The effect of sodium-glucose co-transporter 2 inhibitors on outcomes after cardiac resynchronization therapy.

AIMS: The trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium-glucose co-transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT. METHODS AND RESULTS: We compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy-four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non-ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end-diastolic inner-dimension (LVIDd) and diastolic function (E/A and e/e'). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049). CONCLUSIONS: We observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation.

Myocardial Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart failure cases. This rise is largely attributed to growing rates of obesity, hypertension, and diabetes. Despite its prevalence, the pathophysiological mechanisms of HFpEF are not fully understood. The heart, being the most energy-demanding organ, appears to have a compromised bioenergetic capacity in heart failure, affecting all phenotypes and aetiologies. While metabolic disturbances in heart failure with reduced ejection fraction (HFrEF) have been extensively studied, similar insights into HFpEF are limited. This review collates evidence from both animal and human studies, highlighting metabolic dysregulations associated with HFpEF and its risk factors, such as obesity, hypertension, and diabetes. We discuss how changes in substrate utilisation, oxidative phosphorylation, and energy transport contribute to HFpEF. By delving into these pathological shifts in myocardial energy production, we aim to reveal novel therapeutic opportunities. Potential strategies include modulating energy substrates, improving metabolic efficiency, and enhancing critical metabolic pathways. Understanding these aspects could be key to developing more effective treatments for HFpEF.

Comparison of troponin and natriuretic peptides in Takotsubo syndrome and acute coronary syndrome: a meta-analysis.

OBJECTIVE: Takotsubo syndrome (TTS) is an acute heart failure syndrome which resembles acute coronary syndrome (ACS) at presentation. Differentiation requires coronary angiography, but where this does not occur immediately, cardiac biomarkers may provide additional utility. We performed a meta-analysis to compare troponin and natriuretic peptides (NPs) in TTS and ACS to determine if differences in biomarker profile can aid diagnosis. METHODS: We searched five literature databases for studies reporting NPs (Brain NP (BNP)/NT-pro-BNP) or troponin I/T in TTS and ACS, identifying 28 studies for troponin/NPs (5618 and 1145 patients, respectively). RESULTS: Troponin was significantly lower in TTS than ACS (standardised mean difference (SMD) -0.86; 95% CI, -1.08 to -0.64; p<0.00001), with an absolute difference of 75 times the upper limit of normal (×ULN) higher in ACS than TTS. Conversely, NPs were significantly higher in TTS (SMD 0.62; 95% CI, 0.44 to 0.80; p<0.00001) and 5.8×ULN greater absolutely. Area under the curve (AUC) for troponin in ACS versus TTS was 0.82 (95% CI, 0.70 to 0.93), and 0.92 (95% CI, 0.80 to 1.00) for ST-segment elevation myocardial infarction versus TTS. For NPs, AUC was 0.69 (95% CI, 0.48 to 0.89). Combination of troponin and NPs with logistic regression did not improve AUC. Recursive Partitioning and Regression Tree analysis calculated a troponin threshold ≥26×ULN that identified 95% cases as ACS where and specificity for ACS were 85.71% and 53.57%, respectively, with 94.32% positive predictive value and 29.40% negative predictive value. CONCLUSIONS: Troponin is lower and NPs higher in TTS versus ACS. Troponin had greater power than NPs at discriminating TTS and ACS, and with troponin ≥26×ULN patients are far more likely to have ACS.

