Periodic Paralysis in a Child With Thermosensitive Mitochondrial Trifunctional Protein Deficiency.

Mitochondrial trifunctional protein (MTP) deficiency is a fatty acid oxidation disorder associated with a spectrum of phenotypes. Patients with high residual enzyme activity tend to have milder phenotypes, and recently, fever-induced episodic myopathy was reported in association with a thermosensitive form of MTP deficiency. We report a 10-year-old male with recurrent episodes of acute flaccid paralysis involving upper and lower extremities in association with bulbar muscle weakness in the context of febrile illness, a phenotype reminiscent of recurrent periodic paralysis. The episodes started at the age of 3 years and have always been followed by full recovery within 1-2 weeks with no residual weakness. Whole exome sequencing revealed a homozygous c.2132C > T, p.(Pro711Leu) variant in HADHA. The variant leads to mildly reduced long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain ketoacyl-CoA thiolase (LCKAT) enzyme activities and reduced MTP protein expression in patient's fibroblasts when cultured at 37°C. Enzyme activities and MTP protein expression diminished when fibroblasts were cultured at 40°C. This is the first published report of confirmed recurrent periodic paralysis as a manifestation of a thermosensitive form of MTP deficiency, and it calls for this condition to be considered when evaluating patients with recurrent periodic paralysis given therapeutic implications.

Evaluating non-photochemical quenching (NPQ) kinetics and photosynthetic efficiency in cassava (Manihot esculenta) subjected to variable high light conditions.

Light intensity is a critical environmental factor influencing plant growth and development. To survive high light conditions, plants have evolved various protective mechanisms, including non-photochemical quenching (NPQ). However, NPQ can limit effective photosynthetic yield when transitioning to low light conditions. This phenomenon is underexplored in cassava (Manihot esculenta ), a starchy storage root crop known for its high biological efficiency and climate resilience. To address this knowledge gap, we assessed the photoprotective abilities and growth responses of six cassava varieties under natural environmental light conditions (control) and intermittent high light (IHL) conditions by adding 900µmolm-2 s-1 using full-spectrum LED lights, on top of the natural ambient daylight. Our results demonstrated a significant impact of light treatment on aboveground biomass, total crop biomass, chlorophyll a and b content, photosynthetic rate, and NPQ values during transitions from low to high light and vice versa. Notably, cassava variety 'Sree Suvarna' exhibited the highest yield under both control and IHL conditions. These findings suggest that screening cassava varieties for their ability to postpone photoinhibition and recover quickly from photoinhibition may enhance photosynthetic performance. Such strategies have important implications for improving the efficiency and resilience of cassava crops, ultimately contributing to sustainable agricultural productivity.

Early prediction and impact assessment of CYP3A4-related drug-drug interactions for small molecule anti-cancer drugs using human-CYP3A4-transgenic mouse models.

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here, we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (CYP)3A4 related DDIs of small molecule anti-cancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99 to 1.31 fold from clinical trial results for inhibition with itraconazole, while exposure predictions for the induction with rifampicin were less accurate with deviations of 0.22 to 0.48 fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method. Significance Statement The described method offers an alternative for the early detection and assessment of potential clinical impact of CYP3A4-related DDIs. The model was able to adequately describe the inhibition of CYP3A4 metabolism and the subsequent magnitude of change in exposure. However, it was unable to accurately predict the magnitude of change in exposure of victim drugs in combination with an inducer.

European Society of Intensive Care Medicine guidelines on end of life and palliative care in the intensive care unit.

