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This study aims to empirically test whether family has a unique significance for the self that cannot be captured by the social self alone. Specifically, it examines whether family self-concept, compared to social self-concept, is more closely related to family-specific indicators (i.e., parent-child communication and family functioning) as well as to indicators of emotional maladjustment like mental health deterioration (i.e., psychological distress and depressive symptoms). The sample comprised 4,953 Mexican adolescents, including 2,551 men (51.5%) and 2,402 women, aged 14-17 years ( M = 15.60, SD = 0.92). Confirmatory factor analysis was applied to evaluate the proposed big five-dimensional self-concept model. Cohen's d confidence intervals, derived from the shared variance of Pearson's r correlations, were analyzed to relate self-concept dimensions to parent-child communication, family functioning, and mental health deterioration. Results from factorial confirmatory analysis showed that the five-dimensional oblique model (i.e., academic, social, emotional, physical, and family, as different from social) provided a better fit than competing unidimensional and orthogonal models. Correlation analyses showed that family self-concept was significantly associated with both parent-child communication and family functioning, as well as with psychological distress ( d = -1.10, confidence interval [CI] -1.21 to -1.02) and depressive symptoms ( d = -1.24, CI -1.31 to -1.22). These findings add evidence that family is not accurately represented within the social self-concept. Furthermore, perceiving oneself as unloved and undervalued at home (i.e., low family self-concept) is strongly associated not only with dysfunctional family processes but also with mental health deterioration.

Objectives: Chronobiology is the science that studies biological rhythms based on direct methods and empirical time series of individual subjects. In laboratory medicine, the factor of time is often underestimated, and no methods currently exist to study biological rhythms in population databases of point-like, real-world data (RWD)., Methods: Retrospective databases (24 months, 2022-2023) were extracted for four measurands (sodium, potassium, chloride and leukocytes) from the emergency laboratory. Two different strategies for data grouping were applied: data clouds (with or without outliers) and population-averaged profiles. Cosinor regression analysis was performed on the grouped data to derive circadian parameters. The parameters obtained here were compared to results from the literature, using direct methods and time series., Results: A total of 409,719 data points were analyzed. All measurands exhibited symmetrical data distributions, except for leukocytes. The data clouds did not visually display rhythmicity, but cosinor analysis revealed a significant circadian rhythm. The removal of outliers had minimal impact on the results. In contrast, population-averaged profiles showed visible rhythmicity, which was confirmed by cosinor analysis with a better goodness-of-fit compared to the data clouds., Conclusions: Population-averaged profiles have advantages over data clouds in characterizing circadian rhythms and deriving circadian parameters. Population chronobiology, based on RWD, is presented as an alternative to classical individual chronobiology, based on time series and overcomes the limitations of direct methods. Utilizing RWD provides new insights into the relationship between chronobiology and clinical laboratory practice., (© 2025 Walter de Gruyter GmbH, Berlin/Boston.)

Barth syndrome (BTHS) is a rare genetic disease caused by mutations in the TAFAZZIN gene. It is characterized by neutropenia, cardiomyopathy and skeletal myopathy. Neutropenia in BTHS is associated with life-threatening infections, yet there is little understanding of the molecular and physiological causes of this phenomenon. We combined bone marrow analysis, CRISPR/Cas9 genome editing in hematopoietic stem cells and functional characterization of circulating BTHS patient neutrophils to investigate the role of TAFAZZIN in neutrophils and their progenitors. We demonstrate a partial cell intrinsic differentiation defect, along with a dysregulated neutrophil inflammatory response in BTHS, including elevated degranulation and formation of neutrophil extracellular traps (NETs) in response to calcium flux. Developmental and functional alterations in BTHS neutrophils are underpinned by perturbations in the unfolded protein response (UPR) signaling pathway, suggesting potential therapeutic avenues for targeting BTHS neutropenia., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2025. The Author(s).)

Cytolethal distending toxins (CDTs), encoded by cdtABC genes, have DNase activity leading to cellular and nuclear distention, resulting in actin remodeling, irreversible cell cycle arrest and apoptosis of target cells. PCR cdt-positive Escherichia coli strains have been isolated from children with diarrhea worldwide. However, toxin production and biological activity of cdt + strains are rarely confirmed. Here, we characterized the biological activity of cdt + E. coli of clinical isolates from Mexican children with severe diarrhea and its relationship with the harbored cdt type. Ten isolates from seven patients containing cdt + E. coli, one isolate from a patient containing cdt - E. coli, and a prototype CDT-producing E. coli were used to determine the harbored cdt-type, cell distention, actin remodeling and cell cycle arrest on epithelial cells. Three isolates harbored cdt type I, one type II, two type III, two type IV and two simultaneously type II and III. Lysates from eight cdt + E. coli isolates caused cell distention, actin cytoskeletal remodeling and cell cycle arrest but two isolates from the same patient harboring simultaneously cdt type II/III did not. The cdt genes were necessary and enough to cause the cytolethal distending pathology. Mutants in cdtAB I C (O86:H34 strain; cdt-I) and cdtAB II C (isolate; cdt-II) were complemented by cdtAB II C genes and both recovered the CDT-induced phenotypes. Transformation of E. coli BL21 by cdtAB II C genes caused this cytolethal distending pathology. These data indicate that cdt + E. coli isolates are potentially dangerous bacteria to cause serious epithelial cell damage and cell death to aggravate childhood diarrhea., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background and Objective: Oral ivermectin is recommended as an alternative to topical permethrin in Japanese, European, and CDC-STI guidelines for treating classic scabies. The combination of oral ivermectin and topical permethrin is also used in some settings. Partial economic evaluations conducted in India and Egypt have conflicting results, and no cost-effectiveness analysis in the Philippines has compared ivermectin-based regimens to permethrin for scabies treatment. We aimed to determine the cost-effectiveness of oral ivermectin, alone or in combination with permethrin, compared to permethrin, in the treatment of Filipino adult patients with classic scabies., Methods: We used a decision tree model to estimate the cost-effectiveness of two regimens, oral ivermectin alone or in combination with permethrin, compared with permethrin to treat adults and children aged five years and older with classic scabies in the outpatient setting from the household perspective in the Philippines. We estimated total costs and disability-adjusted life years (DALYs) over a one-month follow-up. Input parameters were obtained from secondary data, such as effect estimates for probabilities of clinical outcomes from a network meta-analysis, DALYs from the Global Burden of Disease 2019, and prevailing market cost in the Philippines (DPRI 2022 with recommended markup by DOH, and leading drugstores) as of August 2022. We computed for incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB) to determine which of the interventions are cost-effective. Univariate and probabilistic sensitivity analyses, and scenario analyses were conducted to assess the impact of parameter and structural uncertainty., Results: Ivermectin-based regimens are suggested to be likely cost-saving compared to permethrin in the Philippine outpatient setting. Base case analysis showed that oral ivermectin had higher cost-savings (change in cost, -1,039.31; change in DALYS, 0.00027), while combination oral ivermectin/permethrin had higher DALYs averted (change in cost, PhP -1,019.78; change in DALYs, 0.00045), compared to permethrin. Combination oral ivermectin/permethrin (56%) was the most cost-effective, followed by oral ivermectin (44%) compared to permethrin (0%) through probabilistic sensitivity analysis. Estimates for ivermectin were sensitive to risk of cure for ivermectin vs permethrin using 1-way deterministic sensitivity analysis. Oral ivermectin was favored over combination oral ivermectin/permethrin at all thresholds based on the cost-effectiveness acceptability curve., Conclusion: Both ivermectin-based regimens seem to be cost-saving compared to permethrin in the treatment of classic scabies in the Philippine outpatient setting. Clinicians may consider oral ivermectin, alone or in combination with permethrin as an alternative first-line or second-line treatment depending on patient preference, adverse event risk profile, availability, and economic capacity. This needs to be confirmed using primary data from Filipino patients to enhance the robustness of the findings and support evidence-based local decision-making in different settings. Less uncertainty in modelled parameters can give greater confidence in the results, which can be adopted for budget impact analysis and allow more rational resource allocation. Value of information analysis can be done to determine whether the expense of future RCTs or surveys in Filipinos to collect primary data is worth it. The cost of reducing uncertainty, if deemed worth the cost of further studies, may facilitate population-level decision-making and budget planning. Findings may further inform practice guideline development, coverage decisions, and national control program planning by providing the most cost-effective scabies intervention., Competing Interests: All authors declared no conflicts of interest., (© 2025 Acta Medica Philippina.)