Cardiovascular risk in a contemporary cohort of patients with myeloproliferative neoplasms'.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of disorders of clonal haemopoiesis associated with an inherent risk of arterial and venous thrombotic complications. The prevalence of thrombotic complications and the impact of cardiovascular risk factors (CVRFs) in contemporary patient cohorts within the current era of MPN treatments have not been completely defined. OBJECTIVES: We aim to characterise the cardiovascular risk of patients with MPN by identifying the prevalence of CVRFs and describing the pattern of thrombotic events. We also aim to utilise the QRISK3 algorithm, which is a validated model used to estimate an individual's risk of developing cardiovascular disease, to further phenotype this cohort of patients. METHODS: We perform a retrospective analysis on a single-centre cohort of 438 patients with MPN. RESULTS: MPN patients continue to carry a high burden of vascular morbidity with a prevalence of arterial thrombotic events in 15.8 % (69/438) and venous thrombotic events in 13.2 % (58/438) of the cohort. The novel use of the QRISK3 algorithm, which showed a mean score of 13.7 % across the MPN population, provides further evidence to suggest an increased cardiovascular risk in MPN patients. CONCLUSION: With an increased risk of cardiovascular disease in patients with MPN, we propose an integrated approach between primary and specialised healthcare services using risk stratification tools such as QRISK3, which will allow aggressive optimisation of CVRFs to prevent thrombosis and reduce the overall morbidity and mortality in patients with MPN.

Percutaneous Coronary Intervention vs. Coronary Artery Bypass Grafting in Left Main Coronary Artery Disease: An Updated Systematic Review and Meta-Analysis.

Recently, both US and European guidelines have predominantly recommended coronary artery bypass grafting (CABG) as the preferred revascularisation method. However, emerging data have raised the possibility of percutaneous coronary intervention (PCI) being a viable and effective alternative. This meta-analysis sought to evaluate the latest insights from major clinical trials to ascertain whether PCI could be as effective as CABG in treating left main coronary artery (LMCA) disease. To achieve this, a comprehensive systematic search was conducted across databases, including Medline (via PubMed), Embase, Cochrane, and clinicaltrials.gov. The search spanned from the inception of these databases to August 20, 2022, and exclusively focused on randomized controlled trials (RCTs). Employing the random effects model, selected studies underwent rigorous analysis. The study outcomes encompassed a spectrum of factors such as all-cause mortality, major adverse cerebrovascular and cardiovascular events (MACCE), myocardial infarction (MI), stroke, and revascularisation procedures. The observation periods of interest included the 30-day mark, 1 year, 5 years, and 10 years. The analysis integrated six RCTs, revealing noteworthy patterns. In terms of all-cause mortality, PCI demonstrated non-inferiority to CABG across all observed time frames: 30 days (OR 0.6), 1 year (OR 0.77), 5 years (OR 1.41), and 10 years (OR 1.08). Analysis of MACCE outcomes favored PCI at 30 days and CABG at 5 years. The utilisation of the original five-year EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularisation) trial definition for MI highlighted higher MI rates for PCI compared to CABG (OR 1.66, P < 0.05). Intriguingly, when the subsequently released EXCEL data, aligned with the third universal MI definition, was incorporated, the five-year data consistently leaned towards CABG. Specifically, the PCI group exhibited 7.5% MI rates in contrast to the 3.6% in the CABG cohort (OR 2.19, P < 0.001). Concerning stroke, PCI proved advantageous at 30 days and 1 year while exhibiting no significant disparity at 5 and 10 years. Revascularisation procedures favoured CABG at one and five years, with comparability at the remaining time points. In summation, the outcomes of this comprehensive meta-analysis suggest that PCI could serve as a feasible alternative to CABG in the context of uncomplicated LMCA disease. It's worth noting that CABG might still hold an advantage for complex lesions.

Therapeutic games to reduce anxiety and depression in young people: A systematic review and exploratory meta-analysis of their use and effectiveness.

OBJECTIVE: The development of serious games for mental wellbeing is a topic of growing interest. The increase in acceptance of games as a mainstream entertainment medium combined with the immersive qualities of games provides opportunities for meaningful support and intervention in mental wellbeing. METHOD: We conducted a systematic review and exploratory meta-analysis to examine if aspects of the interventions influenced outcomes as measured via overall effect sizes. We employed a multilevel meta-analytic approach to accommodate the interdependency of effect sizes (18 effect sizes from 14 studies, with 2027 participants). RESULTS: Overall, the main effect for gaming interventions on any outcome variable was small to medium sized, d = .35 (confidence interval [.23, 47], p < .001). Results revealed that the only significant moderator was the nature of the intervention. Specifically, only interventions that included a rational emotional behavioural focus significantly predicted an improvement in depression and/or anxiety in participants. CONCLUSION: The findings reveal promising effects for therapeutic games for mental health, but replications are needed, alongside the addressing of methodological and procedural concerns.

