The Pictorial Fit-Frail Scale: developing a visual scale to assess frailty

Background: Standardized frailty assessments are needed for early identification and treatment. We aimed to develop a frailty scale using visual images, the Pictorial Fit-Frail Scale (PFFS), and to examine its feasibility and content validity. Methods: In Phase 1, a multidisciplinary team identified domains for measurement, operationalized impairment levels, and re-viewed visual languages for the scale. In Phase 2, feedback was sought from health professionals and the general public. In Phase 3, 366 participants completed preliminary testing on the revised draft, including 162 UK paramedics, and rated the scale on feasibility and usability. In Phase 4, following translation into Malay, the final prototype was tested in 95 participants in Peninsular Malaysia and Borneo. Results: The final scale incorporated 14 domains, each conceptualized with 3–6 response levels. All domains were rated as “understood well” by most participants (range 64–94%). Percentage agreement with positive statements regarding appearance, feasibility, and usefulness ranged from 66% to 95%. Overall feedback from health-care professionals supported its content validity. Conclusions: The PFFS is comprehensive, feasible, and appears generalizable across countries, and has face and content validity. Investigation into the reliability and predictive validity of the scale is currently underway

Influence of pH on Ca2+ current and its control of electrical and Ca2+ signaling in ventricular myocytes

Modulation of L-type Ca2+ current (ICa,L) by H+ ions in cardiac myocytes is controversial, with widely discrepant responses reported. The pH sensitivity of ICa,L was investigated (whole cell voltage clamp) while measuring intracellular Ca2+ (Ca2+i) or pHi (epifluorescence microscopy) in rabbit and guinea pig ventricular myocytes. Selectively reducing extracellular or intracellular pH (pHo 6.5 and pHi 6.7) had opposite effects on ICa,L gating, shifting the steady-state activation and inactivation curves to the right and left, respectively, along the voltage axis. At low pHo, this decreased ICa,L, whereas at low pHi, it increased ICa,L at clamp potentials negative to 0 mV, although the current decreased at more positive potentials. When Ca2+i was buffered with BAPTA, the stimulatory effect of low pHi was even more marked, with essentially no inhibition. We conclude that extracellular H+ ions inhibit whereas intracellular H+ ions can stimulate ICa,L. Low pHi and pHo effects on ICa,L were additive, tending to cancel when appropriately combined. They persisted after inhibition of calmodulin kinase II (with KN-93). Effects are consistent with H+ ion screening of fixed negative charge at the sarcolemma, with additional channel block by H+o and Ca2+i. Action potential duration (APD) was also strongly H+ sensitive, being shortened by low pHo, but lengthened by low pHi, caused mainly by H+-induced changes in late Ca2+ entry through the L-type Ca2+ channel. Kinetic analyses of pH-sensitive channel gating, when combined with whole cell modeling, successfully predicted the APD changes, plus many of the accompanying changes in Ca2+ signaling. We conclude that the pHi-versus-pHo control of ICa,L will exert a major influence on electrical and Ca2+-dependent signaling during acid–base disturbances in the heart

Age patterns of HIV incidence in eastern and southern Africa: a collaborative analysis of observational general population cohort studies

Background: As the HIV epidemic in sub-Saharan Africa matures, evidence about the age distribution of new HIV infections and how this has changed over the epidemic is needed to guide HIV prevention. We assessed trends in age-specific HIV incidence in six population-based cohort studies in eastern and southern Africa, reporting changes in average age at infection, age distribution of new infections, and birth cohort cumulative incidence.Methods: We used a Bayesian model to reconstruct age-specific HIV incidence from repeated observations of individuals’ HIV serostatus and survival collected among population HIV cohorts in rural Malawi, South Africa, Tanzania, Uganda, and Zimbabwe. The HIV incidence rate by age, time and sex was modelled using smooth splines functions. Incidence trends were estimated separately by sex and study. Estimated incidence and prevalence results for 2000-2017, standardised to study population distribution, were used to estimate average age at infection and proportion of new infections by age.Findings: Age-specific incidence declined at all ages, though the timing and pattern of decline varied by study. The average age at infection was higher in men (cohort means: 27·8-34·6 years) than women (cohort means: 24·8-29·6 years). Between 2000 and 2017, the average age at infection increased slightly: cohort means 0·5-2·8 years among men and -0·2-2·5 years among women. Across studies, between 38-63% (cohort means) of women’s infections were among 15-24-year-olds and between 30-63% of men’s infections were in 20-29-year-olds. Lifetime risk of HIV declined for successive birth cohorts.Interpretation: HIV incidence declined in all age groups and shifted slightly, but not dramatically, to older ages. Disproportionate new HIV infections occur among 15-24-year-old women and 20-29-year-old men, supporting focused prevention in these groups. But 40-60% of infections were outside these ages, emphasising the importance of providing appropriate HIV prevention to adults of all ages.Funding: Bill and Melinda Gates Foundation

