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Korean pear (Pyrus pyrifolia cv. Shingo) has been used as a traditional medicine for alleviating alcohol hangover. However, scientific evidence for its effectiveness or mechanism is not clearly established. To investigate its mechanism of alcohol detoxification, both in vitro and in vivo studies were performed with an aldehyde dehydrogenase 2 (ALDH2) alternated animal model. The pear extract (10 mL/kg bw) was administered to Aldh2 normal (C57BL/6) and deficient (Aldh2 -/-) male mice. After 30 min, ethanol (1 g or 2 g/kg bw) was administered to the mice via gavage. Levels of alcohol and acetaldehyde in blood were quantified by GC/MS. First, it was observed that the pears stimulated both alcohol dehydrogenase (ADH) and ALDH activities by 2∼3-  and 1.3-fold in in vitro studies, respectively. Second, mouse PK data (AUC(∞) and C(max) ) showed that the pear extract decreased the alcohol level in blood regardless of ALDH2 genotype. Third, the pear increased the acetaldehyde level in blood in Aldh2 deficient mice but not in Aldh2 normal mice. Therefore, the consistent in vitro and in vivo data suggest that Korean pears stimulate the two key alcohol-metabolizing enzymes. These stimulations could be the main mechanism of the Korean pear for alcohol detoxification. Finally, the results suggest that polymorphisms of human ALDH2 could bring out individual variations in the effects of Korean pear on alcohol detoxification. [ABSTRACT FROM AUTHOR]

Background and Aims: The use of immune checkpoint inhibitors (ICI) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention to treat (ITT) outcomes in the peri transplant setting are currently based on small and heterogenous single center reports., Methods: This first multiregional US study (2016-2023) included 117 consecutive HCC patients assessed for LT and treated preoperatively with ICIs. Intention to treat ITT and survival analyses were conducted with evaluation of post LT rejection rates., Results: In total, 86 (73.5%) patients exceeded MC and 65 (75.6%) were successfully downstaged (DS) within a median of 5.6 months. 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) initially beyond and DS. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included: being beyond MC (p<0.001), AFP doubling from baseline (p=0.014) and radiographic responses (p<0.001). The 3-year ITT survival was 71.1% (73.5% within MC vs 69.7% beyond MC, p=0.329), with 3-year post LT survival rate of 85%. Post-LT rejection occurred in 7 patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss., Conclusions: The first multicenter evaluation of HCC patients receiving ICI pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of AFP levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes., Impact and Implications: The first multicenter evaluation of pre-transplant immune-checkpoint-inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune-checkpoint-inhibitors, either alone or combined with LRT, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated AFP levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pre-transplant use of immune-checkpoint-inhibitors, pending results from ongoing trials., (Copyright © 2024. Published by Elsevier B.V.)

Adolescent inhibition of thalamocortical projections from postnatal days P20 to 50 leads to long-lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamoprefrontal projections in male/female mice from P20 to P35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (mediodorsal thalamus (MD), nucleus accumbens (NAc), or callosal prefrontal projections) 24 h later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III NAc and layer V/VI MD-projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only altered in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intraprefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Petersen et al.)

Purpose: To evaluate the potential of volumetric imaging in predicting survival of advanced hepatocellular carcinoma (HCC) patients receiving immunotherapy., Methods: Retrospective analysis included 40 patients with advanced HCC who received targeted immunotherapy. Baseline and follow-up contrast-enhanced abdominal computed tomography (CT) scans were analyzed. The largest tumor was chosen as the index lesion. Viable tumor volume (qViable) and percentage tumor viability (%Viability) were calculated. Response Evaluation Criteria in Solid Tumors (RECIST) and Tumor volume change after treatment (qRECIST) were measured. Associations with overall survival (OS) were assessed. Cox regression analysis assessed the association between variables and overall survival (OS). A new prognostic stratification system was attempted to categorize patients based on significant predictors of OS. Patients with a baseline %viability > 69% and %viability reduction ≥ 8% were classified as better prognosis. Patients were stratified into better, intermediate and worse prognosis groups based on baseline %viability > 69% and ≥ 8% %viability reduction (better prognosis); baseline %viability ≤ 69% and < 8% %viability reduction (worse prognosis); remainder were intermediate prognosis., Results: Patients with baseline %Viability > 69% and %Viability reduction ≥ 8% showed significantly higher OS. Multivariate analysis confirmed %Viability and %Viability reduction as significant predictors of OS. A prognostic stratification system using these parameters stratified patients into better, intermediate and worse prognosis groups, with the better prognosis showing highest OS. Most patients (97.5%) had stable disease by RECIST while the prognostic model re-classified 47.5% as better prognosis, 37.5% intermediate prognosis, and 15% worse prognosis., Conclusion: Volumetric parameters of %Viability and %Viability reduction predict OS in HCC patients undergoing immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Surgical resection for localized hepatocellular carcinoma (HCC) is typically reserved for a minority of patients with favorable tumor features and anatomy. Neoadjuvant immunotherapy can expand the number of patients who are candidates for surgical resection and potentially reduce the chance for recurrence, but its role in HCC not defined. We retrospectively examined the outcomes of patients who underwent surgical resection for HCC at the Johns Hopkins Hospital and compared the clinical outcomes of patients who received neoadjuvant immunotherapy with those who underwent upfront resection. The clinical cohort included a total of 92 patients, 36 of whom received neoadjuvant immune checkpoint inhibitor (ICI)-based treatment. A majority of patients (61.1%) who received neoadjuvant ICI-based therapy were outside of standard resectability criteria and were more likely to have features known to confer risk of disease recurrence, including α-fetoprotein ≥ 400 ng/mL (P = 0.02), tumor diameter ≥ 5 cm (P = 0.001), portal vein invasion (P < 0.001), and multifocality (P < 0.001). Patients who received neoadjuvant immunotherapy had similar rates of margin-negative resection (P = 0.47) and recurrence-free survival (RFS) as those who underwent upfront surgical resection (median RFS 44.8 months compared with 49.3 months, respectively, log-rank P = 0.66). There was a nonsignificant trend toward superior RFS in the subset of patients with a pathologic response (tumor necrosis ≥ 70%) with neoadjuvant immunotherapy. Neoadjuvant ICI-based therapy may allow high-risk patients, including those who are outside traditional resectability criteria, to achieve comparable clinical outcomes with those who undergo upfront resection., Significance: Surgical resection for localized HCC is typically only reserved for those with solitary tumors without vascular invasion. In this retrospective analysis, we show that neoadjuvant immunotherapy may allow high-risk patients, including those who are outside of standard resection criteria, to undergo successful margin-negative resection and achieve comparable long-term clinical outcomes compared with upfront resection. These findings highlight need for prospective studies on neoadjuvant immunotherapy in HCC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background & Aims: Noninvasive variceal risk stratification systems have not been validated in patients with hepatocellular carcinoma (HCC), which presents logistical barriers for patients in the setting of systemic HCC therapy. We aimed to develop and validate a noninvasive algorithm for the prediction of varices in patients with unresectable HCC., Methods: We performed a retrospective cohort study in 21 centers in the United States including adult patients with unresectable HCC and Child-Pugh A5-B7 cirrhosis diagnosed between 2007 and 2019. We included patients who completed an esophagogastroduodonoscopy (EGD) within 12 months of index imaging but before HCC treatment. We divided the cohort into a 70:30 training set and validation set, with the goal of maximizing negative predictive value (NPV) to avoid EGD in low-risk patients., Results: We included 707 patients (median age, 64.6 years; 80.6% male; 74.0% White). Median time from HCC diagnosis to EGD was 47 (interquartile range, 114) days, with 25.0% of patients having high-risk varices. A model using clinical variables alone achieved an NPV of 86.3% in the validation cohort, whereas a model integrating clinical and imaging variables had an NPV 97.4% in validation. The clinical and imaging model would avoid EGDs in more than half of low-risk patients while misclassifying 7.7% of high-risk patients., Conclusions: A model incorporating clinical and imaging data can accurately predict the absence of high-risk varices in patients with HCC and avoid EGD in many low-risk patients before the initiation of systemic therapy, thus expediting their care and avoiding treatment delays., (Copyright © 2024. Published by Elsevier Inc.)