Microglial and Astrocytic Responses in the Human Midcingulate Cortex in Huntington's Disease.

OBJECTIVE: Patients with Huntington's disease can present with variable difficulties of motor functioning, mood, and cognition. Neurodegeneration occurs in the anterior cingulate cortex of some patients with Huntington's disease and is linked to the presentation of mood symptomatology. Neuroinflammation, perpetrated by activated microglia and astrocytes, has been reported in Huntington's disease and may contribute to disease progression and presentation. This study sought to quantify the density of mutant huntingtin protein and neuroinflammatory glial changes in the midcingulate cortex of postmortem patients with Huntington's disease and determine if either correlates with the presentation of mood, motor, or mixed symptomatology. METHODS: Free-floating immunohistochemistry quantified 1C2 immunolabeling density as an indicative marker of mutant huntingtin protein, and protein and morphological markers of astrocyte (EAAT2, Cx43, and GFAP), and microglial (Iba1 and HLA-DP/DQ/DR) activation. Relationships among the level of microglial activation, mutant huntingtin burden, and case characteristics were explored using correlative analysis. RESULTS: We report alterations in activated microglia number and morphology in the midcingulate cortex of Huntington's disease cases with predominant mood symptomatology. An increased proportion of activated microglia was observed in the midcingulate of all Huntington's disease cases and positively correlated with 1C2 burden. Alterations in the astrocytic glutamate transporter EAAT2 were observed in the midcingulate cortex of patients associated with mood symptoms. INTERPRETATION: This study presents pathological changes in microglia and astrocytes in the midcingulate cortex in Huntington's disease, which coincide with mood symptom presentation. These findings further the understanding of neuroinflammation in Huntington's disease, a necessary step for developing inflammation-targeted therapeutics. ANN NEUROL 2023;94:895-910.

Co-producing Human and Animal Experimental Subjects: Exploring the Views of UK COVID-19 Vaccine Trial Participants on Animal Testing.

Preclinical (animal) testing and human testing of drugs and vaccines are rarely considered by social scientists side by side. Where this is done, it is typically for theoretically exploring the ethics of the two situations to compare relative treatment. In contrast, we empirically explore how human clinical trial participants understand the role of animal test subjects in vaccine development. Furthermore, social science research has only concentrated on broad public opinion and the views of patients about animal research, whereas we explore the views of a public group particularly implicated in pharmaceutical development: experimental subjects. We surveyed and interviewed COVID-19 vaccine trial participants in Oxford, UK, on their views about taking part in a vaccine trial and the role of animals in trials. We found that trial participants mirrored assumptions about legitimate reasons for animal testing embedded in regulation and provided insight into (i) the nuances of public opinion on animal research; (ii) the co-production of human and animal experimental subjects; (iii) how vaccine and medicine testing, and the motivations and demographics of clinical trial participants, change in an outbreak; and (iv) what public involvement can offer to science.

Spatial dynamics of malaria transmission.

The Ross-Macdonald model has exerted enormous influence over the study of malaria transmission dynamics and control, but it lacked features to describe parasite dispersal, travel, and other important aspects of heterogeneous transmission. Here, we present a patch-based differential equation modeling framework that extends the Ross-Macdonald model with sufficient skill and complexity to support planning, monitoring and evaluation for Plasmodium falciparum malaria control. We designed a generic interface for building structured, spatial models of malaria transmission based on a new algorithm for mosquito blood feeding. We developed new algorithms to simulate adult mosquito demography, dispersal, and egg laying in response to resource availability. The core dynamical components describing mosquito ecology and malaria transmission were decomposed, redesigned and reassembled into a modular framework. Structural elements in the framework-human population strata, patches, and aquatic habitats-interact through a flexible design that facilitates construction of ensembles of models with scalable complexity to support robust analytics for malaria policy and adaptive malaria control. We propose updated definitions for the human biting rate and entomological inoculation rates. We present new formulas to describe parasite dispersal and spatial dynamics under steady state conditions, including the human biting rates, parasite dispersal, the "vectorial capacity matrix," a human transmitting capacity distribution matrix, and threshold conditions. An [Formula: see text] package that implements the framework, solves the differential equations, and computes spatial metrics for models developed in this framework has been developed. Development of the model and metrics have focused on malaria, but since the framework is modular, the same ideas and software can be applied to other mosquito-borne pathogen systems.