Understanding and responding to prescribing patterns of sodium valproate-containing medicines in pregnant women and women of childbearing age in Western Cape, South Africa

Growing evidence of the teratogenic potential of sodium valproate (VPA) has changed prescribing practices across the globe; however, the impact of this research and the consequent dissemination of a Dear Health Care Professional Letter (DHCPL) in December 2015, recommending avoidance of the teratogen VPA in women of childbearing age (WOCBA) and pregnant women in South Africa, is unknown. We explored trends and reasons for VPA use among pregnant women and WOCBA in the public sector in Western Cape Province from 1 January 2015 to 31 December 2017. Methods: Using the provincial health information exchange that collates routine electronic health data via unique patient identifiers, we analysed clinical and pharmacy records from 2015 to 2017 to determine prescription patterns of VPA and other antiepileptic drug (AED) and mood-stabilising medicine (MSM) use in WOCBA and pregnant women. Senior clinicians and policy makers were consulted to understand the determinants of VPA use. Results: At least one VPA prescription was dispensed to between 8205 (0.79%) and 9425 (0.94%) WOBCA from a cohort of approximately 1 million WOCBA attending provincial health care facilities per year

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Eighth Grade and Booksmart: Cinematic Representations of American Girlhood in the 2010s

The study of the teen film genre itself is a relatively new and often overlooked area in film studies. However, as a cultural artefact that speaks about conceptions of youth in society, it is important to examine, particularly with regards to the process of identity construction. This is doubly true for film genres concerning female adolescence due to the ‘cinematic adolescent’ often being male. Thus, much of the scholarship surrounding teen film has been male-centred. Even within the wider debate surrounding youth and teen film, scholarship on girl film is relatively new. This thesis aims to contribute to the existing scholarship by exploring cinematic representations of girlhood during the late 2010s, with a focus on identity formation in Eighth Grade (Burnham, 2018) and Booksmart (Wilde, 2019). The thesis utilises textual analysis framed within a review of relevant academic literature as it maps key shifts and changes in genre boundaries, narrative arcs and focalisation, characterisations and tropes, to locate the films under analysis in terms of their negotiation of what is at stake in representations of girlhood. Both the films under analysis are underrepresented in current literature, and they each offer different perspectives on girlhood, as Eighth Grade’s Kayla (Elsie Fisher) is at the beginning of hers, transitioning from middle school to high school, while Booksmart’s Amy (Kaitlyn Dever) and Molly (Beanie Feldstein) transition from high school to college. Within each of the case studies, this thesis argues that the representations of girlhood crystallise a distinctive construction. Eighth Grade’s inclusion of social media marks the film as one of the first in the genre to portray girls’ use of these new tools for self�authorship. Eighth Grade offers a depiction of how identity formation is mediated through social media in girl film, and in particular, the different kinds of performances that Kayla enacts on her YouTube channel, Kayla’s Korner, in contrast to her performances in real life. When Kayla learns to step back from the artifice of her online performance, her relationships with others strengthen as does her happiness. Of particular interest is the cinematic construction of the father-daughter relationship. Whereas previous cinematic representations of father-daughter relationships hinged on a kind of ‘postfeminist’ fatherhood, Eighth Grade exhibits a ‘profeminist’ fatherhood, wherein the father purposely refrains from enacting paternal control and instead encourages agency in his daughter. On the other hand, Booksmart introduces high school seniors and best friends Molly and Amy. Smart but self-righteous overachievers, they have sacrificed their teenage years to be 3 academically successful and attend an Ivy League college, snobbishly assuming that it would be impossible to both study hard and have fun. But when their conviction is shaken, they eventually embrace recklessness. As it follows them on the eve of their high school graduation while they make up for lost time, Booksmart plays with the tropes and conventions of the high school setting, and with contemporaneous discourses around girlhood and feminism, to offer a critical representation of how popular feminism and female friendship intersect in the formation of Molly and Amy’s identitie

Regional acidosis locally inhibits but remotely stimulates Ca2+ waves in ventricular myocytes

Spontaneous Ca2+ waves in cardiomyocytes are potentially arrhythmogenic. A powerful controller of Ca2+ waves is the cytoplasmic H+ concentration ([H+]i), which fluctuates spatially and temporally in conditions such as myocardial ischaemia/reperfusion. H+-control of Ca2+ waves is poorly understood. We have therefore investigated how [H+]i co-ordinates their initiation and frequency