The digitization of healthcare records has revolutionized medical research and patient care, with electronic health records (EHRs) containing a wealth of structured and unstructured data. Extracting valuable information from unstructured clinical text presents a significant challenge, necessitating automated tools for efficient data mining. Natural language processing (NLP) methods have been pivotal in this endeavor, aiming to extract crucial clinical concepts embedded within free-form text. Our research addresses the imperative for robust biomedical entity extraction, focusing specifically on inflammatory bowel disease (IBD). Leveraging novel domain-specific pre-training and entity-aware masking strategies with contrastive learning, we fine-tune and adapt a general language model to be better adapted to IBD-related information extraction scenarios. Our named entity recognition (NER) tool streamlines the retrieval process, supporting annotation, correction, and visualization functionalities. In summary, we developed a comprehensive pipeline for clinical Dutch NER encompassing an efficient domain adaptation strategy with domain-aware masking and model fine-tuning enhancements, and an end-to-end entity extraction tool, significantly advancing medical record curation and clinical workflows., 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 © 2025 Francis, Crema Garcia, Uma, Mestdagh, De Moor and Moens.)

Enteropathogenic Escherichia coli (EPEC) strains are subdivided into typical (tEPEC) and atypical (aEPEC) according to the presence or absence of a virulence-associated plasmid called pEAF. Our research group has previously demonstrated that two aEPEC strains, 0421-1 and 3991-1, induce an increase in mucus production in a rabbit ileal loop model in vivo . This phenomenon was not observed with a tEPEC prototype strain. Few studies on aEPEC strains evaluating their capacity to induce intestinal mucus hypersecretion were done. This study aimed to investigate aEPEC strains regarding their genotypic and phenotypic characteristics, their ability to alter mucus production in an in vivo intestinal infection model, and their potential mucinolytic activity. To investigate the relationship between strains 0421-1 and 3991-1 and 11 other aEPEC strains, their serotypes, sequence types (ST), and virulence factors (VF), several sequencing and genomic analyses were carried out. The study also involved researching the reproduction of mucus hypersecretion in rabbits in vivo . We found that the two mucus-inducing strains and two other strains (1582-4 and 2531-13) shared the same phylogroup (A), ST (378), serotype (O101/O162:H33), and intimin subtype (ι2), were phylogenetically related, and induced mucus hypersecretion in vivo . A wide diversity of VFs was found among the strains, confirming their genomic heterogeneity. However, among the genes studied, no unique virulence factor or gene set was identified exclusively in the mucus-inducing strains, suggesting the multifactorial nature of this phenomenon. The two strains (1582-4 and 2531-13) closely related to the two aEPEC strains that induced mucus production in vivo also induced the phenomenon. The investigation of the mucinolytic activity revealed that all aEPEC strains used mucins as their carbon sources. Ten of the 13 aEPEC strains could cross a mucin layer, and only four adhered better to agar containing mucin than to agar without mucin. The present study paves the way for subsequent investigations into the molecular mechanisms regarding cellular interactions and responses, as well as the correlation between virulence factors and the induction of mucus production/expression during aEPEC infections., 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 Trovão, Vieira, Santos, Puño-Sarmiento, Nunes, Santos, Rocha, Knöbl, Navarro-Garcia and Gomes.)

Introduction: Protective ballistic body armor (BA) may be needed during certain threat postures while deployed. This requirement often adds between 35 and 45lbs of extra weight carried by the service member (SM) for multiple hours during the day. The physical toll of that extra weight and the effect it may have on deployed medical resources has not been clearly characterized in the literature. We sought to evaluate the association of a protective BA wear requirement with musculoskeletal (MSK) complaints and to better characterize how these effects are manifested within the deployed military health care system., Material and Methods: All encounters at a Role III Field Hospital were evaluated and queried for MSK injury. Data collected included the SM type, age, gender, MSK anatomy of concern, type of evaluating provider, disposition, and medications rendered. Injuries and outcomes were then compared between two groups; SMs who were seen for MSK complaints while BA was required (October 2023 to March 2024) and those during a period when BA was not required (No-BA = October 2022 to March 2023)., Results: A total of 2,805 encounters were evaluated. Non-SM visits were excluded (455) leaving 2,350 left for evaluation. In all, 969 (41.2%) were identified as encounters for MSK injury. No-BA had significantly fewer visits of MSK injury at 429 (38%) compared to the BA group at 540 (44%, P = .001). Active duty (AD) and National Guard (NG) SMs made up a larger portion of MSK visits in the BA group at 54% and 41%, respectively, compared to 35% Reserve (AR) and 36% NG in the No-BA group (P < .001). Service member were 12 times more likely to require a physical therapy treatment in the BA group (60%) vs. the No-BA (5%, P < .001). Prescriptions of non-steroidal anti-inflammatory medication were more common in the BA group at 11% of all visits compared to 4% in the No-BA group (P < .001). This was also true for muscle relaxers at 1% vs. 3% (P = .008). Shoulder and back injuries represented the largest proportion of MSK areas of concern at 22% and 24%, respectively, with only neck injuries being higher in the BA group at 8.5% vs. 5% (P = .03)., Conclusions: Required wear of BA was associated with an increase in MSK visits across all types of US SMs. Shoulder and back injuries were the most common with a significant increase in visits to physical therapy in the BA group. Anti-inflammatory and muscle-relaxing medications were prescribed more frequently in the BA group. A dedicated prospective study would help better elucidate the causality of these associations. Risk-benefit analysis of threat posture, with the knowledge of these health care associations, deserves serious consideration., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Environmentally-benign materials play a pivotal role in advancing the scalability of energy storage devices. In particular, conjugated polymers constitute a potentially greener alternative to inorganic- and carbon-based materials. One challenge to wider implementation is the scarcity of n-doped conducting polymers to achieve full cells with high-rate performance. Herein, this work demonstrates the use of a self-doped n-doped conjugated polymer, namely poly(benzodifurandione) (PBDF), for fabricating aqueous supercapacitors. PBDF demonstrates a specific capacitance of 202 ± 3 F g -1 , retaining 81% of the initial performance over 5000 cycles at 10 A g -1 in 2 m NaCl ( aq ) . PBDF demonstrates rate performances of up to 100 and 50 A g -1 at 1 and 2 mg cm -2 , respectively. Electrochemical impedance analysis reveals a surface-mediated charge storage mechanism. Improvements can be achieved by adding reduced graphene oxide (rGO), thereby obtaining a specific capacitance of 288 ± 8 F g -1 and high-rate operation (270 A g -1 ). The performance of PBDF is examined in symmetric and asymmetric membrane-less cells, demonstrating high-rate performance, while retaining 83% of the initial capacitance after 100 000 cycles at 10 A g -1 . PBDF thus offers new prospects for energy storage applications, showcasing both desirable performance and stability without the need for additives or binders and relying on environmentally friendly solutions., (© 2024 Wiley‐VCH GmbH.)

Background and Objective: Oral ivermectin, a broad-spectrum anti-parasitic drug, alone or in combination with permethrin, may be a cheaper and more convenient alternative drug to topical permethrin alone in the treatment of classic scabies. There are no previous studies on the treatment acceptability of the three interventions among individual patients with scabies in the Philippines.The purpose of this study was to understand the experiences and perceptions on treatment acceptability for oral ivermectin, topical permethrin or combination treatment among patients with scabies using the multiple-case study approach., Methods: We conducted a qualitative multiple case study among adult Filipino patients with classic scabies who were prescribed oral ivermectin, topical permethrin or its combination at a government tertiary hospital dermatology outpatient clinic from December 2022 to September 2023. Semi-structured interviews were used as the primary source of data and analyzed together with chart reviews, Dermatology Life Quality Index (DLQI) scores, and clinical images. Interviews were transcribed, coded, and triangulated with other secondary data. A three-person research team employed a reflexive and iterative process of familiarization, coding, and thematic analysis using a modified Theoretical Framework of Acceptability (TFA) to generate case descriptions, within-case analyses, and cross-case syntheses., Results: The acceptability of scabies treatments (permethrin, ivermectin, and combination therapy) was generally positive. Permethrin, used in three patient cases, was generally perceived as effective but itch relief varied. The burden of whole-body application of permethrin was context-dependent, influenced by living arrangements and family support. Perceived affordability of permethrin was linked to socioeconomic status. Ivermectin, used by one patient case, was perceived as highly effective with no side effects. Its single dose use did not interfere with patient routine. Combination therapy was also considered effective but potential antagonistic effects and the cost of adding permethrin made it less preferred. Reluctance in taking oral pills was noted. All patients valued medical advice and deferred to their physicians for treatment decisions., Conclusion and Recommendations: All three treatment options were considered effective and safe. Patients generally preferred permethrin over oral ivermectin due to its topical nature and perceived lower side effects. However, affordability and logistical challenges, especially for large households and low-income families, were noted with permethrin. Oral ivermectin elicited hesitation due to its controversial role in COVID-19 and veterinary use. Concerns about added costs and potential antagonism in combination therapy were raised. Despite these considerations, patients ultimately relied on physicians for treatment decisions. This study underscores the importance of understanding patient perspectives, experiences, and the patient-physician relationship in choosing scabies interventions. Addressing patient concerns, providing education, and ensuring ease of use and affordability can enhance treatment acceptability and adherence for better outcomes., Competing Interests: All authors declared no conflicts of interest., (© 2024 Acta Medica Philippina.)