The collective voice of early phase COVID-19 vaccine trial participants: Insights for improving confidence in novel vaccines.

In early 2020, adult volunteers were invited to participate in a first-in-human trial of the COVID-19 vaccine, ChAdOx1 nCoV-19, in the United Kingdom (UK) at the height of the global pandemic when there was uncertainty regarding vaccine efficacy and side-effects. We conducted a retrospective survey of these uniquely situated individuals to gain insight into their views about the risks, motivations, and expectations of the trial and potential vaccine deployment. Our data from 349 respondents show that these volunteers were educated to a high-level with a clear understanding of the seriousness of the COVID-19 pandemic, as well as an appreciation of the role of science and research in developing a vaccine to address this global problem. Individuals were primarily motivated with altruistic intent and expressed a desire to contribute to the scientific effort. Respondents appreciated that their participation was associated with risk but appeared comfortable that this risk was low. Through our analysis, we highlight these individuals as a group with strong levels of trust in science and a sense of societal responsibility, and therefore are a potential valuable resource to improve confidence in novel vaccines. Vaccine trial participants could offer a credible collective voice to support positive messaging around vaccination.

Use of Cognitive and Behavioral Strategies During a Weight Loss Program: A Secondary Analysis of the Doctor Referral of Overweight People to Low-Energy Total Diet Replacement Treatment (DROPLET) Trial.

BACKGROUND: Achieving a sustained energy deficit is essential for weight loss, but the cognitive and behavioral strategies that support this goal are unclear. OBJECTIVE: The goal of this study was to investigate the number and type of cognitive and behavioral strategies used by participants who were enrolled in a 1-year weight loss trial and to explore associations between strategies and magnitude of weight loss at 3 months and 1 year. DESIGN: The study is a secondary post-hoc exploratory analysis of data collected as part of the Doctor Referral of Overweight People to Low-Energy total diet replacement Treatment (DROPLET), a randomized controlled trial conducted in general practices in England, United Kingdom, between January 2016 and August 2017. PARTICIPANTS/SETTING: This study involved 164 participants from both intervention and control groups of the DROPLET trial who completed the Oxford Food and Behaviours (OxFAB) questionnaire to assess the use of 115 strategies grouped into 21 domains used to manage their weight. INTERVENTIONS: Participants were randomized to either a behavioral weight loss program involving 8 weeks total diet replacement (TDR) and 4 weeks of food reintroduction or a program delivered by a medical practice nurse over a 3-month period (usual care [UC]). MAIN OUTCOME MEASURES: Weight was objectively measured at baseline, 3 months, and 1 year. Cognitive and behavioral strategies used to support weight loss were assessed using the OxFAB questionnaire at 3 months. STATISTICAL ANALYSIS PERFORMED: Exploratory factor analysis was used to generate data-driven patterns of strategy use, and a linear mixed-effects model was used to examine associations between use of these patterns and weight change. RESULTS: No evidence was found of a difference in the number of strategies (mean difference, 2.41; 95% confidence interval [CI], -0.83, 5.65) or the number of domains used (mean difference, -0.23; 95% CI, -0.69, 0.23) between the TDR group and the UC group. The number of strategies was not associated with weight loss at either 3 months (-0.02 kg; 95% CI, -0.11, 0.06) or 1 year (-0.05 kg; 95% CI, -0.14, 0.02). Similarly, the number of domains used was not associated with weight loss at 3 months (-0.02 kg; 95% CI, -0.53, 0.49) or 1 year (-0.07 kg; 95% CI, -0.60, 0.46). Factor analysis identified four coherent patterns of strategy use, identified as Physical Activity, Motivation, Planned Eating, and Food Purchasing patterns. Greater use of strategies in the Food Purchasing (-2.6 kg; 95% CI, -4.42, -0.71) and Planned Eating patterns (-3.20 kg; 95% CI, -4.94, -1.46) was associated with greater weight loss at 1 year. CONCLUSIONS: The number of cognitive and behavioral strategies or domains used does not appear to influence weight loss, but the types of strategy appear of greater importance. Supporting people to adopt strategies linked to planned eating and food purchasing may aid long-term weight loss.