The European Society of Intensive Care Medicine (ESICM) has developed evidence-based recommendations and expert opinions about end-of-life (EoL) and palliative care for critically ill adults to optimize patient-centered care, improving outcomes of relatives, and supporting intensive care unit (ICU) staff in delivering compassionate and effective EoL and palliative care. An international multi-disciplinary panel of clinical experts, a methodologist, and representatives of patients and families examined key domains, including variability across countries, decision-making, palliative-care integration, communication, family-centered care, and conflict management. Eight evidence-based recommendations (6 of low level of evidence and 2 of high level of evidence) and 19 expert opinions were presented. EoL legislation and the importance of respecting the autonomy and preferences of patients were given close attention. Differences in EoL care depending on country income and healthcare provision were considered. Structured EoL decision-making strategies are recommended to improve outcomes of patients and relatives, as well as staff satisfaction and mental health. Early integration of palliative care and the use of standardized tools for symptom assessment are suggested for patients at high risk of dying. Communication training for ICU staff and printed communication aids for families are advocated to improve outcomes and satisfaction. Methods for enhancing family-centeredness of care include structured family conferences and culturally sensitive interventions. Conflict-management protocols and strategies to prevent burnout among healthcare professionals are also considered. The work done to develop these guidelines highlights many areas requiring further research.

Chronotype, sleep quality, depression and pre-sleep rumination: A diary and actigraphy study.

Eveningness has been associated with both disturbed sleep and depression. It is unclear, however, if deprived sleep explains evening types' vulnerability to depression. The role of pre-sleep rumination in these associations also remains understudied. The present study assessed the relationship between eveningness and sleep quality, as well as the possible mediating effect of pre-sleep rumination and the moderating effect of a history of depression, under naturalistic conditions. Eighty-eight Dutch-speaking participants (87.5% females, 21.4 ± 3.7 years) were selected on the basis of their non-intermediate chronotype using the Morningness Eveningness Questionnaire (evening types (n = 53); morning types (n = 35)). Depression status was assessed through a diagnostic interview (healthy (n = 61); remitted depressed (n = 27)). Participants' sleep characteristics were monitored via actigraphy and sleep diaries for seven consecutive days and nights. Pre-sleep rumination was measured via a self-report questionnaire. Evening types had longer subjective and actigraphic sleep onset latency than morning types. Pre-sleep rumination did not mediate the former associations but predicted longer subjective sleep onset latency. Furthermore, the relationship between chronotype and subjective sleep onset latency was moderated by depression history. Remitted depressed evening types reported longer sleep onset latency than healthy evening and morning types, possibly posing the former at a higher risk for depressive relapse. Overall, the current findings address the need to further investigate the physiological signature of circadian rhythms and sleep latency. This could serve as a foundation for the development of prevention and early intervention programs, tailored for mood and sleep disorders.

The effect of active vitamin D supplementation on body weight and composition: A meta-analysis of individual participant data.

BACKGROUND & AIMS: Obesity is associated with vitamin D (VitD) deficiency. However, previous studies showed mixed effects of VitD (25-hydroxyVitD/calcidiol) supplementation on body weight. The biological actions of VitD require the hydroxylation of inactive VitD into active VitD (1.25-dihydroxyVitD/calcitriol). This step is highly regulated; therefore, supplementing with inactive VitD might not be sufficient to overcome the potential adverse health effects of VitD deficiency. The objective of this study was to conduct a systematic review and individual participant data (IPD) meta-analysis of data acquired from randomised placebo-controlled calcitriol trials (RCTs) to determine the effects of calcitriol on body weight and weight-related parameters. METHODS: Studies were identified from MEDLINE, EMBASE, and CENTRAL databases up to January 27, 2024, and excluded those involving dialysis or cancer patients. We obtained IPD from eligible trials and assessed bias using the Cochrane Collaboration risk-of-bias tool and methodological quality using the Heyland Methodological Quality Score. The study was prospectively registered with PROSPERO (CRD42017076202). RESULTS: Although none of the studies reported information regarding our primary objective, we obtained IPD for 411 patients, with 206 randomised to receive calcitriol and 205 to placebo. This dataset enabled us to conduct an IPD meta-analysis with 17,084 person-months of follow-up (median: 11 months). Meta-analysis showed that calcitriol does not alter body weight, BMI, waist circumference, fat mass or lean body mass compared to placebo. Adjusting for age and sex did not alter the outcomes. CONCLUSIONS: In conclusion, this systematic review and IPD meta-analysis indicate that calcitriol does not affect body weight in normal-weight postmenopausal women and lean patients with type 1 diabetes nor in people suffering from obesity, type 2 diabetes and chronic kidney disease. Whether calcitriol lowers body weight in VitD-sufficient people with obesity remains to be elucidated.