Background: The proportion of nitrogen (N) derived from the atmosphere (Ndfa) is a fundamental component of the plant N demand in legume species. To estimate the N benefit of grain legumes for the subsequent crop in the rotation, a simplified N balance is frequently used. This balance is calculated as the difference between fixed N and removed N by grains. The Ndfa needed to achieve a neutral N balance (hereafter θ ) is usually estimated through a simple linear regression model between Ndfa and N balance. This quantity is routinely estimated without accounting for the uncertainty in the estimate, which is needed to perform formal statistical inference about θ . In this article, we utilized a global database to describe the development of a novel Bayesian framework to quantify the uncertainty of θ . This study aimed to (i) develop a Bayesian framework to quantify the uncertainty of θ , and (ii) contrast the use of this Bayesian framework with the widely used delta and bootstrapping methods under different data availability scenarios., Results: The delta method, bootstrapping, and Bayesian inference provided nearly equivalent numerical values when the range of values for Ndfa was thoroughly explored during data collection (e.g., 6-91%), and the number of observations was relatively high (e.g., ≥ 100 ). When the Ndfa tested was narrow and/or sample size was small, the delta method and bootstrapping provided confidence intervals containing biologically non-meaningful values (i.e. < 0% or > 100%). However, under a narrow Ndfa range and small sample size, the developed Bayesian inference framework obtained biologically meaningful values in the uncertainty estimation., Conclusion: In this study, we showed that the developed Bayesian framework was preferable under limited data conditions ─by using informative priors─ and when uncertainty estimation had to be constrained (regularized) to obtain meaningful inference. The presented Bayesian framework lays the foundation not only to conduct formal comparisons or hypothesis testing involving θ , but also to learn about its expected value, variance, and higher moments such as skewness and kurtosis under different agroecological and crop management conditions. This framework can also be transferred to estimate balances for other nutrients and/or field crops to gain knowledge on global crop nutrient balances., (© 2024. The Author(s).)

Immune mediators affect multiple biological functions of intestinal epithelial cells (IECs) and, like Paneth and Paneth-like cells, play an important role in intestinal epithelial homeostasis. IFN-γ a prototypical proinflammatory cytokine disrupts intestinal epithelial homeostasis. However, the mechanism underlying the process remains unknown. In this study, using in vivo and in vitro models we demonstrate that IFN-γ is spontaneously secreted in the small intestine. Furthermore, we observed that this cytokine stimulates mitochondrial activity, ROS production, and Paneth and Paneth-like cell secretion. Paneth and Paneth-like secretion downstream of IFN-γ, as identified here, is mTORC1 and necroptosis-dependent. Thus, our findings revealed that the pleiotropic function of IFN-γ also includes the regulation of Paneth cell function in the homeostatic gut., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Background: School-based targeted preventive chemotherapy (PC), the primary strategy for soil-transmitted helminth (STH) control, typically focusing on primary schoolchildren, was expanded to secondary school students in the Philippines in 2016. This program still excludes adults, who may also suffer from considerable morbidity and can be a significant reservoir of infection. Mass drug administration (MDA), where the entire population is treated, would bring additional health benefits but will also increase implementation costs. The incremental cost of implementing MDA for STH control compared to expanded school-based targeted PC, however, is unknown., Methods: A cost survey was conducted in Zamboanga Peninsula region in 2021 to estimate the economic and financial cost of implementing MDA compared to the expanded school-based targeted PC from a government payer perspective. A budget impact analysis was conducted to estimate the financial cost to the government of implementing MDA over a five-year timeframe. Monte Carlo simulation accounted for uncertainty in cost estimates. Costs were reported in 2021 United States Dollars ($)., Findings: The economic cost of MDA was $809,000 per year (95% CI: $679,000-$950,000) or $0.22 per person targeted (95% CI: $0.19-$0.26), while the expanded school-based targeted PC would cost $625,000 (95% CI: $549,000-$706,000) or $0.57 per person targeted (95% CI: $0.50-$0.64). Over five years, the financial cost to the government for MDA would be $3,113,000 (95% CI: $2,475,000-$3,810,000); $740,000 (95% CI: $486,000-$1,019,000) higher than expanded school-based targeted PC., Interpretation: Implementing MDA in the region will increase the economic and financial costs by 29% and 31%, respectively, when compared to expanded school-based targeted PC. Implementing MDA would require the Department of Health to increase their total expenditure for STH control by 0.2% and could be key in addressing the ongoing STH burden., Funding: The project was funded by the Australian Centre for the Control and Elimination of Neglected Tropical Diseases (NHMRC GA19028), and JPCDT was supported by a UNSW Scientia PhD Scholarship. SVN is funded by an NHMRC Investigator Grant (APP 2018220)., Competing Interests: The authors declare no competing interest., (© 2024 The Author(s).)

Background: This study aims to evaluate healthcare systems and pandemic responses in relation to marginalized and vulnerable groups, identify populations requiring urgent care, and assess the differential impacts on their health during the pandemic., Methods: Data were collected by the Asia-Pacific Observatory on Health Systems and Policies (APO)-National University of Singapore and APO-International Health Policy Program consortium members: Korea, Indonesia, Philippines, and Singapore. Data were collected through a combination of semi-structured interviews, policy document reviews, and analysis of secondary data., Results: Our findings reveal that the pandemic exacerbated existing health disparities, particularly affecting older adults, women, and children. Additionally, the study identified LGBTI individuals, healthcare workers, slum dwellers, and migrant workers as groups that faced particularly severe challenges during the pandemic. LGBTI individuals encountered heightened discrimination and limited access to health services tailored to their needs. Healthcare workers suffered from immense stress and risk due to prolonged exposure to the virus and critical working conditions. Slum dwellers struggled with healthcare access and social distancing due to high population density and inadequate sanitation. Migrant workers were particularly hard hit by high risks of virus transmission and stringent, often discriminatory, isolation measures that compounded their vulnerability. The study highlights the variation in the extent and nature of vulnerabilities, which were influenced by each country's specific social environment and healthcare infrastructure. It was observed that public health interventions often lacked the specificity required to effectively address the needs of all vulnerable groups, suggesting a gap in policy and implementation., Conclusions: The study underscores that vulnerabilities vary greatly depending on the social environment and context of each country, affecting the degree and types of vulnerable groups. It is critical that measures to ensure universal health coverage and equal accessibility to healthcare are specifically designed to address the needs of the most vulnerable. Despite commonalities among groups across different societies, these interventions must be adapted to reflect the unique characteristics of each group within their specific social contexts to effectively mitigate the impact of health disparities., (© 2024. The Author(s).)