Newton's 'De Aere et Aethere' and the introduction of interparticulate forces into his physics.

As well as the mathematically-supported celestial mechanics that Newton developed in his Principia, Newton also proposed a more speculative natural philosophy of interparticulate forces of attraction and repulsion. Although this speculative philosophy was not made public before the 'Queries' which Newton appended to the Opticks, it originated far earlier in Newton's career. This article makes the case that Newton's short, unfinished manuscript, entitled 'De Aere et Aethere', should be seen as an important landmark in Newton's intellectual development, being the first work in which Newton assumed there are repulsive forces operating at a distance between the particles of bodies. The article offers an account of how Newton came to write 'De Aere et Aethere' and why. It also outlines its relationship to the 'Conclusio', with which Newton briefly intended to finish the Principia, and to the 'Queries' in the Opticks. The date of the manuscript is disputed, and the article also aims to settle this dispute. Claims that the 'De Aere et Aethere' must have been written before the 'Hypothesis... of Light' of 1675 are dismissed, and it is suggested, following R. S. Westfall, that it was written after a well-known letter Newton wrote to Boyle early in 1679.

Developing a symptoms-based risk score for infectious syphilis among men who have sex with men.

BACKGROUND: Syphilis incidence is rising among men who have sex with men (MSM). An online tool based on a risk score identifying men with higher risk of infectious syphilis could motivate MSM to seek care. We aimed therefore to develop a symptoms-based risk score for infectious syphilis. METHODS: We included data from all consultations by MSM attending the Amsterdam Centre for Sexual Health in 2018-2019. Infectious syphilis (ie, primary, secondary or early latent syphilis) was diagnosed according to the centre's routine protocol. Associations between symptoms and infectious syphilis were expressed as odds ratios (OR), with 95% confidence intervals (CI). Based on multivariable logistic regression models, we created risk scores, combining various symptoms. We assessed the area under the curve (AUC) and cut-off based on the Youden Index. We estimated which percentage of MSM should be tested based on a positive risk score and which percentage of infectious syphilis cases would then be missed. RESULTS: We included 21,646 consultations with 11,594 unique persons. The median age was 34 years (IQR 27-45), and 14% were HIV positive (93% on antiretroviral treatment). We diagnosed 538 cases of infectious syphilis. Associations with syphilis symptoms/signs were strong and highly significant, for example, OR for a painless penile ulcer was 35.0 (CI 24.9 to 49.2) and OR for non-itching rash 57.8 (CI 36.8 to 90.9). Yet, none of the individual symptoms or signs had an AUC >0.55. The AUC of risk scores combining various symptoms varied from 0.68 to 0.69. For all risk scores using cut-offs based on Youden Index, syphilis screening would be recommended in 6% of MSM, and 59% of infectious syphilis cases would be missed. CONCLUSION: Symptoms-based risk scores for infectious syphilis perform poorly and cannot be recommended to select MSM for syphilis screening. All MSM with relevant sexual exposure should be regularly tested for syphilis.

An exploration of maternity and newborn exposure, training and education among staff working within the North West Ambulance Service.