A scoping review to map the implications of reusing single-use endotracheal suctioning catheter practices in mechanically ventilated patients.

INTRODUCTION: Currently there is limited evidence of the frequency of using endotracheal suctioning catheters. Due to limited resources, many low- and middle-income countries still reuse single-use suction catheters multiple times during the length of a nursing shift. This scoping review was conducted to map the impact of reusing single-use endotracheal suctioning catheters practices on mechanically ventilated patients' outcomes. METHODS: The scoping review was conducted in accordance with the JBI methodology for scoping reviews. Four databases systematically searched using predefined keywords (CINAHL, EMBASE, MEDLINE, GLOBAL HEALTH). Key electronic journals were hand searched, while reference lists of included documents and grey literature sources were screened thoroughly. Two independent reviewers completed the study selection and data extraction. A third reviewer made the final decision on any disagreements disputed records. RESULTS: In total 22 articles were identified, and 14 non-duplicate records were screened, and 8 articles were screened for full text. Six articles met the inclusion criteria and were included in this review. Differences were observed on the findings of included studies, two studies identified that reusing single-use suction catheter might increases the risk of respiratory infection, while two other studies identified no difference in contamination rate between single used or multiple-used catheters. One study indicated that reusing single-use catheters are a safe and cost-effective intervention and finally one study reported that reusing single-use catheters might reduce incidence of ventilator associated pneumonia if flushed with chlorhexidine after suctioning. CONCLUSIONS: There is no strong evidence of the frequency of using endotracheal suction catheters. Further research is needed comparing single-used versus multiple-used endotracheal suction catheters in mechanically ventilated patients. IMPLICATION FOR CLINICAL PRACTICE: Nurses in resource-limited countries can follow their hospital policy regarding the changing frequency of endotracheal suction catheters due to lack of a robust evidence. Flushing suction circuits with chlorhexidine while reusing single-use catheters might reduce the risk of respiratory infections in these hospitals.

Improving Quality of Life With Dynamic Compression Bracing in Patients With Pectus Carinatum.

BACKGROUND: Patients with pectus carinatum have lower quality of life and self-esteem than their peers. We assessed the impact of dynamic compression system bracing on quality of life in patients with pectus carinatum. METHODS: We conducted a prospective cohort study on patients aged 10-21 years. We assessed quality of life using the Child Health Questionnaire-87, the State-Trait Anxiety Inventory-6, the World Health Organization Quality of Life-BREF, the 36-Item Short Form Survey, and the Single-Step Questionnaire adapted for pectus carinatum. RESULTS: Between March 2013 and March 2016, 225 patients treated with dynamic compression system bracing were included. Patients showed improvements across the overall scores of the 36-Item Short Form Survey (Δ7.7 (2.9-12.4)), Single-Step Questionnaire (Δ4.1 (2.0-6.3)) and three out of four World Health Organization Quality of Life-BREF domains (physical health (Δ8.7 (3.7-13.7)), psychological health (Δ11.8 (6.1-17.5)), environment (Δ5.7 (0.2-11.3))). No changes across the Child Health Questionnaire-87 overall score were observed (Δ5.5 (-0.5-11.5)). Most improvement occurred within six to twelve months after treatment initiation, stabilizing thereafter. Anxiety scores on the State-Trait Anxiety Inventory-6 did not improve (Δ0.5 (-0.1-1.2)). Scores on physical complaints, pain, psychological health and self-esteem/self-image improved across all questionnaires. In contrast to the successfully treated group, the unsuccessfully treated group showed no improvement on any of the questionnaires. Most patients (87.2 %) would choose bracing again, 94.9 % of patients were satisfied with the treatment. CONCLUSIONS: Dynamic compression system bracing improves quality of life, reduces physical complaints and pain and boosts psychological health and self-esteem in patients with pectus carinatum.

Estimates of life-history and growth parameters of exploited fish species in lakes Edward and George: Implications on exploitation status, population dynamics, management, and conservation of native species.