Background: Neutrophils are granulocytes with essential antimicrobial effector functions and short lifespans. During infection or sterile inflammation, emergency granulopoiesis leads to release of immature neutrophils from the bone marrow, serving to boost circulating neutrophil counts. Steady state and emergency granulopoiesis are incompletely understood, partly due to a lack of genetically amenable models of neutrophil development., Methods: We optimised a method for ex vivo production of human neutrophils from CD34 + haematopoietic progenitors. Using flow cytometry, we phenotypically compared cultured neutrophils with native neutrophils from donors experiencing emergency granulopoiesis, and steady state neutrophils from non-challenged donors. We carry out functional and proteomic characterisation of cultured neutrophils and establish genome editing of progenitors., Results: We obtain high yields of ex vivo cultured neutrophils, which phenotypically resemble immature neutrophils released into the circulation during emergency granulopoiesis. Cultured neutrophils have similar rates of ROS production and bacterial killing but altered degranulation, cytokine release and antifungal activity compared to mature neutrophils isolated from peripheral blood. These differences are likely due to incomplete synthesis of granule proteins, as demonstrated by proteomic analysis., Conclusion: Ex vivo cultured neutrophils are genetically tractable via genome editing of precursors and provide a powerful model system for investigating the properties and behaviour of immature neutrophils., (© 2024. The Author(s).)

Introduction: Sanquin donor medicine department is informed when donations or their components are rejected. This can occur isolated or frequently. It is undesirable because the donations cannot be used and there may be an underlying medical cause. Based on regional approaches, a uniform procedure was developed., Methods: Information about whole blood, plasma- plateletpheresis donations from which one or more components were rejected for filtration time (>2 h), hemolysis or clots were extracted from blood bank information system. After rejection of two successive components or donations or total ≥3 the donor is contacted. Depending on the medical history and investigation by the family doctor, the donor carrier is re-evaluated. We looked for the causes of the discarded products and performed a survey among blood services regarding polices with discarded products., Results: One or more components from 1742 of about 2.2 million successful donations (0.08%) were rejected. The highest percentage of rejection was seen in plateletpheresis (1.5%), all for clots. No underlying medical causes were found. 24 whole blood donors were found to have sickle cell trait (SCT) and were permanently deferred. The policies for follow-up after discarded products or acceptance of SCT donors vary between the 16 blood banks. Six organizations do not follow-up donors and seven accept SCT for blood or plasma donation., Conclusion: Informing donors with repeated discarded products avoids the non-use of donations. Causes of repeated discarded products can be found by follow-up of donors. The results of the survey indicate a large discrepancy in policies applied worldwide., (© 2024 AABB.)

Background and Objective: The focusing of resources to COVID-19 response hampered and disadvantaged primary care services including that for Non-Communicable Diseases (NCDs), compromising continuity of care and hence, patients' disease status. However, studies from low- and middle-income countries (LMICs) remain sparse; therefore, evidence generation on how the pandemic impacted the provision of these primary care services in LMICs will help further understand how policies can be reframed, and programs be made more efficient and effective despite similar crises. To bridge this gap, the study investigated how the pandemic affected the implementation of NCD care at the primary care level in the Philippines., Methods: Thirty-one online focus group discussions via Zoom Meetings were conducted among 113 consenting physicians, nurses, midwives, and community health workers from various facilities - community health centers and stations, free-standing clinics, infirmaries, and level 1 hospitals - located within two provinces in the Philippines. All interviews were video-recorded upon participants' consent and transcribed verbatim. Inductive thematic analysis was employed through NViVo 12 ® to generate themes, identify categories, and describe codes., Results: The impact of COVID-19 on NCD care at the primary care level revolved around heightened impediments to service delivery, alongside worsening of pre-existing challenges experienced by the healthcare workforce; subsequently compelling the public to resort to unhealthy practices. These detriments to the primary healthcare system involved resource constraints, discontinued programs, referral difficulties, infection, overburden among workers, and interrupted training activities. Citizens were also observed to adopt poor healthcare seeking behavior, thereby discontinuing treatment regimen., Conclusion: Healthcare workers asserted that disadvantages caused by the pandemic in their NCD services at the primary care level possibly threaten patients' health status. Besides the necessity to address such detriments, this also emphasizes the need for quantitative studies that will aid in drawing inferences and evaluating the effect of health crises like the pandemic on such services to bridge gaps in improving quality of care., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Acta Medica Philippina.)

Molecular chaperones are critical for protein homeostasis and are implicated in several human pathologies such as neurodegeneration and cancer. While the binding of chaperones to nascent and misfolded proteins has been studied in great detail, the direct interaction between chaperones and RNA has not been systematically investigated. Here, we provide the evidence for widespread interaction between chaperones and RNA in human cells. We show that the major chaperone heat shock protein 70 (HSP70) binds to non-coding RNA transcribed by RNA polymerase III (RNA Pol III) such as tRNA and 5S rRNA. Global chromatin profiling revealed that HSP70 binds genomic sites of transcription by RNA Pol III. Detailed biochemical analyses showed that HSP70 alleviates the inhibitory effect of cognate tRNA transcript on tRNA gene transcription. Thus, our study uncovers an unexpected role of HSP70-RNA interaction in the biogenesis of a specific class of non-coding RNA with wider implications in cancer therapeutics., Competing Interests: Declaration of interests S.L. and P.A. are employees of AstraZeneca. F.A.-G. is employee of Cytena GmbH., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To study the suitability of costsensitive ordinal artificial intelligence-machine learning (AIML) strategies in the prognosis of SARS-CoV-2 pneumonia severity., Materials & Methods: Observational, retrospective, longitudinal, cohort study in 4 hospitals in Spain. Information regarding demographic and clinical status was supplemented by socioeconomic data and air pollution exposures. We proposed AI-ML algorithms for ordinal classification via ordinal decomposition and for cost-sensitive learning via resampling techniques. For performance-based model selection, we defined a custom score including per-class sensitivities and asymmetric misprognosis costs. 260 distinct AI-ML models were evaluated via 10 repetitions of 5×5 nested cross-validation with hyperparameter tuning. Model selection was followed by the calibration of predicted probabilities. Final overall performance was compared against five well-established clinical severity scores and against a 'standard' (non-cost sensitive, non-ordinal) AI-ML baseline. In our best model, we also evaluated its explainability with respect to each of the input variables., Results: The study enrolled n = 1548 patients: 712 experienced low, 238 medium, and 598 high clinical severity. d = 131 variables were collected, becoming d ' = 148 features after categorical encoding. Model selection resulted in our best-performing AI-ML pipeline having: a) no imputation of missing data, b) no feature selection (i.e. using the full set of d ' features), c) 'Ordered Partitions' ordinal decomposition, d) cost-based reimbalance, and e) a Histogram-based Gradient Boosting classifier. This best model (calibrated) obtained a median accuracy of 68.1% [67.3%, 68.8%] (95% confidence interval), a balanced accuracy of 57.0% [55.6%, 57.9%], and an overall area under the curve (AUC) 0.802 [0.795, 0.808]. In our dataset, it outperformed all five clinical severity scores and the 'standard' AI-ML baseline., Discussion & Conclusion: We conducted an exhaustive exploration of AI-ML methods designed for both ordinal and cost-sensitive classification, motivated by a real-world application domain (clinical severity prognosis) in which these topics arise naturally. Our model with the best classification performance exploited successfully the ordering information of ground truth classes, coping with imbalance and asymmetric costs. However, these ordinal and cost-sensitive aspects are seldom explored in the literature.

Plasmid-encoded toxin (Pet) is an autotransporter protein of the serine protease autotransporters of Enterobacteriaceae (SPATE) family, important in the pathogenicity of Escherichia coli . The pet gene was initially found in the enteroaggregative E. coli (EAEC) virulence plasmid, pAA2. Although this virulence factor was initially described in EAEC, an intestinal E. coli pathotype, pet may also be present in other pathotypes, including extraintestinal pathogenic strains (ExPEC). The complement system is an important defense mechanism of the immune system that can be activated by invading pathogens. Proteases produced by pathogenic bacteria, such as SPATEs, have proteolytic activity and can cleave components of the complement system, promoting bacterial resistance to human serum. Considering these factors, the proteolytic activity of Pet and its role in evading the complement system were investigated. Proteolytic assays were performed by incubating purified components of the complement system with Pet and Pet S260I (a catalytic site mutant) proteins. Pet, but not Pet S260I, could cleave C3, C5 and C9 components, and also inhibited the natural formation of C9 polymers. Furthermore, a dose-dependent inhibition of ZnCl 2 -induced C9 polymerization in vitro was observed. E. coli DH5α survived incubation with human serum pre-treated with Pet. Therefore, Pet can potentially interfere with the alternative and the terminal pathways of the complement system. In addition, by cleaving C9, Pet may inhibit membrane attack complex (MAC) formation on the bacterial outer membrane. Thus, our data are suggestive of a role of Pet in resistance of E. coli to human serum., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Correa, Freire, Dibo, Huerta-Cantillo, Navarro-Garcia, Barbosa, Elias and Moraes.)