Aim: Providing emergency and urgent care to pregnant patients and newborns in the pre-hospital setting often presents some of the most challenging and complex incidents attended to by ambulance staff. A service evaluation survey was undertaken to explore current levels of maternity and newborn education, preferred methods of training delivery, exposure and perceived support surrounding maternity and newborn care provision among pre-hospital clinicians working within the North West Ambulance Service (NWAS) NHS Trust. Methods: An online, anonymised survey compromising of 22 questions using multiple choice options and free-text questions was circulated among NWAS staff between 27 May 2021 and 21 June 2021. Questions explored the levels of training, education, exposure and confidence relating to maternal and newborn care in the pre-hospital setting. Insights into preferred approaches to engaging with continuing professional development (CPD) activities were also captured. Data were analysed using built-in Microsoft Forms analytics for quantitative response, with a basic thematic analysis undertaken to synthesise qualitative responses. Results: The survey received 509 responses, with data providing valuable insight relating to gaps in training provision, preferred approaches to CPD and barriers to engagement. Key themes focused on 'pre-registration standards and variations', 'barriers and facilitators to continuing professional development' and 'exposure and skill decline: confidence and knowledge'. Conclusion: Areas for service improvement are highlighted, providing ambulance trusts and integrated care systems with key recommendations. These include maternity and newborn standards for education among paramedic science degree programmes; recognition of pre-hospital emergency maternity and newborn care among maternity providers; the need for exposure and regular multidisciplinary team (MDT) skills training for staff; and a collaborative system-led approach to scaling up and delivering MDT training that acknowledges pre-hospital clinicians as key care providers.

Monitoring of Post-Brain Injuries By Measuring Plasma Levels of Neuron-Derived Extracellular Vesicles.

Background: Extracellular vesicles (EV) released from neurons into the blood can reflect the state of nervous tissue. Measurement of neuron derived EV (NDE) may serve as an indicator of brain injury. Methods: A sandwich immunoassay was established to measure plasma NDE using anti-neuron CD171 and anti-EV CD9 ([CD171 + CD9+]). Plasma samples were obtained from commercial sources, cross-country (n = 9), football (n = 22), soccer (n = 19), and rugby (n = 18) athletes over time. Plasma was also collected from patients undergoing total aortic arch replacement (TAR) with selective cerebral perfusion during cardiopulmonary bypass before and after surgery (n = 36). Results: The specificity, linearity, and reproducibility of NDE assay (measurement of [CD171 + CD9+]) were confirmed. By scanning electron microscopy and nanoparticle tracking, spherical vesicles ranging in size from 150 to 300 nm were confirmed. Plasma levels of NDE were widely spread over 2 to 3 logs in different individuals with a significant age-dependent decrease. However, NDE were very stable in each individual within a ± 50% change over time (cross-country, football, soccer), whereas rugby players were more variable over 4 years. In patients undergoing TAR, NDE increased rapidly in days post-surgery and were significantly (P = .0004) higher in those developing postoperative delirium (POD) (n = 13) than non-delirium patients (n = 23). Conclusions: The blood test to determine plasma levels of NDE was established by a sandwich immunoassay using 2 antibodies against neuron (CD171) and exosomes (CD9). NDE levels varied widely in different individuals and decreased with age, indicating that NDE levels should be considered as a normalizer of NDE biomarker studies. However, NDE levels were stable over time in each individual, and increased rapidly after TAR with greater increases associated with patients developing POD. This assay may serve as a surrogate for evaluating and monitoring brain injuries.

Dynein localization and pronuclear movement in the C. elegans zygote.

Centrosomes serve as a site for microtubule nucleation and these microtubules will grow and interact with the motor protein dynein at the cortex. The position of the centrosomes determines where the mitotic spindle will develop across all cell types. Centrosome positioning is achieved through dynein and microtubule-mediated force generation. The mechanism and regulation of force generation during centrosome positioning are not fully understood. Centrosome and pronuclear movement in the first cell cycle of the Caenorhabditis elegans early embryo undergoes both centration and rotation prior to cell division. The proteins LET-99 and GPB-1 have been postulated to have a role in force generation associated with pronuclear centration and rotation dynamics. When the expression of these proteins is perturbed, pronuclear positioning exhibits a movement defect characterized by oscillatory ("wobble") behavior of the pronuclear complex (PNC). To determine if this movement defect is due to an effect on cortical dynein distribution, we utilize RNAi-mediated knockdown of LET-99 and GPB-1 to induce wobble and assay for any effects on GFP-tagged dynein localization in the early C. elegans embryo. To compare and quantify the movement defect produced by the knockdown of LET-99 and GPB-1, we devised a quantification method that measures the strength of wobble ("wobble metric") observed under these experimental conditions. Our quantification of pronuclear complex dynamics and dynein localization shows that loss of LET-99 and GPB-1 induces a similar movement defect which is independent of cortical dynein localization in the early C. elegans embryo.