Background: Due to cognitive impairments, people with dementia (PWD) often have difficulties in eating and drinking. This study aimed to assess the nutritional status, dietary quality and eating disturbance issues among PWD in Vietnam., Methods: We conducted a cross-sectional study at the Vietnamese National Geriatric Hospital from April to December 2022. We used Mini-Mental State Exam (MMSE) to classify the severity levels of dementia. Mini Nutritional Assessment (MNA), 24-hour recall, eating disturbance questionnaires, and anthropometric indicators were used to evaluate the nutritional status, dietary quality, and eating disorders of study subjects., Results: Overall, among 63 study participants, 74.6 per cent of PWD were at risk of or having malnutrition. By dementia classification according to MMSE scale, people with moderate and severe dementia accounted for 53.3 per cent of those who met the recommended energy levels, compared to 42.4 per cent of people with mild dementia and normal people. In the above two groups, around three per cent of participants reached the recommended amount of fibre. Calcium (50-70%), vitamin A (80-90%), and D (90%) were found to be the most severe deficiency forms of minerals and vitamins in both male and female participants. The majority of participants (90.5%) had at least one form of eating disorders with the most frequent issue being appetite changes (76.2%) and swallowing issues (50.8%)., Conclusions: PWD in our sample frequently experienced malnutrition, a lack of essential nutrients, difficulties swallowing, changes in eating habits and appetite. It is neccesary to early screen and assess nutritional status and swallowing disturbance in PWD, and instruct their caregivers to prepare nutritious meals for them., (© 2024. The Author(s).)

Background and Objectives: A comprehensive nutritional management is necessary for favourable outcomes in patients with chronic kidney disease (CKD). We aimed to assess the changes in nutritional status and disease progression with nutritional management where renal replacement therapy (RRT) was not in place., Methods and Study Design: A quasi-experiment intervention was conducted on 70 CKD patients at stages 3-5 from July to December 2022. Participants were excluded if they underwent RRT, including dialy-sis (hemodialysis or peritoneal dialysis), or kidney transplantation. The nutritional regimen covered nutrition-al counseling, samples of the dietary menu, and supplement products. We evaluated nutritional status using Subjective Global Assessment (SGA) scale and sub-clinical blood test at T0 (hospital admission) and T1 (two weeks after the admission or 24 hours before the discharge)., Results: After the intervention, the number of patients classified as malnutrition or at risk of malnourished reduced significantly (65.7% to 54.3% and 25.7% and 5.7%, respectively). The serum concentration of urea, creatinine and parathyroid hormone decreased remarkably, especially in patients receiving nutritional management. In the intervention group, the dietary pattern provided increased intakes of calcium and iron at T1, while phosphorus, sodium and potassium decreased after follow-up. Nausea/vomiting, loss of appetite, tiredness and sleep disorders were improved in the intervention compared to the control group., Conclusions: Nutritional therapy enhanced the nutritional sta-tus, and quality of dietary and renal function in CKD patients without RRT. Applying nutrition education and treatment at an early stage can slow CKD progression, which should be applicable elsewhere in Vietnam., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could constitute a potential conflict of interest

Background & Aim: Esophageal varices (EV) screening guidelines have evolved with improved risk stratification to avoid unnecessary esophagogastroduodenoscopy (EGD) in individuals with low bleeding risks. However, uncertainties persist in the recommendations for certain patient groups, particularly those with hepatocellular carcinoma (HCC) and/or receiving non-selective beta-blockers (NSBB) without prior endoscopy. This study assessed the efficacy of imaging in ruling out EVs and their high-risk features associated with bleeding in patients with cirrhosis and with HCC. We also evaluated the impact of NSBB on the detection of these characteristics., Methods: A total of 119 patients undergoing EGD with CT and/or MRI within 90 days of the procedure were included. 87 patients had HCC. A new imaging grading system was developed utilizing the size of EVs and the extent of their protrusion into the esophagus lumen. The negative predictive value (NPV) of EVimaging(-) versus EVimaging (+) (grades 1-3) in ruling out the presence of EV and/or high-risk features by EGD was calculated. The predictive performance of imaging was determined by logistic regression., Results: The NPV of imaging for detecting EV and high-risk features was 81 % and 92 %, respectively. Among HCC patients, the NPV for EV and high-risk features was 80 % and 64 %, respectively. Being on NSBB didn't statistically impact the imaging detection of EV. Imaging was a better predictor of high-risk EGD findings than Child-Turcotte-Pugh scores., Conclusions: Our results suggest that imaging can effectively rule out the presence of EV and high-risk features during EGD, even in patients with HCC and/or receiving NSBB., Competing Interests: Declaration of competing interest The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: This study aims to investigate the trends in treatment coverage through dispensing diabetes medications in Vietnam from 2015 to 2021. The findings will serve to inform health policies to mitigate the health burden of Type 2 diabetes mellitus (T2DM)., Methods: We collected information on major antidiabetic medicines from General Department of Vietnam Customs and payments for antidiabetics via the National Health Insurance Program. We applied ordinary least squares models, accounting for economic and health outcome characteristics, to estimate the association between the annual mass of medications and related factors., Results: Nationally, the total mass/doses of all antidiabetic drugs increased rapidly from 2015 to 2021, based on both databases. Metformin was the most frequently prescribed medicine, with the total mass increasing nearly threefold over the study period. Gliclazide, a Sulfonylureas drug, ranked second. In the multivariate regression analysis, a one-unit increase in adults with diabetes (in 1,000 s) was associated with 0.11 % (95 %CI = 0.0005; 0.0076) and 0.13 % (95%CI = 0.0007; 0.0242) higher mass of Metformin and Glimepiride, respectively., Conclusion: Our data suggested that policies changes were related to significant increase in antidiabetic medication dispenses in Vietnam. The high treatment coverage indicates impressive progress in achieving universal health coverage in Vietnam, meeting the UN Sustainable Development Goal (SDG)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

CropLife Europe collected literature values from monitoring studies measuring air concentrations of Plant Protection Products (PPPs) that may be inhaled by humans located in rural areas but not immediately adjacent to PPP applications. The resulting "Combined Air Concentration Database" (CACD) was used to determine whether air concentrations of PPPs reported by the French "Agency for Food, Environmental and Occupational Health & Safety" (ANSES) are consistent with those measured by others to increase confidence in values of exposure to humans. The results were put into risk assessment context. Results show that 25-90% of samples do not contain measurable PPP concentrations. Measured respirable fractions were below EU default air concentrations used for risk assessment for resident exposure by the European Food Safety Authority. All measured exposures in the CACD were also below established toxicological endpoints, even when considering the highest maximum average reported concentrations and very conservative inhalation rates. The highest recorded air concentration was for prosulfocarb (0.696 μg/m³ measured over 48 h) which is below the EFSA default limit of 1 μg/m³ for low volatility substances. In conclusion, based on the CACD, measured air concentrations of PPPs are significantly lower than EFSA default limits and relevant toxicological reference values., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Anne-Kim Vinck, Edgars Felkers, Michel Urtizberea, Kathrin Bürling and Alistair Morriss are employees of companies that conduct and evaluate risk assessments for regulatory purposes in the context of authorization and marketing of their companies' products. They contribute as scientific experts to the industry association CropLife Europe for evaluation and development of the state-of-the-art methodology. Nicola Hewitt is a scientific consultant., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To review the literature data on the prevalence of benzodiazepines abuse and poisoning in older adults; the prevalence of polypharmacy with benzodiazepines in this demographic; and determine whether benzodiazepine anxiolytics or hypnotics were more frequently implicated in the cases of abuse and poisoning., Methods: We searched PubMed and Scopus for relevant studies published from January 1, 2013, to May 1, 2023. Twelve studies were included in the final selection., Results: The review highlights the diverse prevalence rates of benzodiazepine abuse and poisoning in the older adult population. Benzodiazepine anxiolytics were more frequently associated with negative outcomes than benzodiazepine hypnotics. Concurrent use of benzodiazepines, benzodiazepine-related medications, and opioids was reported, although these medications were not the only ones commonly used by the elderly., Conclusion: It is essential to increase awareness about adhering to prescribed pharmacological therapies to mitigate issues related to drug abuse and poisoning among older adults.