The spleen is an important mediator of both adaptive and innate immunity. As such, attempts to modulate the immune response provided by the spleen may be conducive to improved outcomes for numerous diseases throughout the body. Here, biomimicry is used to rationally design nanomaterials capable of splenic retention and immunomodulation for the treatment of disease in a distant organ, the postinfarct heart. Engineered senescent erythrocyte-derived nanotheranostic (eSENTs) are generated, demonstrating significant uptake by the immune cells of the spleen including T and B cells, as well as monocytes and macrophages. When loaded with suberoylanilide hydroxamic acid (SAHA), the nanoagents exhibit a potent therapeutic effect, reducing infarct size by 14% at 72 h postmyocardial infarction when given as a single intravenous dose 2 h after injury. These results are supportive of the hypothesis that RBC-derived biomimicry may provide new approaches for the targeted modulation of the pathological processes involved in myocardial infarction, thus further experiments to decisively confirm the mechanisms of action are currently underway. This novel concept may have far-reaching applicability for the treatment of a number of both acute and chronic conditions where the immune responses are either stimulated or suppressed by the splenic (auto)immune milieu., (© 2023 Wiley-VCH GmbH.)

Objective: This study analyzes whether parental strictness, which is shared by authoritative parenting (strictness and warmth) and authoritarian parenting (strictness without warmth) styles, always acts as a main protective factor against drug use and psychosocial maladjustment in children. This conclusion has already been stated in numerous classic studies, though emergent research suggests that there are benefits to parental warmth regardless of whether strictness is present or not. Method: Sample were 2,095 Spanish participants (1,227 females, 58.6%), 581 adolescent children (aged 12-18 years, 27.7%) and 1,514 adult children (72.3%). The measures were the main parenting style dimensions (warmth and strictness), drug use, and a set of indicators of psychosocial adjustment. A 4 × 2 × 4 MANOVA was applied for all outcomes with parenting style, sex, and age as independent variables. Results: Indulgent parenting (warmth without strictness) was related to less drug use than parenting without warmth (authoritarian and neglectful). Additionally, indulgent and authoritative parenting styles were related to better scores on psychosocial adjustment than authoritarian and neglectful styles, although the indulgent parenting was the only style related to the optimal scores being equal or even more effective than the authoritative style. Conclusion: Contrary to classical studies, present findings suggest that it is the parental warmth instead of the parental strictness that seems to be effective in protecting against drug use and psychosocial maladjustment., Competing Interests: Conflict of Interest: The authors of this article declare no conflict of interest., (Copyright © 2024, Colegio Oficial de la Psicología de Madrid.)

Building fair, equitable, and beneficial partnerships between institutions collaborating in research in low- and middle-income countries (LMIC) and high-income countries (HIC) has become an integral part of research capacity building in global health in recent years. In this paper, we offer an example of an academic collaboration between the University of California Los Angeles, Center for Health Policy and Research (UCLA CHPR) and the University of Philippines, Manila, College of Public Health (UPM CPH) that sought to build an equitable partnership between research institutions. The partnership was built on a project to build capacity for research and produce data for policy action for the prevention and care of non-communicable diseases (NCDs) through primary healthcare in the Philippines. The specific objectives of the project were to: (1) locally adapt the Primary Care Assessment Tool for the Philippines and use the adapted tool to measure facility-level primary care delivery, (2) conduct focus group discussions (FGDs) to gather qualitative observations regarding primary care readiness and capacity, and (3) conduct a comprehensive population-based health survey among adults on NCDs and prior healthcare experience. We describe here the progression of the partnership between these institutions to carry out the project and the elements that helped build a stronger connection between the institutions, such as mutual goal setting, cultural bridging, collaborative teams, and capacity building. This example, which can be used as a model depicting new directionality and opportunities for LMIC-HIC academic partnerships, was written based on the review of shared project documents, including study protocols, and written and oral communications with the project team members, including the primary investigators. The innovation of this partnership includes: LMIC-initiated project need identification, LMIC-based funding allocation, a capacity-building role of the HIC institution, and the expansion of scope through jointly offered courses on global health.

The photoluminescence properties (PL) of Eu 3+ hosted in the hydroxide layers of layered double hydroxides (LDHs) enables calibrationless quantification of anions in the interlayers. The concept is demonstrated during the nitrate-to-carbonate ion exchange in Zn 2+ /Al 3+ /Eu 3+ LDHs and can be implemented as a remote optical sensor to detect intrusion of anions such as Cl - or CO 3 2- .

The peptide toxin candidalysin, secreted by Candida albicans hyphae, promotes stimulation of neutrophil extracellular traps (NETs). However, candidalysin alone triggers a distinct mechanism for NET-like structures (NLS), which are more compact and less fibrous than canonical NETs. Candidalysin activates NADPH oxidase and calcium influx, with both processes contributing to morphological changes in neutrophils resulting in NLS formation. NLS are induced by leucotoxic hypercitrullination, which is governed by calcium-induced protein arginine deaminase 4 activation and initiation of intracellular signalling events in a dose- and time-dependent manner. However, activation of signalling by candidalysin does not suffice to trigger downstream events essential for NET formation, as demonstrated by lack of lamin A/C phosphorylation, an event required for activation of cyclin-dependent kinases that are crucial for NET release. Candidalysin-triggered NLS demonstrate anti-Candida activity, which is resistant to nuclease treatment and dependent on the deprivation of Zn 2+ . This study reveals that C. albicans hyphae releasing candidalysin concurrently trigger canonical NETs and NLS, which together form a fibrous sticky network that entangles C. albicans hyphae and efficiently inhibits their growth., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Introduction: Obesity is a known risk factor for urinary incontinence (UI). As bariatric surgery can result in significant and sustainable weight loss, many chronic diseases closely linked to obesity have likewise shown improvement after surgical weight loss. We propose that bariatric surgery may significantly improve obesity-related UI symptoms as well as improve quality of life., Methods and Procedures: This is an interim analysis of an ongoing, prospective, single-institution observational study looking at UI in women enrolled in a bariatric surgery program. Participants completed the Pelvic Floor Distress Inventory (PFDI-20), International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI-SF), King's Health Questionnaire (KHQ), and Patient Global Impression of Improvement (PGI-I). Questionnaires were administered upon enrollment, pre-operatively, and at 3, 6, and 12 months post-operatively. Demographic data were collected at each interval and analyzed with descriptive statistics., Results: At analysis, 108 patients had enrolled in the study and 60% had progressed to surgery. We analyzed the following surveys: enrollment (n = 108), pre-operative (n = 43), 3-month (n = 29), 6-month (n = 26), and 1-year (n = 27). Mean BMI decreased from 49.8 to 31.1 at 1-year. All surveys showed significant improvement in UI symptoms over time. Overall, UI symptoms (PDFI-20) are correlated with BMI at time of survey and %TBWL (p = 0.03, p = 0.019). Additionally, perception of symptom improvement with surgery (PGI-I) improved over time (3-month p = 0.0289, 6-month p = 0.0024, 12-month p = 0.0035). Quality of life related to UI symptoms (KHQ) significantly improved after surgery (p = 0.0047 3-month, p = 0.0042 6-month, p = 0.0165 1-year)., Conclusions: Although the relationship is complex and likely depends on many factors, weight loss after bariatric surgery is associated with improvement in UI symptoms and UI-related quality of life. Bariatric surgery can play a role in the long-term treatment of UI in women with obesity that may negate the need for further invasive UI procedures., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Secondary hyperparathyroidism (SHPT) after bariatric surgery has significant adverse implications for bone metabolism, increasing the risk for osteoporosis and fracture. Our aim was to characterize prevalence and identify risk factors for SHPT in bariatric surgery patients., Methods: We performed a single-institution, retrospective chart review of patients who underwent bariatric surgery from June 2017 through December 2021. Demographic and clinical data were collected, including serum parathyroid hormone, calcium, and vitamin D3 at enrollment and 3, 6, and 12-months postoperatively. Chi-square or Fisher's exact tests were used to analyze categorical data and Mann-Whitney U test for continuous data. Multivariable analysis using binomial logistic regression assessed risk factors for SHPT. P-values ≤ 0.05 were considered significant., Results: 350 patients were analyzed. SHPT prevalence at any time point was 72.9%. 65.8% had SHPT at enrollment; 45.9% resolved with intensive vitamin supplementation; and 19.7% had recurrent SHPT. New-onset SHPT occurred in 8.6%. Persistent SHPT was present in 42.4% at 1-year. Baseline SHPT correlated with black race and T2DM. SHPT at any time point correlated with T2DM and higher baseline BMI. 1-year SHPT correlated with RYGB, depression, and longer time in program. SHPT was not correlated with %TBWL at any time point. In patients with SHPT, vitamin D3 deficiency prevalence was significantly higher at baseline (77.0%) compared to all post-bariatric time points (16.7%, 17.3%, and 23.1%; P < 0.0001)., Conclusions: SHPT is highly prevalent in patients with obesity seeking weight loss surgery. 42% had persistent SHPT at 1-year despite appropriate vitamin supplementation. Current vitamin D3 and calcium supplementation protocols may not effectively prevent SHPT in many post-bariatric patients. Low prevalence of concomitant vitamin D3 deficiency with SHPT after bariatric surgery suggests that there may be alternative mechanisms in this population. Further studies are needed to develop effective treatment strategies to mitigate the adverse effects of bariatric surgery on bone metabolism., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We report a rationally designed membrane-intercalating conjugated oligoelectrolyte (COE), namely COE-IC, which endows aerobic N 2 -fixing bacteria Azotobacter vinelandii with a light-harvesting ability that enables photosynthetic ammonia production. COE-IC possesses an acceptor-donor-acceptor (A-D-A) type conjugated core, which promotes visible light absorption with a high molar extinction coefficient. Furthermore, COE-IC spontaneously associates with A. vinelandii to form a biohybrid in which the COE is intercalated within the lipid bilayer membrane. In the presence of L-ascorbate as a sacrificial electron donor, the resulting COE-IC/A. vinelandii biohybrid showed a 2.4-fold increase in light-driven ammonia production, as compared to the control. Photoinduced enhancement of bacterial biomass and production of L-amino acids is also observed. Introduction of isotopically enriched 15 N 2 atmosphere led to the enrichment of 15 N-containing intracellular metabolites, consistent with the products being generated from atmospheric N 2 ., (© 2023 Wiley-VCH GmbH.)