Quality of life of cutaneous leishmaniasis suspected patients in the Ecuadorian Pacific and Amazon regions: a cross sectional study.

BACKGROUND: Yearly, up to 1 million patients worldwide suffer from cutaneous leishmaniasis (CL). In Ecuador, CL affects an estimated 5000 patients annually. CL leads to reduced Health Related Quality of Life (HRQL) as a result of stigma in the Asian and Mediterranean contexts, but research is lacking for Ecuador. The objective of this study was to explore the influence of CL suspected lesions on the quality of life of patients in the Pacific and Amazon regions. METHODS: Patients for this study were included in the Amazonian Napo, Pastaza, and Morona Santiago provinces and the Pacific region of the Pichincha province. Participating centers offered free of charge CL treatment. All patients suspected of CL and referred for a cutaneous smear slide microscopy examination were eligible. This study applied the Skindex-29 questionnaire, a generic tool to measure HRQL in patients with skin diseases. All statistical analysis was done with SPSS Statistics version 28. RESULTS: The skindex-29 questionnaire was completed adequately by 279 patients who were included in this study. All patient groups from the Amazon scored significantly (P < 0.01) higher (indicating worse HRQL) on all the dimensions of the Skindex-29 questionnaire than Mestizo patients from the Pacific region. The percentage of patients with health seeking delay of less than a month was significantly (P < 0.01) lower in the Amazon region (38%) than in the Pacific (66%). CONCLUSIONS: The present study revealed that the influence of suspected CL lesions on the HRQL of patients in the Ecuadorian Amazon and Pacific depends on the geographic region more than on patient characteristics such as gender, age, number of lesions, lesion type, location of lesions, health seeking delay, or posterior confirmation of the Leishmania parasite. The health seeking delay in the Amazon might result from a lack of health infrastructure or related stigma. Together, the impaired HRQL and prolonged health seeking delay in the Amazon lead to prolonged suffering and a worse health outcome. Determinants of health seeking delay should be clarified in future studies and CL case finding must be improved. Moreover, HRQL analysis in other CL endemic regions could improve local health management.

Infection age as a predictor of epidemiological metrics for malaria.

BACKGROUND: Accurate estimation of the burden of Plasmodium falciparum is essential for strategic planning for control and elimination. Due in part to the extreme heterogeneity in malaria exposure, immunity, other causes of disease, direct measurements of fever and disease attributable to malaria can be difficult. This can make a comparison of epidemiological metrics both within and between populations hard to interpret. An essential part of untangling this is an understanding of the complex time-course of malaria infections. METHODS: Historic data from malariatherapy infections, in which individuals were intentionally infected with malaria parasites, were reexamined in aggregate. In this analysis, the age of each infection was examined as a potential predictor describing aggregate patterns across all infections. A series of piecewise linear and generalized linear regressions were performed to highlight the infection age-dependent patterns in both parasitaemia and gametocytaemia, and from parasitaemia and gametocytaemia to fever and transmission probabilities, respectively. RESULTS: The observed duration of untreated patent infection was 130 days. As infections progressed, the fraction of infections subpatent by microscopy was seen to increase steadily. The time-averaged malaria infections had three distinct phases in parasitaemia: a growth phase for the first 6 days of patency, a rapid decline from day 6 to day 18, and a slowly declining chronic phase for the remaining duration of the infection. During the growth phase, parasite densities increased sharply to a peak. Densities sharply decline for a short period of time after the peak. During the chronic phase, infections declined steadily as infections age. gametocytaemia was strongly correlated with lagged asexual parasitaemia. Fever rates and transmission efficiency were strongly correlated with parasitaemia and gametocytaemia. The comparison between raw data and prediction from the age of infection has good qualitative agreement across all quantities of interest for predicting averaged effects. CONCLUSION: The age of infection was established as a potentially useful covariate for malaria epidemiology. Infection age can be estimated given a history of exposure, and accounting for exposure history may potentially provide a new way to estimate malaria-attributable fever rates, transmission efficiency, and patent fraction in immunologically naïve individuals such as children and people in low-transmission regions. These data were collected from American adults with neurosyphilis, so there are reasons to be cautious about extending the quantitative results reported here to general populations in malaria-endemic regions. Understanding how immune responses modify these statistical relationships given past exposure is key for being able to apply these results more broadly.