Background: People living with dementia (PLWD) may experience substantial cognitive decline as the disease progresses, which interferes with their daily activities. This study aimed to assess physical activity (PA) performance and care dependency (CD) and identify factors related to PA among PLWD., Methods: We conducted a cross-sectional study in 63 PLWD from National Geriatrics Hospital, Vietnam, from 2021 to 2023. We used the Mini Nutritional Assessment (MNA), International Physical Activity Questionnaire (IPAQ), and Care Dependency Scale (CDS) to assess the nutritional status and the levels of PA and CD, respectively. We used the Mann-Whitney test to compare the differences in the PA types and CD levels between dementia levels and a multivariable logistics regression model to analyze factors related to PA., Results: More than half of the subjects had mild dementia. In total, 35% of the PLWD had a low level of PA, and 46.3% were completely independent of care. The mean score in each CDS aspect of the subjects with moderate/severe dementia was statistically significantly lower than that of those with mild dementia ( p ≤ 0.05). Lower dependency (OR = 0.9; 95% CI = 0.88-0.99) and malnutrition (OR = 15.4; 95% CI = 1.18-20.21) were associated with insufficient PA in the PLWD., Conclusion: Formal caregivers and healthcare workers should encourage PLWD to perform physical activities at any level and personalize the development of tailored and nutritional care strategies for each individual.

LDL lipoprotein receptor-related protein 11 (LRP11) plays a role in several tumors. However, their roles in hepatocellular carcinoma remain unclear. The present study aimed to explore the expression profile and prognostic value of LRP11 in liver hepatocellular carcinoma (LIHC) patients using various cancer databases and bioinformatic tools. In bioinformatics analysis, The Cancer Genome Atlas datasets showed increased LRP11 expression in tumor tissues compared to that in non-tumor tissues in various cancers. Moreover, patients with high expression LRP11 correlated with poor prognosis and clinical features. The LRP11 expression positively correlated with the infiltration of immune cells such as macrophages, neutrophils, and myeloid-derived suppressor cells and a combination of high LRP11 expression and high immune infiltrates was associated with the worst survival in LIHC tumors. Our results also indicated that LRP11 expression was closely associated with immune-modulate function, such as antigen presentation. In DNA methylation profiling, hypomethylation of LRP11 is widely observed in tumors and has prognostic value in LIHC patients. Functional enrichment analysis revealed that LIHC-specific LRP11 interacting genes are involved in protein binding, intracellular processing, and G-protein-related signaling pathways. Analyses of drug sensitivity and immune checkpoint inhibitor predict a number of drugs that could potentially be used to target LRP11. In addition, in vitro experiments verified the promoting effect of LRP11 on the migration, invasion, and colony formation capacity of hepatocellular carcinoma cells. Collectively, our results aided a better understanding of the clinical significance of LRP11 in gene expression, functional interactions, and epigenetic regulation in LIHC and suggested that it may be a useful prognostic biomarker for LIHC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yoo, Kim, Kook and Noh.)

Targeting proximity-labeling enzymes to specific cellular locations is a viable strategy for profiling subcellular proteomes. Here, we generated transgenic mice (MAX-Tg) expressing a mitochondrial matrix-targeted ascorbate peroxidase. Comparative analysis of matrix proteomes from the muscle tissues showed differential enrichment of mitochondrial proteins. We found that reticulon 4-interacting protein 1 (RTN4IP1), also known as optic atrophy-10, is enriched in the mitochondrial matrix of muscle tissues and is an NADPH oxidoreductase. Interactome analysis and in vitro enzymatic assays revealed an essential role for RTN4IP1 in coenzyme Q (CoQ) biosynthesis by regulating the O-methylation activity of COQ3. Rtn4ip1-knockout myoblasts had markedly decreased CoQ 9 levels and impaired cellular respiration. Furthermore, muscle-specific knockdown of dRtn4ip1 in flies resulted in impaired muscle function, which was reversed by dietary supplementation with soluble CoQ. Collectively, these results demonstrate that RTN4IP1 is a mitochondrial NAD(P)H oxidoreductase essential for supporting mitochondrial respiration activity in the muscle tissue., (© 2023. The Author(s).)

The present study strived to gain a more profound understanding of the distinctions in development between swimmers who are considered to be on track to the elite level at late junior age (males aged 16; females aged 15) compared to those who are not. In this effort, swimmers were followed during their pubertal years (males aged 13-15; females aged 12-14), which marks a period when performance development aligns with maturation. Longitudinal data of 90 talented sprint and middle-distance swimmers on season best times (SBT) and underlying performance characteristics (anthropometrics, maximal swimming velocity, stroke index [SI] and countermovement jump [CMJ]) were collected over three swimming seasons. Based on their SBT at late junior age (males aged 16; females aged 15), swimmers were classified as high-performing late juniors or lower-performing late juniors. Retrospectively studying these swimmers, we found that all but two high-performing late juniors were already on track to the elite level at early junior age (males aged 13; females aged 12), evidenced with faster SBT throughout puberty compared to their lower-performing peers ( p  < 0.05). Independent sample t-tests revealed that high-performing late juniors significantly outscored their lower-performing peers when they were early juniors on maximal swimming velocity (males aged 13-15 and females aged 12-14), SI (males aged 13 and 14; females aged 12), CMJ (females aged 14) and height (females aged 13 and 14, p  < 0.05). Additionally, multilevel models showed faster rates of development for high-performing late juniors on maximal swimming velocity (males and females) and SI (males) compared to lower-performing peers throughout puberty ( p  < 0.05). Higher initial levels of SBT and underlying performance characteristics at early junior age as well as the faster rates of development on SBT, maximal swimming velocity and SI (males only) during the pubertal years, may be crucial factors in maintaining the trajectory towards the elite level after puberty.

An optimized hepatocellular carcinoma (HCC)-targeted methylation next generation sequencing assay was developed to discover HCC-associated methylation markers directly from urine for HCC screening. Urine cell-free DNA (ucfDNA) isolated from a discovery cohort of 31 non-HCC and 30 HCC was used for biomarker discovery, identifying 29 genes with differentially methylated regions (DMRs). Methylation-specific qPCR (MSqPCR) assays were developed to verify the selected DMRs corresponding to 8 genes (GRASP, CCND2, HOXA9, BMP4, VIM, EMX1, SFRP1, and ECE). Using archived ucfDNA, methylation of GRASP, HOXA9, BMP4, and ECE1, were found to be significantly different (p < 0.05) between HCC and non-HCC patients. The four markers together with previously reported GSTP1 and RASSF1A markers were assessed as a 6-marker panel in an independent training cohort of 87 non-HCC and 78 HCC using logistic regression modeling. AUROC of 0.908 (95% CI, 0.8656-0.9252) was identified for the 6-marker panel with AFP, which was significantly higher than AFP-alone (AUROC 0.841 (95% CI, 0.778-0.904), p = 0.0026). Applying backward selection method, a 4-marker panel was found to exhibit similar performance to the 6-marker panel with AFP having 80% sensitivity compared to 29.5% by AFP-alone at a specificity of 85%. This study supports the potential use of methylated transrenal ucfDNA for HCC screening., (© 2023. The Author(s).)