We used proximity loggers to map the social network of 15 group-housed suckling Holstein calves over a 70-day period divided into five trial periods. Tag ID, encountered tag ID, and encounter start time and length were collected from the proximity loggers. Use of 3D matrices and trendlines distinguished three encounter types: "rapid decline" (up to ~ 120 s), "moderate decline" (~120 to ~ 600 s), and "exponential decline" (longer than ~ 600 s). We hypothesized that a random encounter between two calves with an agonistic relationship would terminate quickly, whereas affiliative encounters would linger. Quadratic assignment with 5000 random permutations revealed a significant negative correlation between short encounters ("agonistic") and long encounters ("affiliative") matrices in periods 1 and 5 ( r  = -0.490 and -0.767, respectively), tendency toward negative correlation in period 3 ( r  = -0.141, p  = 0.104), and no significant correlations in periods 2 and 4. These results were in accordance with the social network analyses revealing agonistic (short encounters) relationships in those periods. We suggest using this method in further studies on the effects of various factors on social network dynamics and its effect on health, intake, growth, and efficiency.

Our current understanding of biomolecular condensate formation is largely based on observing the final near-equilibrium condensate state. Despite expectations from classical nucleation theory, pre-critical protein clusters were recently shown to form under subsaturation conditions in vitro; if similar long-lived clusters comprising more than a few molecules are also present in cells, our understanding of the physical basis of biological phase separation may fundamentally change. Here, we combine fluorescence microscopy with photobleaching analysis to quantify the formation of clusters of NELF proteins in living, stressed cells. We categorise small and large clusters based on their dynamics and their response to p38 kinase inhibition. We find a broad distribution of pre-condensate cluster sizes and show that NELF protein cluster formation can be explained as non-classical nucleation with a surprisingly flat free-energy landscape for a wide range of sizes and an inhibition of condensation in unstressed cells., (© 2023. Springer Nature Limited.)

Interfacing bacteria as biocatalysts with an electrode provides the basis for emerging bioelectrochemical systems that enable sustainable energy interconversion between electrical and chemical energy. Electron transfer rates at the abiotic-biotic interface are, however, often limited by poor electrical contacts and the intrinsically insulating cell membranes. Herein, we report the first example of an n-type redox-active conjugated oligoelectrolyte, namely COE-NDI, which spontaneously intercalates into cell membranes and mimics the function of endogenous transmembrane electron transport proteins. The incorporation of COE-NDI into Shewanella oneidensis MR-1 cells amplifies current uptake from the electrode by 4-fold, resulting in the enhanced bio-electroreduction of fumarate to succinate. Moreover, COE-NDI can serve as a "protein prosthetic" to rescue current uptake in non-electrogenic knockout mutants., (© 2023 Wiley-VCH GmbH.)

Serine protease autotransporters of Enterobacteriaceae (SPATE) constitute a superfamily of virulence factors, resembling the trypsin-like superfamily of serine proteases. SPATEs accomplish multiple functions associated to disease development of their hosts, which could be the consequence of SPATE cleavage of host cell components. SPATEs have been divided into class-1 and class-2 based on structural differences and biological effects, including similar substrate specificity, cytotoxic effects on cultured cells, and enterotoxin activity on intestinal tissues for class-1 SPATEs, whereas most class-2 SPATEs exhibit a lectin-like activity with a predilection to degrade a variety of mucins, including leukocyte surface O-glycoproteins and soluble host proteins, resulting in mucosal colonization and immune modulation. In this review, the structure of class-1 and class-2 are analyzed, making emphasis on their putative functional subdomains as well as a description of their function is provided, including prototypical mechanism of action., (© 2023 The Author. Molecular Microbiology published by John Wiley & Sons Ltd.)

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity., Competing Interests: Declaration of interests K.H.V. is on the board of directors and shareholder of Bristol Myers Squibb, a shareholder of GRAIL, and on the science advisory board of PMV Pharma, RAZE Therapeutics, Volastra Pharmaceuticals, and Ludwig Cancer. She is a co-founder and consultant of Faeth Therapeutics, funded by Khosla Ventures. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca and contributed to CRUK Cancer Research Technology filing of patent application WO/2017/144877., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this work, process models were developed to capture the impact of biomanufacturing costs on a commercial scale and emphasize the way in which facility design and operation must balance meeting product demand while minimizing production costs. Using a scenario-based modeling approach, several facility design strategies were evaluated, including a traditional large stainless-steel facility and a small footprint, portable-on-demand (POD)-based facility. Bioprocessing platforms were compared by estimating their total production costs across different facility types and specifically illustrating how continuous bioprocessing has gained in popularity as a novel and cost-effective approach to manufacture high-quality biopharmaceuticals. The analysis showed how fluctuations in market demand have a dramatic effect on manufacturing costs and plant utilization, with far-reaching implications on the total cost to patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘During the writing of this article, the authors were employees of Just-Evotec Biologics, Inc.’., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The present study is focused on the determination of low-volatile chemosignals excreted or secreted by mouse pups in their early days of life involved in maternal care induction in mice adult females. Untargeted metabolomics was employed to differentiate between samples collected with swabs from facial and anogenital area from neonatal mouse pups receiving maternal care (first two weeks of life) and the elder mouse pups in the weaning period (4th week old). The sample extracts were analysed by ultra-high pressure liquid chromatography (UHPLC) coupled to ion mobility separation (IMS) in combination with high resolution mass spectrometry (HRMS). After data processing with Progenesis QI and multivariate statistical analysis, five markers present in the first two weeks of mouse pups life and putatively involved in materno-filial chemical communication were tentatively identified: arginine, urocanic acid, erythro-sphingosine (d17:1), sphingosine (d18:1) and sphinganine. The four-dimensional data and the tools associated to the additional structural descriptor obtained by IMS separation were of great help in the compound identification. The results demonstrated the great potential of UHPLC-IMS-HRMS based untargeted metabolomics to identity putative pheromones in mammals., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Dengue remains a major public health problem in the Philippines, particularly in urban areas of the National Capital Region. Thematic mapping using geographic information systems complemented by spatial analysis such as cluster analysis and hot spot detection can provide useful information to guide preventive measures and control strategies against dengue. Hence, this study was aimed to describe the spatiotemporal distribution of dengue incidence and identify dengue hot spots by barangay using reported cases from Quezon City, the Philippines from 2010 to 2017., Methods: Reported dengue case data at barangay level from January 1, 2010 to December 31, 2017 were obtained from the Quezon City Epidemiology and Surveillance Unit. The annual incidence rate of dengue from 2010 to 2017, expressed as the total number of dengue cases per 10,000 population in each year, was calculated for each barangay. Thematic mapping, global cluster analysis, and hot spot analysis were performed using ArcGIS 10.3.1., Results: The number of reported dengue cases and their spatial distribution varied highly between years. Local clusters were evident during the study period. Eighteen barangays were identified as hot spots., Conclusions: Considering the spatial heterogeneity and instability of hot spots in Quezon City across years, efforts towards the containment of dengue can be made more targeted, and efficient with the application of hot spot analysis in routine surveillance. This may be useful not only for the control of dengue but also for other diseases, and for public health planning, monitoring, and evaluation., (© 2023. The Author(s).)