Barriers and Motives for Complying With "Sexual Distancing" Among Men Who Have Sex With Men During the First COVID-19 Pandemic Lockdown in Amsterdam: A Qualitative Study.

BACKGROUND: Between March 15 and May 31, 2020, the Dutch government imposed lockdown and health measures to curb the coronavirus disease 2019 (COVID-19) pandemic. As part of social distancing, sexual distancing was one of these measures. Sexual distancing implied refraining from sex with partners outside of one's household. We aimed to elucidate barriers and motives for complying with sexual distancing and related factors that could have led to (non)compliance among men who have sex with men. METHODS: In this exploratory qualitative study, we interviewed men who have sex with men who visited the center for sexual health in Amsterdam during the first COVID-19 lockdown using a semistructured interview guide from March to May 2020. We interviewed both men who complied and did not comply with sexual distancing. The interviews were transcribed verbatim and analyzed using an open-coding process in MAXQDA. RESULTS: We included 18 noncompliers and 4 compliers to COVID-19 sexual distancing. Barriers to compliance were the following: lack of information on, or understanding of, the need for sexual distancing; being single; having had an active sex life before COVID-19; a high perceived importance of the social aspect of sex; a strong urge for sex; using sex to cope with the negative impact of the pandemic; being under the influence of alcohol or drugs; and not perceiving COVID-19 as a serious health threat. Motives for compliance were the following: perceiving COVID-19 as a serious health threat, direct confrontation with critically ill COVID-19 patients, protecting someone dear from COVID-19, and being convinced of the importance of social and/or sexual distancing measures. CONCLUSIONS: Information on sexual distancing needs to be made more explicit, accessible, understandable, inclusive, customized to individual barriers, and relatable to the key populations. This may improve the effectiveness of measures and health recommendations in both the current COVID-19 pandemic and future respiratory outbreaks.

Lifestyle advice for hypertension or diabetes: trend analysis from 2002 to 2017 in England.

BACKGROUND: Guidelines recommend that GPs give patients lifestyle advice to manage hypertension and diabetes. Increasing evidence shows that this is an effective and practical treatment for these conditions, but it is unclear whether GPs offer this support. AIM: To investigate trends in the percentage of patients with hypertension/diabetes receiving lifestyle advice versus medication. DESIGN AND SETTING: This was a trend analysis of self-reported data from the annual Health Survey for England (HSE) (2003-2017) and GP-recorded data from the QResearch database (2002-2016). METHOD: The percentage of patients with hypertension or diabetes who received lifestyle advice or medication was calculated in each year. Associations between likelihood of receiving lifestyle advice and characteristics were assessed using multivariable logistic regression. RESULTS: The percentage of patients receiving lifestyle advice was consistently lower than those receiving medication in both self-reported and medical records. There was consistent evidence of increasing trends in the percentage of patients with hypertension receiving lifestyle advice (HSE 13.8% to 20.1%; Ptrend <0.001; QResearch 11.0% to 22.7%; Ptrend <0.001). For diabetes, there was a non-significant decline in self-reported receipt of lifestyle advice (45.0% to 27.9%; Ptrend = 0.111) and a significant increase in medically recorded delivery of this advice (20.7% to 40.5%; Ptrend <0.001). Patients with hypertension who were overweight or obese were more likely to receive lifestyle advice than those of a healthy weight, whereas the opposite was true for diabetes. CONCLUSION: Only a minority of patients with diabetes or hypertension report receiving lifestyle advice or have this recorded in their medical records. Interventions beyond guidelines are needed to increase the delivery of behavioural interventions to treat these conditions.