Adequate knowledge is essential for responsible inland fisheries. However, many inland fisheries lack monitoring, and therefore, decision-making for fisheries management is not reliable. In this paper, we used data from surveys and literature to estimate the life-history and growth parameters of 16 exploited fish stocks in the Ugandan part of Lake Edward and Lake George (East Africa). The estimated parameters are pivotal indicators of fish stock status, particularly in data-poor fisheries. The estimated parameters included maximum length (Lmax) and mean length (Lmean) as indicators of size structure in experimental and commercial catches, coefficients of length-weight relationships, length at 50% maturity (Lm50), fecundity, von Bertalanffy parameters, total mortality (Z), and natural mortality (M). These parameters were estimated using empirical formulae, statistical methods, and analyses of length frequencies. Only two stocks of semutundu Bagrus docmak exhibited significant and increasing trends in Lmax (Lake Edward) and Lmean (Lake George). The estimates for the remaining parameters were consistent with those in FishBase and other literature resources, either for the same species or related species. This consistency indicates their reliability for application in decision-making and further assessments. Some parameters showed evidence of unsustainable fishing. For example, estimates of Lm50 for four of the assessed stocks belonging to two species (Nile tilapia Oreochromis niloticus and marbled lungfish Protopterus aethiopicus) were lower than baseline estimates in the studied waterbodies. Furthermore, the Lmean in catches for all the stocks were less than the optimum lengths (Lopt), which maximize catches with a minimal impact on biomass and size structure. No significant changes in Lmean, length-frequency distributions, and size at maturity could be attributed to the management changes implemented in 2018, probably because it is too early to observe changes in these parameters. However, there are positive signs attributable to the changes in management as shown by a high proportion of mature individuals in commercial catches for most of the stocks for which the proportion was calculated, and an increase in Lmean and Lmax for some stocks, such as B. docmak, in commercial or experimental catches. New estimates from this study will enhance decision-making and further assessments of fisheries. Routine monitoring is recommended to update and improve the estimates.

Mean cycloplegic refractive error in emmetropic adults – The Tehran Eye Study / Error refractivo ciclopléjico medio en adultos emétropes: estudio ocular de Teherán

Purpose: In children under 20 years, refractive development targets a cycloplegic refractive error of +0.5 to +1.5D, while presbyopes over 40 years generally have non-cycloplegic errors of ≥ +1D. Some papers suggest these periods are separated by a period of myopic refractive error (i.e., ≤ –0.50D), but this remains unclear. Hence, this work investigates the mean cycloplegic refractive error in adults aged between 20 – 40 years. Methods: In 2002 a cross-sectional study with stratified cluster sampling was performed on the population of Tehran, providing cycloplegic and non-cycloplegic refractive error data for the right eyes of 3,576 participants, aged 30.6 ± 18.6 years (range: 1–86 years). After grouping these data into age groups of 5 years, the refractive error histogram of each group was fitted to a Bigaussian function. The mean of the central, emmetropized peak was used to estimate the mean refractive error without the influence of myopia. Results: The mean cycloplegic refractive error at the emmetropized peak decreased from +1.10 ± 0.11D (95 % confidence interval) to +0.50 ± 0.04D before 20 years and remains stable at that value until the age of 50 years. The non-cycloplegic refractive error also sees a stable phase at 0.00 ± 0.04D between 15 – 45 years. After 45 – 50 years both cycloplegic and non-cycloplegic refractive error become more hypermetropic over time, +1.14 ± 0.12D at 75 years. Conclusions: The cycloplegic refractive error in adults is about +0.50D between 20 – 50 years, disproving the existence of the myopic period at those ages.(AU)

Selective processing of clinical information related to correct and incorrect diagnoses: An eye-tracking experiment.