A database of field measurements of air concentrations of pesticide active ingredients has previously been compiled by CropLife Europe with an aim to revise the default air concentration values and assumptions applied in assessing vapour exposure in the risk assessment of bystanders and residents. The BROWSE model, released in 2014, which is a regulatory risk assessment model that includes the exposure of residents and bystanders has a component relating to post-application vapour inhalation. Predictions of concentration deduced from exposures obtained using the BROWSE model were compared with field measurements of 24-h and 7-day average concentrations. The methodology for obtaining concentration estimates from the BROWSE model is described, and the criteria for including field studies in the comparison are given. The field data were adjusted to account for differences between the field experiment and the BROWSE scenario using factors derived from a separate plume dispersion model. This showed that BROWSE provides a satisfactory level of conservatism in determining potential exposures of residents and bystanders to vapour and could be a reliable alternative to replace the current EFSA approach for predicting vapour inhalation exposures for pesticides where no compound-specific data are available., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Edgars Felkers, Sarah Adham, Anne-Kim Vinck, Kathrin Bürling and Neil Morgan are employees of companies that conduct and evaluate risk assessments for regulatory purposes in the context of authorization and marketing of their companies' products. They contribute as scientific experts to the industry association CropLife Europe for evaluation and development of the state-of-the-art methodology. Clare Butler Ellis is employed by an independent business which receives contract income from companies that conduct and evaluate risk assessments for regulatory purposes in the context of authorization and marketing of their companies' products., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study evaluated the impact of cell debris and 7-day room temperature storage on the quality and yield of transrenal DNA. Archived urine specimens collected from five hepatocellular carcinoma (HCC) patients and two pregnant women carrying male fetuses were used to assess the impact of cell debris on urine cell-free DNA (ucfDNA) isolation as measured by quantitative PCR for Y-chromosome DNA, or HCC-associated mutation and methylation markers, and by capillary electrophoresis. Prospectively collected urine from 21 HCC patients was aliquoted after collection for paired immediate freezing versus 7-day room temperature storage followed by freezing for further analysis. Cell debris contained more Y-chromosome DNA than supernatant in three of the six urine specimens tested from pregnant women, suggesting that cell debris can be associated with 20.6% to 84.9% of transrenal ucfDNA. Ninety-five percent (20 of 21) of frozen and room temperature urine pairs had overlapping DNA size distribution. ucfDNA quantity determined by quantitative PCR for TP53, CTNNB1, TERT, and HCC-associated urine circulating tumor DNA markers were statistically similar between room temperature and frozen samples. This suggests no significant difference in DNA degradation between the groups. The association of transrenal ucfDNA with cell debris and HCC circulating DNA stability at room temperature is significant to further the understanding of transrenal circulating tumor DNA pre-analytical handling for HCC screening., Competing Interests: Disclosure Statement W.S., S.Y.L., Z.W., and Y.-H.S. are shareholders of JBS Science, Inc. Y.-H.S. has received funding from JBS Science, Inc. A.K.K. is a consultant for AstraZeneca and Exclixis. The remaining authors declare no conflicts of interest., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Cancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety of clinical screening guidelines are used in healthcare settings to help clinicians detect patients who have a higher likelihood of having a CPS. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is an electronic health decision support tool that uses algorithms to help clinicians determine if a child/adolescent diagnosed with cancer should be referred to genetics for a CPS evaluation., Methods: This study assessed MIPOGG's performance in identifying Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin (nevoid basal cell carcinoma) syndromes in a retrospective series of 84 children diagnosed with cancer and one of these four CPSs in Canadian hospitals over an 18-year period., Results: MIPOGG detected 82 of 83 (98.8%) evaluable patients with any one of these four genetic conditions and demonstrated an appropriate rationale for suggesting CPS evaluation. When compared with syndrome-specific clinical screening criteria, MIPOGG's ability to correctly identify children with any of the four CPSs was equivalent to, or outperformed, existing clinical criteria respective to each CPS., Conclusion: This study adds evidence that MIPOGG is an appropriate tool for CPS screening in clinical practice. MIPOGG's strength is that it starts with a specific cancer diagnosis and incorporates criteria relevant for associated CPSs, making MIPOGG a more universally accessible diagnostic adjunct that does not require in-depth knowledge of each CPS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: As sufficient nutrition helps alleviate catabolic stress and modulate the systemic inflammatory response of the body, it plays an indispensable role in the good prognosis of critically ill patients. Thus, this study aimed to investigate the malnutrition of patients with severe COVID-19 and its association with adverse treatment outcomes., Methods: We conducted a retrospective cross-sectional study in two provincial hospitals in Hanoi from February to April 2022. Participants were patients with severe COVID-19 admitted to the Intensive Care Unit (ICU). Malnutrition risk were evaluated by Nutritional Risk Screening-2002 (NRS), Global Leadership Initiative on Malnutrition (GLIM), Prognostic Nutritional Index (PNI), and the adverse prognosis was assessed by Acute Physiology and Chronic Health Evaluation II (APACHE II). The multivariate receiver-operating characteristic (ROC) curve was applied to estimate the predictive ability of those criteria regarding worse treatment results., Results: The percentages of malnutrition measured by NRS, GLIM, PNI, and BMI were 62.6, 51.5, 42.9, and 16.6%, respectively. Patients with more severe malnutrition assessed by GLIM, PNI, and having above target fasting blood glucose (FBG) (≥10.0 mmol/L) were more likely to have higher APACHE scores. PNI had a better diagnostic performance than NRS and BMI (AUC = 0.84, 0.81, and 0.82, respectively). In addition, FBG revealed a good prognostic implication (AUC = 0.84)., Conclusion: A relatively high percentage of patients experienced moderate and severe malnutrition regardless of screening tools. Individuals at higher risk of malnutrition and high FBG were predicted to have more adverse treatment outcomes. It is recommended that nutritional screening should be conducted regularly, and personalizing nutritional care strategies is necessary to meet patients' nutrient demands and prevent other nutrition-related complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nguyen, Dang, Tran, Phan, Doan, Nguyen, Tran, Do, Nguyen, Nguyen, Nguyen and Le.)

Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A ( LDHA ) and cluster of differentiation 36 ( CD36 ) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 ( IL1R1 , IL1R2 ), and matrix metalloproteinase 8, 9 ( MMP8, MMP9 ) appeared in multiple canonical pathways. LDHA -knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

Amorphous lithium phosphorus oxynitrides (LiPON), prepared by reactive magnetron sputtering, have become the electrolytes of choice for all-solid-state thin film microbatteries since its discovery in early 1990s. Nevertheless, there is still a lack of understanding of their atomic-level structure and its influence on ionic conductivity. Solid-state NMR spectroscopy represents a promising technique to determine the atomic-level structure of LiPON glasses but is challenging owing to its low sensitivity in the case of thin film materials. Recently, 31 P solid-state NMR spectra of LiPON thin films were acquired under magic-angle spinning (MAS) conditions and assigned with the help of density functional theory (DFT) calculations of NMR parameters. However, the identification of the different P local environments in these materials is still a challenge owing to their amorphous structure and the lack of resolution of the 31 P MAS NMR spectra. We show herein how the NMR observation of internuclear proximities helps to establish the nature of P sites in LiPON thin films. The 31 P- 14 N proximities are probed by a transfer of population in double resonance (TRAPDOR) experiment, whereas 31 P- 31 P proximities are observed using one-dimensional (1D) 31 P double-quantum (DQ)-filtered and two-dimensional (2D) 31 P homonuclear correlation spectra as well as dipolar dephasing experiments using DQ-DRENAR (DQ-based dipolar-recoupling effects nuclear alignment reduction) technique. The obtained NMR data further support the recently proposed assignment of 31 P NMR signals of LiPON thin films. With the help of this assignment, the simulation of the quantitative 1D 31 P NMR spectrum indicates that PO 4 3- orthophosphate anions prevail in LiPON thin films and N atoms are mainly incorporated in [O 3 PNPO 3 ] 5- dimeric anions. PO 3 N 4- isolated tetrahedra and [O 3 POPO 3 ] 4- anions are also present but in smaller amounts., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Olivier Lafon reports financial support was provided by French National Research Agency.]., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background/aim: Although the expression of mucin 1(MUC1) and prostate stem cell antigen (PSCA) genes is correlated with gastric cancer development and progression, the utility of these two genes as biomarkers of gastric cancer prognosis still needs to be confirmed in clinical practice. This study aimed to develop a model predictive of gastric cancer that integrates several significant single nucleotide polymorphisms (SNPs) of MUC1 and PSCA genes, and some health-risk behavior factors in a Vietnamese population., Patients and Methods: A total of 302 patients with primary gastric carcinoma and 304 healthy persons were included in a case-control study. The generalized linear model was used with the profile of age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases, and the SNPs of MUC1 and PSCA. The prognostic value of the model was assessed by the area under a receiver operating characteristic curve (AUC) and Akaike Information Criterion (AIC) values., Results: In male participants, the final model, consisting of age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases and SNP MUC1 rs4072037, provided acceptable discrimination, with an AUC of 0.6374 and the lowest AIC value (539.53). In female participants, the predictive model including age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases, SNPs MUC1 rs4072037 and rs2070803 had an AUC of 0.6937 and AIC of 266.80. The calibration plots of the male model approximately fitted the ideal calibration line., Conclusion: The predictive model based on age, sex, medical history, and genetic and health-risk behavior factors has a high potential in determining gastric cancer. Further studies that elucidate other genetic variants should be carried out to define high-risk gastric cancer groups and propose appropriate personalized prevention., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Neuropathic pain is a debilitating condition resulting from various etiologies such as diabetes, multiple sclerosis, and infection, and is associated with decreased quality of life, poor health outcomes, and increased economic burden. However, epidemiological studies on neuropathic pain have been largely limited in Vietnam., Methods: A cross-sectional study was conducted on adult Vietnamese industrial workers across three manufacturing plants. Demographic, socioeconomic, occupational and health data were collected. Prevalence of neuropathic pain was assessed using the Douleur Neuropathique 4 (DN4) scale. Regression modeling was utilized to identify predictors of pain., Results: Among 276 workers, 43.1 and 24.3% reported that they had suffered from spinal pain and osteoarthritis pain, respectively. In terms of work conditions, people maintaining constant posture when working from 30 to 60 min (OR = 3.15, 95% CI = 1.07; 9.29), or over 60 min (OR = 2.59; 95% CI = 1.12; 5.98) had a higher risk of suffering from spinal pain. People who worked in conditions lacking adequate lighting and with exposures to toxic chemicals were also likely to be suffering from osteoarthritis pain with OR = 4.26, 95% CI = 1.02; 17.74 and Coef. = 1.93; 95% CI = 1.49; 2.50, respectively. Regular health examinations and higher expenditure for healthcare were correlated with a lower prevalence of neuropathic pain., Discussion: These results may inform the adoption of pain screening and other programs that increase health care access for this population, as well as more stringent occupational health and safety standards., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nguyen, Nguyen, Vu, Chiu, Nguyen, Nguyen, Nguyen, Dang, Do, Nguyen, Nguyen, Ngo, Tran, Latkin, Ho and Ho.)

Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at 'CpG' sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case-control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe 'cg15939386' in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy., (© 2023. Springer Nature Limited.)

Importance: Nutritional status of infants, measured by birth weight and length, is an essential factor in neonatal development. Malnutrition in newborns may lead to a higher risk of mortality, neurological and cognitive impairment, and poor language development., Objective: This study aims to assess the nutritional status of infants and related factors regarding maternal anthropometric characteristics and medical history., Methods: A cross-sectional study was conducted at the National Hospital of Obstetrics and Gynecology, Vietnam from May 2021 to May 2022 on 340 infants and mothers. Low birth weight was defined following the Intergrowth-21 standards. Stunting was evaluated using the Fenton growth chart when the length was below the 10% percentile line of the gestational week. Multivariate regression models were applied to identify factors associated with the nutritional status of infants., Results: We found that 12.4% and 14.1% of infants in our study fell into stunted and underweight categories, respectively. Infants of mothers over 35 years old, having a height lower than 150 cm or experiencing anemia during pregnancy were more likely to be stunted or have low birth weight. Serum albumin deficiency during pregnancy was strongly associated with the infant being underweight (odds ratio [OR]  =  2.8, 95% confidence interval [95%CI] 1.1-7.3). Newborns were more likely to be stunted if their mothers had a history of preterm birth (OR = 3.3, 95%CI 1.1-10.2)., Interpretation: Maternal nutritional status is closely related to infant malnutrition, particularly in preterm infants. Improving the understanding of mothers regarding prenatal care, reproductive healthcare, adequate nutritional diet, and multi-micronutrient supplements during pregnancy is therefore important., Competing Interests: The authors declare no conflict of interest., (© 2023 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.)

Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring., (© 2023. The Author(s).)

Background: Self-medication is recognized as an effective form of treatment and is increasingly encouraged to treat minor illnesses. However, misuse of self-medication leaves devastating impacts on human health and causes antimicrobial resistance. Using medication without a prescription among farmers could cause more severe effects on their health than non-farm workers since they suffer from several occupational hazards such as excessive exposure to pesticides., Methods: A cross-sectional study was conducted in 197 residents living in Moc Chau from August to September. A structured questionnaire and face-to-face were used to collecting data. The multivariate logistic model was applied to indicate associated factors with the self-medication., Results: The prevalence of self-medication among farmers was 67%. Pain relievers (66.7%) and antibiotics (32.5%) were the types of medicines that were the most commonly purchased and used without a medical prescription. Ethnics and health status also significantly affected the self-medication practice as well as the purchase and use of antibiotics. The distance to travel to a medical center and the dangerous or difficult travel, participants with arthritis or inpatient treatment had significantly associated with buying and using the medicine and antibiotics without the medical prescription of farmers., Conclusion: Our research highlights a considerably high prevalence of self-medication among farmers residing in the mountainous area of Vietnam. Individual factors such as ethnics, health status, distance to health centers, and dangerous or difficult travel were found to be related to the SM practice as well as the purchase and use of antibiotics. From that, the current study suggests interventions. For instance, official guidelines are needed to raise awareness and minimize the disadvantages of self-medication; and digital health technologies should be applied to reduce the gap in healthcare service between mountainous and other areas of Vietnam., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nguyen, Nguyen, Boyer, Auquier, Fond, Do, Dang, Do, Latkin, Ho and Ho.)