The growing need of next generation feedstocks for biotechnology spurs an intensification of research on the utilization of methanol as carbon and energy source for biotechnological processes. In this paper, we introduced the methanol-based overproduction of riboflavin into metabolically engineered Bacillus methanolicus MGA3. First, we showed that B. methanolicus naturally produces small amounts of riboflavin. Then, we created B. methanolicus strains overexpressing either homologous or heterologous gene clusters encoding the riboflavin biosynthesis pathway, resulting in riboflavin overproduction. Our results revealed that the supplementation of growth media with sublethal levels of chloramphenicol contributes to a higher plasmid-based riboflavin production titre, presumably due to an increase in plasmid copy number and thus biosynthetic gene dosage. Based on this, we proved that riboflavin production can be increased by exchanging a low copy number plasmid with a high copy number plasmid leading to a final riboflavin titre of about 523 mg L -1 in methanol fed-batch fermentation. The findings of this study showcase the potential of B. methanolicus as a promising host for methanol-based overproduction of extracellular riboflavin and serve as basis for metabolic engineering of next generations of riboflavin overproducing strains., (© 2023 The Authors. Microbial Biotechnology published by Applied Microbiology International and John Wiley & Sons Ltd.)

Purpose: Classic studies mainly of European-American families broadly identify the benefits of parental strictness combined with parental warmth. However, current research tends to identify parental warmth as positive for adjustment, even without parental strictness. In addition, less is known about the relationship between parenting and adjustment beyond adolescence. The present study examined warmth and strictness and its relationship with self, sexism, and stimulation values. Self-esteem, academic-professional self-concept, benevolent sexism, and stimulation values were used to capture adjustment., Patients and Methods: Participants (n = 1125) were adolescents and adult children of middle-age from Spain. The statistical analyses used were correlation analysis and multiple linear regression., Results: In general, the relationship between parenting and adjustment was found to have a similar pattern for adolescent and middle-aged adult children, although more marked in adolescents. Parental warmth and strictness were predictors of adjustment, but in a different direction. Specifically, parental warmth positively predicted academic-professional self-concept and self-esteem, whereas parental strictness was detrimental as a predictor of higher benevolent sexism., Conclusion: Overall, the present findings suggest that an effective socialization during the socialization years and even beyond can be positively predicted by parental warmth, whereas parental strictness might be unnecessary or even detrimental., Competing Interests: Dr Oscar F Garcia reports grants from Generalitat Valenciana and grants from European Social Fund, during the conduct of the study. Marta Alcaide reports grants from Ministry of Universities, Government of Spain, during the conduct of the study. Professor Fernando Garcia reports grants from Conselleria for Innovation, Universities, Science and Digital Society, Generalitat Valenciana, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2023 Martinez-Escudero et al.)

Introduction: Previous parenting studies with European-American families have identified optimal parenting as being based on warmth combined with strictness (i.e., authoritative parenting). The present study analyzes, in adolescents and adults, their adjustment and maladjustment related to age and their early experiences in the family., Methods: The sample consisted of 2,158 Spanish people (58.29% women): 624 adolescents, 630 young adults, 504 middle-aged adults, and 400 older adults. The families were classified into one of the four parental typologies (authoritative, indulgent, authoritarian, and neglectful) based on their scores in the two main dimensions (warmth and strictness). Child functioning was measured as components of adjustment (self-esteem, emotional self-concept, and empathy) and maladjustment (aggression and hostile sexism)., Results: Overall, only adolescents and adult children raised in indulgent families reported the highest self-esteem, emotional self-concept, and empathy, and the lowest aggression and hostile sexism. Authoritative parenting (warmth with strictness) was related to a lower emotional self-concept and greater aggression and hostile sexism than indulgent parenting (warmth without strictness). The worst scores corresponded to authoritarian and neglectful parenting., Discussion: The present findings provide new evidence about early experiences in the family, even after parental socialization has ended. Interestingly, contrary to the main findings from classic studies with European-American families, only high parental warmth combined with low parental strictness (i.e., indulgent parenting) is always positive for greater adjustment and less maladjustment in all age groups., 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 Alcaide, Garcia, Queiroz and Garcia.)

Right ventricular (RV) dysfunction is a major cause of morbidity and mortality in intensive care and cardiac surgery. Early detection of RV dysfunction may be facilitated by continuous monitoring of RV waveform obtained from a pulmonary artery catheter. The objective is to evaluate the extent to which RV pressure monitoring can detect changes in RV systolic performance assess by RV end-systolic elastance (E es ) following the development of an acute RV ischemic in a porcine model., Hypothesis: RV pressure monitoring can detect changes in RV systolic performance assess by RV E es following the development of an acute RV ischemic model., Methods and Models: Acute ischemic RV dysfunction was induced by progressive embolization of microsphere in the right coronary artery to mimic RV dysfunction clinically experienced during cardiopulmonary bypass separation caused by air microemboli. RV hemodynamic performance was assessed using RV pressure waveform-derived parameters and RV E es obtained using a conductance catheter during inferior vena cava occlusions., Results: Acute ischemia resulted in a significant reduction in RV E es from 0.26 mm Hg/mL (interquartile range, 0.16-0.32 mm Hg/mL) to 0.14 mm Hg/mL (0.11-0.19 mm Hg/mL; p < 0.010), cardiac output from 6.3 L/min (5.7-7 L/min) to 4.5 (3.9-5.2 L/min; p = 0.007), mean systemic arterial pressure from 72 mm Hg (66-74 mm Hg) to 51 mm Hg (46-56 mm Hg; p < 0.001), and mixed venous oxygen saturation from 65% (57-72%) to 41% (35-45%; p < 0.001). Linear mixed-effect model analysis was used to assess the relationship between E es and RV pressure-derived parameters. The reduction in RV E es best correlated with a reduction in RV maximum first derivative of pressure during isovolumetric contraction (dP/dt max ) and single-beat RV E es . Adjusting RV dP/dt max for heart rate resulted in an improved surrogate of RV E es ., Interpretation and Conclusions: Stepwise decreases in RV E es during acute ischemic RV dysfunction were accurately tracked by RV dP/dt max derived from the RV pressure waveform., Competing Interests: Mr. Moses, Dr. Potes, Mr. Garcia, and Dr. Paster work for Edwards Lifesciences—a manufacturer of healthcare devices and critical care solutions. Dr. Denault is on the speaker’s bureau for CAE Healthcare (2012), Masimo (2017) and received an equipment grant from Edwards (2019). He is a consultant for Masimo (2020) and CAE Healthcare (2020). Dr. Monge García is a consultant for Edwards Lifesciences and Dextera Medical. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: Recent research is fully questioning whether the combination of parenting warmth and strictness (the authoritative style) is always identified as positive parenting across the globe. This study analyzes parenting styles and the positive health of adolescents and adult children., Methods: The sample was 2,090 Spanish children (59.9% women), from four age groups: 600 adolescents, 591 young adults, 507 middle-aged adults, and 392 older adults. Parenting styles (indulgent, authoritative, authoritarian, and neglectful) were obtained by warmth and strictness measures. Children's positive health was measured by self (family self-concept, self-esteem, and negative self-efficacy), universalism values, and emotional vulnerability., Results: The main results showed that the indulgent parenting style was associated with equal and even better scores than the authoritative style, whereas the authoritarian and neglectful styles were consistently associated with low scores in positive health indicators for all age groups. However, two triple interactions of sex by age group by parenting style showed that women children from neglectful families reported the lowest family self-concept in old age and the highest emotional vulnerability in middle age., Discussion: The study findings question the universal benefits of the so-called positive parenting (the authoritative style) for positive health., 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 © 2022 Palacios, Garcia, Alcaide and Garcia.)

