplines (exercise science, nutrition, dietetics, health promotion, public health, nursing, early childhood education, family and consumer sciences, biology, biostatistics, and counseling) began developing the TOP graduate certificate program which is currently in its 5th year. The primary goal of this report is to outline the overall framework and components of the TOP graduate certificate program, providing information, strategies and considerations other institutions can apply in developing effective and sustainable transdisciplinary, interprofessional education to their existing graduate programs

Innovation and Collaboration: Creating a Transdisciplinary Childhood Obesity Prevention (TOP) Graduate Certificate Program

Preparing future professionals to work in transdisciplinary settings with a skill set to effectively foster collaborations and sustainable change requires a thoughtful and concerted interprofessional educational approach. Through an inter-university partnership in 2010 with name of university and the name of university, a group of faculty convened to propose the Transdisciplinary Obesity Prevention (TOP) graduate certificate program. With funding supported by a United States (US) Department of Agriculture (USDA) National Institute of Food and Agriculture grant in 2011, a team of faculty from name of university and name of university representing various disciplines (exercise science, nutrition, dietetics, health promotion, public health, nursing, early childhood education, family and consumer sciences, biology, biostatistics, and counseling) began developing the TOP graduate certificate program which is currently in its 5th year. The primary goal of this report is to outline the overall framework and components of the TOP graduate certificate program, providing information, strategies and considerations other institutions can apply in developing effective and sustainable transdisciplinary, interprofessional education to their existing graduate programs

Continuous glucose monitoring as an additional tool in early cystic fibrosis-related diabetes monitoring and in evaluation of short-term sitagliptin response

Cystic fibrosis-related diabetes (CFRD) is a complication associated with a negative prognosis in patients with cystic fibrosis (CF). Although the oral glucose tolerance test (OGTT) is the widely recommended screening test for CFRD diagnosis, continuous glucose monitoring (CGM) is increasingly considered a useful and easy-to-perform test for diagnosis and follow-up in clinical practice. Regarding CFRD treatment, although insulin is the classic approved pharmacological option, incretins could also be a helpful alternative in early stages. CGM could be also a useful tool to measure the early response to this therapy. METHODS: We studied 25 CF patients with abnormal OGTT results and compared glucose and insulin levels during the OGTTs with CGM results as a tool for early CFRD diagnosis. In addition, we evaluated glycaemic control with CGM before and after treatment with sitagliptin. RESULTS: A correlation was found between lower plasma insulin levels during the OGTTs and higher average sensor glucose (p = 0.009) and hyperglycaemic excursions (p = 0.017). The CGM data on sitagliptin treatment (n = 25) showed an average glycaemic improvement from 124.2 to 117.2 mg/dL (p = 0.002) with a 5.6-point standard deviation of glucose decrease (p < 0.001). Hyperglycaemic excursions ≥200 mg/dL diminished 57.1% (p = 0.021). Both time in range and time above 180 mg/dL improved during treatment (p = 0.036 and p = 0.006, respectively). CONCLUSION: CGM is a useful tool that offers valuable information for both the diagnosis and the management of CFRD. Lower plasma insulin levels during OGTTs are associated with a poor ambulatory glucose profile in CGM. Sitagliptin could play an important role in the treatment of the early stages of CFRDThis work was funded by Proyectos de Investigacion en Salud (FIS) PI19-00584 and PI22/01404 (funded by Instituto de Salud Carlos III), TIRONET2-CM, B2017/BMD-3724, iTIRONET. P2022/BMD7379 (funded by Comunidad de Madrid), and co-financed by FEDER funds to Mónica Marazuela Azpiro

Arylstibonic acids are potent and isoform-selective inhibitors of Cdc25a and Cdc25b phosphatases

Arylstibonates structurally resemble phosphotyrosine side chains in proteins and here we addressed the ability of such compounds to act as inhibitors of a panel of mammalian tyrosine and dual-specificity phosphatases. Two arylstibonates both possessing a carboxylate side chain were identified as potent inhibitors of the protein tyrosine phosphatase PTP-β. In addition, they inhibited the dual-specificity, cell cycle regulatory phosphatases Cdc25a and Cdc25b with sub-micromolar potency. However, the Cdc25c phosphatase was not affected demonstrating that arylstibonates may be viable leads from which to develop isoform specific Cdc25 inhibitors

Being Tamil, being Hindu:Tamil migrants’ negotiations of the absence of Tamil Hindu spaces in the West Midlands and South West of England

This paper considers the religious practices of Tamil Hindus who have settled in the West Midlands and South West of England in order to explore how devotees of a specific ethno-regional Hindu tradition with a well-established UK infrastructure in the site of its adherents’ population density adapt their religious practices in settlement areas which lack this infrastructure. Unlike the majority of the UK Tamil population who live in the London area, the participants in this study did not have ready access to an ethno-religious infrastructure of Tamil-orientated temples and public rituals. The paper examines two means by which this absence was addressed as well as the intersections and negotiations of religion and ethnicity these entailed: firstly, Tamil Hindus’ attendance of temples in their local area which are orientated towards a broadly imagined Hindu constituency or which cater to a non-Tamil ethno-linguistic or sectarian community; and, secondly, through the ‘DIY’ performance of ethnicised Hindu ritual in non-institutional settings

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Factors influencing physical activity and rehabilitation in survivors of critical illness: a systematic review of quantitative and qualitative studies

PURPOSE: To identify, evaluate and synthesise studies examining the barriers and enablers for survivors of critical illness to participate in physical activity in the ICU and post-ICU settings from the perspective of patients, caregivers and healthcare providers. METHODS: Systematic review of articles using five electronic databases: MEDLINE, CINAHL, EMBASE, Cochrane Library, Scopus. Quantitative and qualitative studies that were published in English in a peer-reviewed journal and assessed barriers or enablers for survivors of critical illness to perform physical activity were included. Prospero ID: CRD42016035454. RESULTS: Eighty-nine papers were included. Five major themes and 28 sub-themes were identified, encompassing: (1) patient physical and psychological capability to perform physical activity, including delirium, sedation, illness severity, comorbidities, weakness, anxiety, confidence and motivation; (2) safety influences, including physiological stability and concern for lines, e.g. risk of dislodgement; (3) culture and team influences, including leadership, interprofessional communication, administrative buy-in, clinician expertise and knowledge; (4) motivation and beliefs regarding the benefits/risks; and (5) environmental influences, including funding, access to rehabilitation programs, staffing and equipment. CONCLUSIONS: The main barriers identified were patient physical and psychological capability to perform physical activity, safety concerns, lack of leadership and ICU culture of mobility, lack of interprofessional communication, expertise and knowledge, and lack of staffing/equipment and funding to provide rehabilitation programs. Barriers and enablers are multidimensional and span diverse factors. The majority of these barriers are modifiable and can be targeted in future clinical practice