The association between individual-level poverty and relapse in children receiving maintenance treatment for acute lymphoblastic leukemia (ALL) remains unclear. In a secondary analysis of COG-AALL03N1, we used data from US Census Bureau to categorize patients living below year-specific federal poverty thresholds, calculated using self-reported annual household income and size of household. Participants with federal poverty thresholds above 120% of their yearly household income were categorized as living in extreme poverty. Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression for patients living in extreme poverty while receiving ALL maintenance therapy after adjusting for relevant predictors. Among 592 patients in this analysis, 12.3% of the patients were living in extreme poverty. After a median follow-up of 7.9 years, the cumulative incidence of relapse at 3 years from study enrollment among those living in extreme poverty was significantly higher (14.3%) than those not living in extreme poverty (7.6%). Multivariable analysis demonstrated that children living in extreme poverty had a 1.95-fold greater hazard of relapse than those not living in extreme poverty; this association was mitigated after the inclusion of race/ethnicity in the model, likely because of collinearity between race/ethnicity and poverty. A greater proportion of children living in extreme poverty were nonadherent to mercaptopurine (57.1% vs 40.9%); however, poor adherence did not completely explain the association between poverty and relapse risk. Future studies need to understand the mechanisms underlying the association between extreme poverty and relapse risk. This trial was registered at www.clinicaltrials.gov as #NCT00268528., (© 2023 by The American Society of Hematology.)

Sleep quality is an important indicator of treatment outcome for patients with traffic accident injuries. In Vietnam, the impacts of injury on sleep status are usually amplified in urban areas due to disproportionate distribution of mental care services between the city and less developed settings. Our study investigated deterioration in sleep quality and identified associated demographic factors among traffic injury patients in an small urban setting of Vietnam. A cross-sectional study was conducted among 408 patients in one provincial hospital and five district hospitals in Thai Binh, Vietnam from October to December 2018. A structured questionnaire was designed based on 3 standardized scales: Health-related Quality of Life, the Pittsburgh Sleep Quality Index and the Kessler Scale. Face-to-face interviews and medical records were conducted by trained health professionals on patients hospitalized in the Trauma-Orthopedic/Burn Department and Surgery and General Department. About 16.9% of respondents had sleep disturbances, and there was a statistically significant difference between age group (p < 0.01), education level (p < 0.01), and monthly household income (p < 0.01) between participants who with and without sleep disturbances. Furthermore, more than half (50.7%) of respondents sleep less than 5 h per day, while 18.7% of the sampled also reported that the habitual sleep efficiency was below 85%. Current results indicated that people being female, suffering from traumatic brain injury, being comatose at hospitalization, and having higher psychological distress scores were more likely to suffer from sleep problems. Our study is one of the first evidence in Vietnam to assess sleep disturbances in road traffic injury patients and their correlated factors. It is important to identify patients who are at risk of sleep disturbances based on socio-demographic and clinical characteristics, as well as psychological distress status. Therefore, a holistic approach should be taken to include sleep quality and psychological state in the treatment process and outcome assessment for road traffic injury patients., (© 2023. The Author(s).)

Aims: Chronic stress is a well-known risk factor for the development of hypertension. However, the underlying mechanisms remain unclear. Corticotropin-releasing hormone (CRH) neurons in the central nucleus of the amygdala (CeA) are involved in the autonomic responses to chronic stress. Here, we determined the role of CeA-CRH neurons in chronic stress-induced hypertension., Methods and Results: Borderline hypertensive rats (BHRs) and Wistar-Kyoto (WKY) rats were subjected to chronic unpredictable stress (CUS). Firing activity and M-currents of CeA-CRH neurons were assessed, and a CRH-Cre-directed chemogenetic approach was used to suppress CeA-CRH neurons. CUS induced a sustained elevation of arterial blood pressure (ABP) and heart rate (HR) in BHRs, while in WKY rats, CUS-induced increases in ABP and HR quickly returned to baseline levels after CUS ended. CeA-CRH neurons displayed significantly higher firing activities in CUS-treated BHRs than unstressed BHRs. Selectively suppressing CeA-CRH neurons by chemogenetic approach attenuated CUS-induced hypertension and decreased elevated sympathetic outflow in CUS-treated BHRs. Also, CUS significantly decreased protein and mRNA levels of Kv7.2 and Kv7.3 channels in the CeA of BHRs. M-currents in CeA-CRH neurons were significantly decreased in CUS-treated BHRs compared with unstressed BHRs. Blocking Kv7 channel with its blocker XE-991 increased the excitability of CeA-CRH neurons in unstressed BHRs but not in CUS-treated BHRs. Microinjection of XE-991 into the CeA increased sympathetic outflow and ABP in unstressed BHRs but not in CUS-treated BHRs., Conclusions: CeA-CRH neurons are required for chronic stress-induced sustained hypertension. The hyperactivity of CeA-CRH neurons may be due to impaired Kv7 channel activity, which represents a new mechanism involved in chronic stress-induced hypertension., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Estimating and analyzing trends and patterns of health loss are essential to promote efficient resource allocation and improve Peru's healthcare system performance., Methods: Using estimates from the Global Burden of Disease (GBD), Injuries, and Risk Factors Study (2019), we assessed mortality and disability in Peru from 1990 to 2019. We report demographic and epidemiologic trends in terms of population, life expectancy at birth (LE), mortality, incidence, prevalence, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) caused by the major diseases and risk factors in Peru. Finally, we compared Peru with 16 countries in the Latin American (LA) region., Results: The Peruvian population reached 33.9 million inhabitants (49.9% women) in 2019. From 1990 to 2019, LE at birth increased from 69.2 (95% uncertainty interval 67.8-70.3) to 80.3 (77.2-83.2) years. This increase was driven by the decline in under-5 mortality (-80.7%) and mortality from infectious diseases in older age groups (+60 years old). The number of DALYs in 1990 was 9.2 million (8.5-10.1) and reached 7.5 million (6.1-9.0) in 2019. The proportion of DALYs due to non-communicable diseases (NCDs) increased from 38.2% in 1990 to 67.9% in 2019. The all-ages and age-standardized DALYs rates and YLLs rates decreased, but YLDs rates remained constant. In 2019, the leading causes of DALYs were neonatal disorders, lower respiratory infections (LRIs), ischemic heart disease, road injuries, and low back pain. The leading risk factors associated with DALYs in 2019 were undernutrition, high body mass index, high fasting plasma glucose, and air pollution. Before the COVID-19 pandemic, Peru experienced one of the highest LRIs-DALYs rates in the LA region., Conclusion: In the last three decades, Peru experienced significant improvements in LE and child survival and an increase in the burden of NCDs and associated disability. The Peruvian healthcare system must be redesigned to respond to this epidemiological transition. The new design should aim to reduce premature deaths and maintain healthy longevity, focusing on effective coverage and treatment of NCDs and reducing and managing the related disability., Competing Interests: CB participation on a data safety monitoring board for COVID-out: Metformin and other COVID treatment study and is a member of the American Heart Association Epidemiology Leadership committee, outside the submitted work. LC-H is an employee of the Instituto Nacional de Salud Pública, Mexico and Universidad Peruana Cayetano Heredia. S Cortes reports support for the present manuscript from Fondo de Financiamiento de Centros de Investigacion en Areas Prioritarias (FONDAP) (grant number 15130011). VG reports grants or contracts from the National Health and Medical Research Council (NHMRC), Australia, paid directly to their institution, outside the submitted work. FK reports grants or contracts from Belgian Directorate of Development Cooperation (DGD) through the Framework Agreement between the Belgian DGD and the Institute of Tropical Medicine, Belgium; Fogarty International Center of the National Institutes of Health and the University of California Global Health Institute under Award Number D43TW009343; Fogarty International Center, and National Institute of Child Health & Human Development of the National Institutes of Health under Award Number D43 TW009763, outside the submitted work. WM is a United Nations Population Fund staff at the Peru Country Office, which does not necessarily endorse these results. JM reports grants from Alliance for Health Policy and Systems Research (HQHSR1206660), Bloomberg Philanthropies (grant 46129, via University of North Carolina at Chapel Hill School of Public Health), FONDECYT via CIENCIACTIVA/CONCYTEC, British Council, British Embassy and the Newton-Paulet Fund (223-2018, 224-2018), DFID/MRC/Wellcome Global Health Trials (MR/M007405/1), Fogarty International Center (R21TW009982, D71TW010877, R21TW011740), Grand Challenges Canada (0335–04), International Development Research Center Canada (IDRC 106887, 108167), Inter-American Institute for Global Change Research (IAI CRN3036), National Cancer Institute (1P20CA217231), National Heart, Lung and Blood Institute (HHSN268200900033C, 5U01HL114180, 1UM1HL134590), National Institute of Mental Health (1U19MH098780), Swiss National Science Foundation (40P740-160366), UKRI BBSRC (BB/T009004/1), UKRI EPSRC (EP/V043102/1), UKRI MRC (MR/P008984/1, MR/P024408/1, MR/P02386X/1), Wellcome (074833/Z/04/Z, 093541/Z/10/Z, 103994/Z/14/Z, 107435/Z/15/Z, 205177/Z/16/Z, 214185/Z/18/Z, 218743/Z/19/Z) and the World Diabetes Foundation (WDF15-1224), paid to their institution, and contracts from Health Action International; unpaid participation on data safety monitoring board, Nigeria Sodium Study (NaSS); Trial Steering Committee, INTEnsive care bundle with blood pressure Reduction in Acute Cerebral haemorrhage Trial (INTERACT 3); International Advisory Board, Latin American Brain Health institute (BrainLat), Universidad Adolfo Ibáñez (Chile); Consultative Board, Programa de Gastronomía, Facultad de Estudios Interdisciplinarios, Pontificia Universidad Católica del Perú; and Advisory Board, InterAmerican Heart Foundation (IAHF); and is the co-chair of the Independent Group of Scientists (IGS), 2023 Global Sustainable Development Report, United Nations; a is member of the Scientific Expert Committee, Global Data Collaborative for CV Population Health, World Health Federation, Microsoft, and Novartis Foundation; the Scientific and Technical Advisory Committee (STAC), Alliance for Health Policy and Systems Research, World Health Organization; the WHO Technical Advisory Group on NCD-related Research and Innovation (TAG/RI), Noncommunicable Diseases Department, World Health Organization; and the Advisory Scientific Committee, Instituto de Investigación Nutricional (Peru), all unpaid, outside the submitted work. DV reports scholarship support from the Canadian Institutes of Health Research and is an unpaid board member for the Global Alliance for Rheumatic and Congenital Hearts, all outside the submitted work. IZ was employed by Sina Medical Biochemistry Technologies Co. Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rios-Blancas, Pando-Robles, Razo, Carcamo, Mendoza, Pacheco-Barrios, Miranda, Lansingh, Demie, Saha, Okonji, Yigit, Cahuana-Hurtado, Chacón-Uscamaita, Bernabe, Culquichicon, Chirinos-Caceres, Cárdenas, Alcalde-Rabanal, Barrera, Quintanilla, Shorofi, Wickramasinghe, Ferreira, Almidani, Gupta, Karimi, Alayu, Benziger, Fukumoto, Mostafavi, Redwan, Gebrehiwot, Khatab, Koyanagi, Krapp, Lee, Noori, Qattea, Rosenthal, Sakshaug, Wagaye, Zare, Ortega-Altamirano, Murillo-Zamora, Vervoort, Silva, Oulhaj, Herrera-Serna, Mehra, Amir-Behghadami, Adib, Cortés, Dang, Nguyen, Mokdad, Hay, Murray, Lozano and García.)