INTRODUCTION: Diagnostic errors are often attributed to erroneous selection and interpretation of patients' clinical information, due to either cognitive biases or knowledge deficits. However, whether the selection or processing of clinical information differs between correct and incorrect diagnoses in written clinical cases remains unclear. We hypothesised that residents would spend more time processing clinical information that was relevant to their final diagnosis, regardless of whether their diagnosis was correct. METHODS: In this within-subjects eye-tracking experiment, 19 internal or emergency medicine residents diagnosed 12 written cases. Half the cases contained a correct diagnostic suggestion and the others an incorrect suggestion. We measured how often (i.e. number of fixations) and how long (i.e. dwell time) residents attended to clinical information relevant for either suggestion. Additionally, we measured confidence and time to diagnose in each case. RESULTS: Residents looked longer and more often at clinical information relevant for the correct diagnostic suggestion if they received an incorrect suggestion and were able to revise this suggestion to the correct diagnosis (dwell time: M: 6.3 seconds, SD: 5.1 seconds; compared to an average of 4 seconds in other conditions; number of fixations: M: 25 fixations, SD: 20; compared to an average of 16-17 fixations). Accordingly, time to diagnose was longer in cases with an incorrect diagnostic suggestion (M: 86 seconds, SD: 47 seconds; compared to an average of 70 seconds in other conditions). Confidence (range: 64%-67%) did not differ depending on residents' accuracy or the diagnostic suggestion. DISCUSSION: Selectivity in information processing was not directly associated with an increase in diagnostic errors but rather seemed related to recognising and revising a biased suggestion in favour of the correct diagnosis. This could indicate an important role for case-specific knowledge in avoiding biases and diagnostic errors. Future research should examine information processing for other types of clinical information.

Soil and water pollution and cardiovascular disease.

Healthy, uncontaminated soils and clean water support all life on Earth and are essential for human health. Chemical pollution of soil, water, air and food is a major environmental threat, leading to an estimated 9 million premature deaths worldwide. The Global Burden of Disease study estimated that pollution was responsible for 5.5 million deaths related to cardiovascular disease (CVD) in 2019. Robust evidence has linked multiple pollutants, including heavy metals, pesticides, dioxins and toxic synthetic chemicals, with increased risk of CVD, and some reports suggest an association between microplastic and nanoplastic particles and CVD. Pollutants in soil diminish its capacity to produce food, leading to crop impurities, malnutrition and disease, and they can seep into rivers, worsening water pollution. Deforestation, wildfires and climate change exacerbate pollution by triggering soil erosion and releasing sequestered pollutants into the air and water. Despite their varied chemical makeup, pollutants induce CVD through common pathophysiological mechanisms involving oxidative stress and inflammation. In this Review, we provide an overview of the relationship between soil and water pollution and human health and pathology, and discuss the prevalence of soil and water pollutants and how they contribute to adverse health effects, focusing on CVD.

Prevalence of rheumatic and musculoskeletal diseases (RMDs) in nursing home residents: a systematic literature review.

PURPOSE: The objective of this systematic literature review was to: (1) estimate the prevalence of (symptoms of) rheumatic and musculoskeletal diseases (RMDs) and (2) explore how (symptoms of) RMDs are identified and documented in studies among nursing home residents. METHODS: Prevalence data of (symptoms of) RMDs in permanently admitted nursing home residents ≥ 60 years were included. Data extraction, data synthesis and risk of bias assessment were performed by two reviewers independently. Included studies were categorized based on case ascertainment and case definition comprising: (location of) musculoskeletal pain, general terms for RMDs or a specific type of RMD. Results were summarized descriptively. RESULTS: Out of 6900 records, 53 studies were included. Case ascertainment comprised databases (n = 5), physical examination (n = 1), self-report questionnaires (n = 14), review of medical charts (n = 23) and self-report questionnaires combined with review of medical charts (n = 10). Prevalence ranged between 0.9 and 77.0% for (localized) musculoskeletal pain (n = 19) and between 0.6 and 67.5% for RMDs in general (n = 39). Prevalence rates of specific type of RMDs ranged between 0.7 and 47.5% for gout, between 3.3 and 11.0% for rheumatoid arthritis and between 2.8 and 75.4% for osteo-arthritis (n = 14). Heterogeneity with regard to documentation of (symptoms of) RMDs in medical data of nursing home residents was high. CONCLUSION: The overall prevalence of (symptoms of) RMDs varied to a great extent. This was mainly due to large heterogeneity in documentation of (symptoms of) RMDs. Establishing agreement on a useful and practical classification may ultimately increase identification of RMDs in the nursing home setting.