Neutrophils are vital in defence against pathogens, but excessive neutrophil activity can lead to tissue damage and promote acute respiratory distress syndrome. COVID-19 is associated with systemic expansion of immature neutrophils, but the functional consequences of this shift to immaturity are not understood. We used flow cytometry to investigate activity and phenotypic diversity of circulating neutrophils in acute and convalescent COVID-19 patients. First, we demonstrate hyperactivation of immature CD10 - subpopulations in severe disease, with elevated markers of secondary granule release. Partially activated immature neutrophils were detectable 12 wk post-hospitalisation, indicating long term myeloid dysregulation in convalescent COVID-19 patients. Second, we demonstrate that neutrophils from moderately ill patients down-regulate the chemokine receptor CXCR2, whereas neutrophils from severely ill individuals fail to do so, suggesting an altered ability for organ trafficking and a potential mechanism for induction of disease tolerance. CD10 - and CXCR2 hi neutrophil subpopulations were enriched in severe disease and may represent prognostic biomarkers for the identification of individuals at high risk of progressing to severe COVID-19., (© 2022 Rice et al.)

Introduction: Classical research mainly conducted with European-American families has identified the combination of warmth and strictness (authoritative style) as the parenting always associated with the highest scores on developmental outcomes. Additionally, despite the benefits of empathy for prosocial behaviors and protection against antisocial behaviors, most research has considered the contribution of specific practices (e.g., reasoning or power assertion), but not so much the parenting styles. Similarly, family studies tend to study the relationship between parenting and global self-perceptions (self-esteem), but not so much those of each dimension (self-concept)., Methods: In the present study, 600 Spanish adolescents from 12 to 17 years old ( M  = 15.25, SD  = 2.01) were classified within one of the four household typologies (i.e., authoritative, indulgent, authoritarian, or neglectful). Adolescent developmental outcomes were cognitive empathy (adopting perspectives and emotional understanding), emotional empathy (empathic stress and empathic happiness), and self-concept (academic, social, emotional, family and physical)., Results: The results showed that the indulgent parenting (warmth but not strictness) was related to equal or even better empathy and self-concept than the authoritative style (warmth and strictness), whereas non-warm parenting (authoritarian and neglectful) was consistently associated with poor results., Discussion: Overall, the present findings seriously question that parental strictness combined with parental warmth (authoritative style) is always the parenting style related to the greatest outcomes. By contrast, it seems that reasoning, warmth and involvement, without strictness (indulgent parenting) help adolescents to achieve a good orientation toward others in terms of cognitive and affective empathy and a good self-evaluation in terms of self-concept., 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 © 2022 Fuentes, Garcia, Alcaide, Garcia-Ros and Garcia.)

Although parental socialization has an influence on child development, current research is questioning which combination of parental strictness and warmth acts as protective or risk factors, especially during adolescence when the child is more vulnerable. The sample was 2125 participants, 58.7% female, divided into four age groups: adolescents (28.57%), young adults (28.38%), middle-aged adults (23.95%), and older adults (19.11%). The families were classified into four parenting styles: neglectful, indulgent, authoritative, and authoritarian according to their warmth and strictness scores. The psychosocial adjustment was measured by children's scores on academic/professional self-concept, self-esteem, delinquency during adolescence, and benevolence values. A MANOVA 4 × 2 × 4 was applied with parenting styles, sex, and age group as independent variables. The results showed that, for adolescents and adult children, only parenting styles characterized by warmth (i.e., indulgent, and authoritative) were found to factor against delinquency during adolescence and benefit greater academic/professional self-concept, self-esteem, and benevolence values, while parenting without warmth (i.e., authoritarian, and neglectful) were identified as risk factors. Contrary to classical research, the present findings seriously question the universal benefits of strict parenting as the only optimal strategy to protect not only against delinquency, but also to foster an adequate self and the internalization of social values.

The COVID-19 pandemic will not be the last of its kind. As the world charts a way towards an equitable and resilient recovery, Public Health and Social Measures (PHSMs) that were implemented since the beginning of the pandemic need to be made a permanent feature of health systems that can be activated and readily deployed to tackle sudden surges in infections going forward. Although PHSMs aim to blunt the spread of the virus, and in turn protect lives and preserve health system capacity, there are also unintended consequences attributed to them. Importantly, the interactions between PHSMs and their accompanying key indicators that influence the strength and duration of PHSMs are elements that require in-depth exploration. This research employs case studies from six Asian countries, namely Indonesia, Singapore, South Korea, Thailand, the Philippines and Vietnam, to paint a comprehensive picture of PHSMs that protect the lives and livelihoods of populations. Nine typologies of PHSMs that emerged are as follows: (1) physical distancing, (2) border controls, (3) personal protective equipment requirements, (4) transmission monitoring, (5) surge health infrastructure capacity, (6) surge medical supplies, (7) surge human resources, (8) vaccine availability and roll-out and (9) social and economic support measures. The key indicators that influence the strength and duration of PHSMs are as follows: (1) size of community transmission, (2) number of severe cases and mortality, (3) health system capacity, (4) vaccine coverage, (5) fiscal space and (6) technology. Interactions between PHSMs can be synergistic or inhibiting, depending on various contextual factors. Fundamentally, PHSMs do not operate in silos, and a suite of PHSMs that are complementary is required to ensure that lives and livelihoods are safeguarded with an equity lens. For that to be achieved, strong governance structures and community engagement are also required at all levels of the health system., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pasteurellaceae family members obtain iron directly from host proteins or through siderophore-dependent mechanisms. Although Gallibacterum anatis expresses different virulence factors, its response to growth under iron restriction is unknown. G. anatis cultured in the presence of 2,2'-dipyridyl, up-expressed an approximately 65 kDa protein and repressed the expression of a 70 kDa protein. MALDI-TOF analysis of those proteins indicated homology with CirA (65 kDa), a protein involved in iron-siderophore acquisition in Mannheimia succinoproducens and a TonB-dependent receptor (70 kDa protein), a protein that binds chicken hemoglobin; however, G. anatis siderophore production was not detected by chromo azurol S (CAS)-BHI agar determination. This putative G. anatis siderophore receptor is under Fur control, but not the hemoglobin binding protein, as observed in G. anatis 12656-12 fur mutant (Ω fur 126.13) grown in the presence or not of 2,2'-dipyridyl. The addition of FeCl 3 to the culture medium diminished the growth and biofilm production in approximately 30% and 35%, respectively, in the wild-type strain, but the growth of Ω fur 126.13 strain was not affected and biofilm production increased in 35%. G. anatis Ω fur 126.13 presented lower virulence when it was inoculated to 35-day-old chickens in comparison to the wild-type strain. The induction of more than one iron uptake mechanism could benefit pathogenic microorganisms such as Gallibacterium ., 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 © 2022 Chantes-Guerra, Maldonado-Puga, Rojas-Ruiz, Rea-Hernandez, Montes-Garcia, Trujillo-Ruiz, Yañez-Aguilar, Vazquez-Cruz, Sanchez-Alonso and Negrete-Abascal.)

The precise regulation of RNA Polymerase II (Pol II) transcription after genotoxic stress is crucial for proper execution of the DNA damage-induced stress response. While stalling of Pol II on transcription-blocking lesions (TBLs) blocks transcript elongation and initiates DNA repair in cis, TBLs additionally elicit a response in trans that regulates transcription genome-wide. Here we uncover that, after an initial elongation block in cis, TBLs trigger the genome-wide VCP-mediated proteasomal degradation of promoter-bound, P-Ser5-modified Pol II in trans. This degradation is mechanistically distinct from processing of TBL-stalled Pol II, is signaled via GSK3, and contributes to the TBL-induced transcription block, even in transcription-coupled repair-deficient cells. Thus, our data reveal the targeted degradation of promoter-bound Pol II as a critical pathway that allows cells to cope with DNA damage-induced transcription stress and enables the genome-wide adaptation of transcription to genotoxic stress., (© 2022. The Author(s).)