Open-access publishing promotes accessibility to scholarly research at no cost to the reader. The emergence of predatory publishers, which exploit the author-pay model by charging substantial publication fees for publication in journals with questionable publishing processes, is on the rise. Authors are solicited through aggressive marketing tactics, though who is targeted is not well described. The purpose of this study was to identify characteristics associated with critical care pharmacists that make them targets of unsolicited invitations to publish. A prospective, observational study of critical care pharmacists was performed. Participants archived emails received by their professional email that were unsolicited invitations to submit their original work for publication in a journal (unsolicited journals). Variables were evaluated to determine which were associated with unsolicited invitations; these were compared to legitimate journals, defined as all PubMed-indexed journals in which the participants were previously published. Twenty-three pharmacist participants were included, all of whom were residency and/or fellowship trained and practicing in an academic medical center. Participants had a median of 7 years of experience since their post-graduate training, 6 years since their last change in professional email address, and 2 years since their first PubMed-indexed publication. From these participants, 136 unsolicited and 59 legitimate journals were included. The average number of invitations increased 1.04 (95% CI, 1.02-1.05) times for every additional PubMed-indexed publication ( P < .001). Most unsolicited journals were considered predatory. Legitimate and unsolicited journals differed significantly. The number of previous PubMed-indexed publications strongly correlates with the likelihood of critical care pharmacists receiving unsolicited publication invitations, often from predatory journal.

Monitoring the consumption of artificial sweeteners in the population is essential to help public health authorities understand the level of sugar consumption. There is a gap in knowledge of patterns and levels of artificial sweetener consumption in Vietnam. Using wastewater-based epidemiology (WBE), this study aims to evaluate the use of artificial sweeteners in an urban population in Hanoi, Vietnam. A total of 184 wastewater samples were collected at two sampling sites in an urban canal, receiving sewage from over 400,000 people in three different periods between 2018 and 2020. The population normalized per capita consumption of the five detected artificial sweeteners varied from 0.87 mg d -1 p -1 (sucralose) to 5.2 mg d -1 p -1 (aspartame). The daily consumption of artificial sweeteners was found to be stable throughout the week, however the consumption of artificial sweeteners was influenced by season with higher consumption in summer. Significant correlations (p < 0.01) were found among levels of artificial sweeteners and caffeine in urban canal samples, suggesting these chemicals had common sources. Population-weighted consumption load of artificial sweeteners and caffeine was compared in Vietnam, China and Australia, and the per capita consumption load mainly depended on the habitual of tea/coffee drinking in different countries. This was the first study that provided information on the artificial sweetener consumption by wastewater analysis in Vietnam. However, several sources of uncertainty (sample collection, population estimation, other sources of artificial sweeteners in wastewater, etc.) were acknowledged in this study. Further investigations on the spatial-temporal variation of artificial sweetener consumption with more intensive sampling scheme in Vietnam are recommended., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: This study aimed to use a large-scale longitudinal design to investigate the development of the distribution of effort (e.g., pacing) in adolescent swimmers, specifically disentangling the effects of age and experience and differentiating between performance levels in adulthood., Methods: Season best times and 50-m split times of 100- and 200-m freestyle swimmers from five continents were gathered between 2000 and 2021. Included swimmers competed in a minimum of three seasons between 12 and 24 yr old (5.3 ± 1.9 seasons) and were categorized by performance level in adulthood (elite, sub-elite, high-competitive; 100-m: n = 3498 (47% female); 200-m: n = 2230 (56% female)). Multilevel models in which repeated measures (level 1) were nested within individual swimmers (level 2) were estimated to test the effects of age, race experience, and adult performance level on the percentage of total race time spent in each 50-m section ( P < 0.05)., Results: In the 100-m, male swimmers develop a relatively faster first 50-m when becoming older. This behavior also distinguishes elite from high-competitive swimmers. No such effects were found for female swimmers. Conversely, more experienced male and female swimmers exhibit a slower initial 50-m. With age and race experience, swimmers develop a more even velocity distribution in the 200-m. Adolescent swimmers reaching the elite level adopt a more even behavior compared with high-competitive. This differentiation occurs at a younger age in female (>13 yr) compared with male (>16 yr) swimmers., Conclusions: Pacing behavior development throughout adolescence is driven by age-related factors besides race experience. Swimmers attaining a higher performance level during adulthood exhibit a pacing behavior that better fits the task demands during adolescence. Monitoring and individually optimizing the pacing behavior of young swimmers is an important step toward elite performance., (Copyright © 2022 by the American College of Sports Medicine.)

Background: Post-operative appetite loss is an important complication affecting surgical outcomes. It has been estimated that nearly 60% of patients having gastrointestinal or major elective surgeries suffer from malnutrition. Appetite refers to the physical desire for food appetite, and losing appetite after surgery may result in a decrease in body weight, impairment of intestinal absorption and eventually, malnutrition among postoperative patients. This study aims to assess appetite status and other relevant factors among abdominal postoperative patients in Vietnam., Methods: A cross-sectional study was conducted on 169 abdominal postoperative patients from June 1st to August 30th, 2016 at Hanoi Medical University Hospital, Hanoi, Vietnam. Appetite score was computed by using the Council on Nutrition Appetite Questionnaire (CNAQ). This study used GEE to account for the potential correlation of outcomes of the longitudinal assessment, assuming an independent correlation structure., Results: The primary and secondary outcome measures: highest average appetite score was recorded in the preoperative day and the score declined throughout seven-day duration. Patients who were female, under general anesthetics and being under open surgery tended to get lower appetite scores. The majority of patients had moderate to good appetite in both the preoperative day and seven days post-operation., Conclusion: Women should receive more care and help in regaining their appetite after surgery. Treatment for appetite loss through non-pharmaceutical measures should be prioritized. Interventions that increase the appetite of patients after abdominal surgery should be targeted on patients being under general anesthetic as well as open surgery and be undertaken with caution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nguyen, Ta, Dang, Nguyen, Dam, Latkin, Ho and Ho.)

Purpose: Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication)., Methods: A genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1., Results: Two SNPs (rs17736312 [ ROBO2 ]) and rs113230990 (near a CCCTC-binding factor insulator [< 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m 2 , the AA genotype and anthracyclines > 250 mg/m 2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-β1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect ( TGF-β1 , P = .007); gene*anthracycline interaction ( ROBO2 *anthracycline, P = .0003); and gene*gene*anthracycline interaction ( SLIT2 * TGF-β1* anthracycline, P = .009)., Conclusion: These findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-β1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 ( ROBO2 ) and anthracycline-related cardiomyopathy.

Agriculture in the current century is seeking sustainable tools in order to generate plant production systems with minimal negative environmental impact. In recent years it has been shown that the use of insect frass is an option to be used for this purpose. The present work studied the effect of low doses (0.1, 0.5, and 1.0% w / w ) of cricket frass ( Acheta domesticus ) in the substrate during the cultivation of tomatos under greenhouse conditions. Plant performance and antioxidant enzymatic activities were measured in the study as explicative variables related to plant stress responses in order to determine possible biostimulant or elicitor effects of cricket frass treatments during tomato cultivation under greenhouse conditions. The main findings of this study indicated that tomato plants responded in a dose dependent manner to cricket frass treatments, recalling the hormesis phenomenon. On the one hand, a 0.1% ( w / w ) cricket frass treatment showed typical biostimulant features, while on the other hand, 0.5 and 1.0% treatments displayed elicitor effects in tomato plants under evaluated conditions in the present study. These results support the possibility that low doses of cricket frass might be used in tomato cultivation (and perhaps in other crops) for biostimulant/elicitor input into sustainable production systems.

Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection., Significance: There is a great need for accessible and sensitive screening approaches for HCC worldwide. We have developed an approach for examining genome-wide cfDNA fragmentation features to provide a high-performing and cost-effective approach for liver cancer detection. See related commentary Rolfo and Russo, p. 532. This article is highlighted in the In This Issue feature, p. 517., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis., Objectives: The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms. Using leads from DEGs, candidate copy number variants (CNVs) and single-nucleotide variants (SNVs) were genotyped., Methods: Messenger RNA sequencing was performed on total RNA from peripheral blood of 40 survivors with cardiomyopathy (cases) and 64 matched survivors without cardiomyopathy (control subjects). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest radiation was used to assess the associations between gene expression and cardiomyopathy and between CNVs and SNVs and cardiomyopathy., Results: Haptoglobin ( HP ) was identified as the top DEG. Participants with higher HP gene expression had 6-fold greater odds of developing cardiomyopathy (OR: 6.4; 95% CI: 1.4-28.6). The HP2 -specific allele among the HP genotypes (HP1-1, HP1-2, and HP2-2) had higher transcript levels, as did the G allele among SNVs previously reported to be associated with HP gene expression (rs35283911 and rs2000999). The HP1-2 and HP2-2 genotypes combined with the G/G genotype for rs35283911 and/or rs2000999 placed the survivors at 4-fold greater risk (OR: 3.9; 95% CI: 1.0-14.5) for developing cardiomyopathy., Conclusions: These findings provide evidence of a novel association between HP2 allele and cardiomyopathy. HP binds to free hemoglobin to form an HP-hemoglobin complex, thereby preventing oxidative damage from free heme iron, thus providing biological plausibility to the mechanistic basis of the present observation., Competing Interests: This research is supported by the National Cancer Institute (R35CA220502; principal investigator [PI], S. Bhatia), Leukemia and Lymphoma Society (6563-19; PI, S. Bhatia), and the V Foundation (DT2019-010; PI, S. Bhatia). The Children’s Oncology Group study (COG-ALTE03N1 [NCT00082745]; PI, S. Bhatia) reported here is supported by the National Clinical Trials Network Operations Center Grant (U10CA180886; PI, D.S. Hawkins), the National Clinical Trials Network Statistics & Data Center Grant (U10CA180899; PI, Alonzo), the Children’s Oncology Group Chair’s Grant (U10CA098543; PI, Adamson), the Children’s Oncology Group Statistics & Data Center Grant (U10CA098413; PI, Anderson), the National Cancer Institute Community Oncology Research Program Grant (UG1CA189955; PI, Pollock), and the Community Clinical Oncology Program Grant (U10CA095861; PI, Pollock), and the St. Baldrick’s Foundation through an unrestricted grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Despite the efficacy of immune checkpoint inhibitors (ICIs), adverse events including hepatotoxicity limit their ongoing use. We investigated the outcomes and management of patients with immune-mediated hepatitis (IMH) and clinical predictors of toxicity resolution., Methods: Patients referred to our multidisciplinary immunotherapy-related toxicity group from August 2017 to December 2020 for IMH were evaluated. Toxicity was defined according to CTCAEv4.0. IMH resolution was defined as liver enzyme normalization after steroid initiation., Results: Thirty-three patients were included in the study, 62% female, and 71% Caucasian. The most common ICI used was PD-1/PD-L1 (76%). Peak IMH occurred at a median of 89 [45,193] days, for which most patients received 1-2 mg/kg/day prednisone equivalent with 35% requiring MMF. Median follow-up was 123 [33,472] days with IMH resolution seen in 48% of patients at a median of 111 [41,214] days. While high-dose steroid use was not associated with IMH resolution, liver enzyme improvement one week after steroids predicted resolution in univariate analysis (p = 0.041). All 11 patients without IMH resolution died from cancer progression or complications with three patients having acute liver failure. Available liver biopsies showed bile duct injury, with varying degrees of portal and lobular inflammation., Conclusion: IMH improvement one week after steroid initiation may predict ultimate IMH resolution., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)