Cosmetic outcome in patients with early stage breast cancer after accelerated partial breast irradiation using intraoperative or external beam radiotherapy.

Purpose: The aim of this study is to evaluate the cosmetic outcome among early stage breast cancer patients who underwent accelerated partial breast irradiation with either intraoperative electron radiotherapy (IOERT) or photon external beam radiotherapy (EB-APBI). Materials and methods: This prospective multicenter cohort study enrolled women aged 60 years and older who underwent breast-conserving therapy. Following breast-conserving surgery, patients were treated with either IOERT or EB-APBI. Cosmetic outcome was evaluated over a 5 year follow-up period using both subjective scoring by patients and physicians, as well as objective scoring using BCCT.core software. Differences between treatments over time were described with mixed model analyses. Results: A total of 241 patients treated with IOERT and 164 patients treated with EB-APBI were eligible for cosmetic analysis. In both groups, the majority of patients reported a satisfactory cosmetic outcome, with no significant differences between treatments over time (p = 0.538). This was also observed by physicians, with satisfactory outcomes ranging from 94 % (170/181) to 91 % (69/76) over time in the IOERT group and from 93 % (124/133) to 95 % (54/57) in the EB-APBI group (p = 0.579). BCCT.core analysis returned satisfactory cosmetic outcomes in 75 % (54/72) of the IOERT patients at 3 years and in 77 % (20/26) at 5 years. These numbers were 86 % (72/84) and 90 % (36/40) for the EB-APBI patients, with no significant differences between treatment over time (p = 0.834). Conclusion: Regarding the cosmetic results, IOERT and EB-APBI yield comparable and satisfactory outcomes over 5 years follow-up in the treatment of early stage breast cancer.

Should workers be physically active after work? Associations of leisure-time physical activity with cardiovascular and all-cause mortality across occupational physical activity levels-An individual participant data meta-analysis.

BACKGROUND: There is insufficient evidence to provide recommendations for leisure-time physical activity among workers across various occupational physical activity levels. This study aimed to assess the association of leisure-time physical activity with cardiovascular and all-cause mortality across occupational physical activity levels. METHODS: This study utilized individual participant data from 21 cohort studies, comprising both published and unpublished data. Eligibility criteria included individual-level data on leisure-time and occupational physical activity (categorized as sedentary, low, moderate, and high) along with data on all-cause and/or cardiovascular mortality. A 2-stage individual participant data meta-analysis was conducted, with separate analysis of each study using Cox proportional hazards models (Stage 1). These results were combined using random-effects models (Stage 2). RESULTS: Higher leisure-time physical activity levels were associated with lower all-cause and cardiovascular mortality risk across most occupational physical activity levels, for both males and females. Among males with sedentary work, high compared to sedentary leisure-time physical activity was associated with lower all-cause (hazard ratios (HR) = 0.77, 95% Confidence interval(95%CI): 0.70-0.85) and cardiovascular mortality (HR = 0.76, 95%CI: 0.66-0.87) risk. Among males with high levels of occupational physical activity, high compared to sedentary leisure-time physical activity was associated with lower all-cause (HR = 0.84, 95%CI: 0.74-0.97) and cardiovascular mortality (HR = 0.79, 95%CI: 0.60-1.04) risk, while HRs for low and moderate levels of leisure-time physical activity ranged between 0.87 and 0.97 and were not statistically significant. Among females, most effects were similar but more imprecise, especially in the higher occupational physical activity levels. CONCLUSION: Higher levels of leisure-time physical activity were generally associated with lower mortality risks. However, results for workers with moderate and high occupational physical activity levels, especially women, were more imprecise. Our findings suggests that workers may benefit from engaging in high levels of leisure-time physical activity, irrespective of their level of occupational physical activity.

Revealing real-time 3D in vivo pathogen dynamics in plants by label-free optical coherence tomography.

Microscopic imaging for studying plant-pathogen interactions is limited by its reliance on invasive histological techniques, like clearing and staining, or, for in vivo imaging, on complicated generation of transgenic pathogens. We present real-time 3D in vivo visualization of pathogen dynamics with label-free optical coherence tomography. Based on intrinsic signal fluctuations as tissue contrast we image filamentous pathogens and a nematode in vivo in 3D in plant tissue. We analyze 3D images of lettuce downy mildew infection (Bremia lactucae) to obtain hyphal volume and length in three different lettuce genotypes with different resistance levels showing the ability for precise (micro) phenotyping and quantification of the infection level. In addition, we demonstrate in vivo longitudinal imaging of the growth of individual pathogen (sub)structures with functional contrast on the pathogen micro-activity revealing pathogen vitality thereby opening a window on the underlying molecular processes.

Predicting early-stage coronary artery disease using machine learning and routine clinical biomarkers improved by augmented virtual data.

Aims: Coronary artery disease (CAD) is a highly prevalent disease with modifiable risk factors. In patients with suspected obstructive CAD, evaluating the pre-test probability model is crucial for diagnosis, although its accuracy remains controversial. Machine learning (ML) predictive models can help clinicians detect CAD early and improve outcomes. This study aimed to identify early-stage CAD using ML in conjunction with a panel of clinical and laboratory tests. Methods and results: The study sample included 3316 patients enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. A comprehensive array of attributes was considered, and an ML pipeline was developed. Subsequently, we utilized five approaches to generating high-quality virtual patient data to improve the performance of the artificial intelligence models. An extension study was carried out using data from the Young Finns Study (YFS) to assess the results' generalizability. Upon applying virtual augmented data, accuracy increased by approximately 5%, from 0.75 to -0.79 for random forests (RFs), and from 0.76 to -0.80 for Gradient Boosting (GB). Sensitivity showed a significant boost for RFs, rising by about 9.4% (0.81-0.89), while GB exhibited a 4.8% increase (0.83-0.87). Specificity showed a significant boost for RFs, rising by ∼24% (from 0.55 to 0.70), while GB exhibited a 37% increase (from 0.51 to 0.74). The extension analysis aligned with the initial study. Conclusion: Accurate predictions of angiographic CAD can be obtained using a set of routine laboratory markers, age, sex, and smoking status, holding the potential to limit the need for invasive diagnostic techniques. The extension analysis in the YFS demonstrated the potential of these findings in a younger population, and it confirmed applicability to atherosclerotic vascular disease.

Totally endoscopic coronary artery bypass grafting: experience in 1500 patients.

OBJECTIVES: Totally endoscopic coronary artery bypass grafting (TECAB) is a minimally invasive approach to achieve surgical revascularization through a minimally invasive approach. Still, data regarding non-robotic TECAB are limited. This report presents the results of a TECAB technique using long-shafted instruments, defined as Endo-CABG, from a single-centre experience in 1500 consecutive patients. METHODS: One thousand and five hundred patients underwent Endo-CABG between January 2016 and February 2023. Data were collected retrospectively, and patients were followed up for 1 year. The primary outcome of this study was major adverse cardiac and cerebrovascular events (MACCE)-free survival. Secondary efficacy outcomes were graft failure and mortality. Furthermore, we analysed factors influencing long-term freedom from MACCE and all-cause mortality. RESULTS: The mean age was 68 [61-75] years, of which 193 (12.87%) were octogenarians. Multivessel disease was present in 1409 (93.93%) patients, and the mean EuroSCORE II was 1.64 [1.09-2.92] %. All patients underwent full arterial revascularization with bilateral internal mammary grafting in 88.47%. Graft failure occurred in 1.80% of cases after 1 year (n = 27). Thirty-day mortality was 1.73% (n = 26), 1-year survival was 94.7% (95% CI: 93.5-95.9%; n = 26) and 1-year MACCE-free survival was 91.7% (95% CI: 90.2-93.2%). Age, left ventricular ejection fraction, arterial hypertension and urgency were significantly associated with 1-year MACCE-free survival. CONCLUSIONS: Endo-CABG appears to be a safe procedure, achieves surgical revascularization and provides good outcomes regarding graft failure and MACCE at 1 year, while age, left ventricular ejection fraction, arterial hypertension and urgency were associated with 1-year outcomes.

'I am happy to be listened to': co-creation of a simple tool to measure women's experiences of respectful maternity care in urban Tanzania.

BACKGROUND: Rights-based Respectful Maternity Care (RMC) is crucial for quality of care and improved birth outcomes, yet RMC measurements are rarely included in facility improvement initiatives. We aimed to (i) co-create a routine RMC measurement tool (RMC-T) for congested maternity units in Dar es Salaam, Tanzania, and (ii) assess the RMC-T's acceptability among women and healthcare stakeholders. METHOD: We employed a participatory approach utilizing multiple mixed methods. This included a scoping review, stakeholder engagement involving postnatal women, healthcare providers, health leadership, and global researchers through interviews, focus groups, and two surveys involving 201 and 838 postnatal women. Cronbach's alpha and factor analysis were conducted for validation using Stata 15. Theories of social practice and Thematic Framework of Acceptability guided the assessment of stakeholder priorities and tool acceptability. RESULTS: The multi-phased iterative co-creation process produced the 25-question RMC-T that measures satisfaction, communication, mistreatment (including physical, verbal, and sexual abuse; neglect; discrimination; lack of privacy; unconsented care; post-birth clean-up; informal payments; and denial of care), supportive care (such as food intake and mobility), birth companionship, post-procedure pain relief, bed-sharing, and newborn respect. The pragmatic validation process prioritized stakeholder feedback over strict statistics, lowering Cronbach's alpha from 0.70 in version 1 to 0.57 for the RMC-T. Women valued the opportunity to share their experiences. CONCLUSIONS: The RMC-T is contextualized, validated, and acceptable for measuring women's experiences of RMC. Routine use in facility-based quality improvement initiatives, along with targeted actions to address gaps, will advance rights-based RMC. Further validation and community-based studies are needed.

• Main findings: This study describes the participatory approach involving postnatal women, healthcare providers, health leadership, and global researchers to co-create and validate a tool for measuring women's experiences of respectful maternity care in Dar es Salaam's urban health facilities.• Added knowledge: The iterative process produced a concise, 25-item Respectful Maternity Care Measurement tool that is user-friendly, administered in 15­20 minutes and addresses all mistreatment domains. The tool reflects women's priorities and is well accepted by postnatal women and health leaders.• Global health impact for policy and action: Regular use of the tool can enhance awareness of childbirth rights and drive actions to improve and normalize respectful maternity care in low-resource urban settings.

Brain Exposure to the Macrocyclic ALK Inhibitor Zotizalkib is Restricted by ABCB1, and Its Plasma Disposition is Affected by Mouse Carboxylesterase 1c.

Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC). We here evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux transporters, OATP1 influx transporters and the metabolizing enzymes CES1 and CYP3A in plasma and tissue disposition of zotizalkib after oral administration in relevant mouse models. Zotizalkib was efficiently transported by hABCB1 in vitro. In vivo, a significant ∼9-fold higher brain-to-plasma ratio was observed in Abcb1a/b-/- and Abcb1a/b;Abcg2-/- compared to wild-type mice. No change in brain disposition was observed in Abcg2-/- mice, suggesting that mAbcb1a/b markedly restricts the brain accumulation of zotizalkib. ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities. In Oatp1a/b-/- mice, no marked changes in plasma exposure or tissue-to-plasma ratios were observed, indicating that zotizalkib is not a substantial in vivo substrate for mOatp1a/b. Zotizalkib may further be metabolized by CYP3A4 but only noticeably at low plasma concentrations. In Ces1-/- mice, a 2.5-fold lower plasma exposure was seen compared to wild-type, without alterations in tissue distribution. This suggests increased plasma retention of zotizalkib by binding to the abundant mouse plasma Ces1c. Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors.