The short-term impact of Schistosoma mansoni infection on health-related quality of life: implications for current elimination policies.

The WHO aims to eliminate schistosomiasis as a public health problem by 2030. However, standard morbidity measures poorly correlate to infection intensities, hindering disease monitoring and evaluation. This is exacerbated by insufficient evidence on Schistosoma's impact on health-related quality of life (HRQoL). We conducted community-based cross-sectional surveys and parasitological examinations in moderate-to-high Schistosoma mansoni endemic communities in Uganda. We calculated parasitic infections and used EQ-5D instruments to estimate and compare HRQoL utilities in these populations. We further employed Tobit/linear regression models to predict HRQoL determinants. Two-thirds of the 560 participants were diagnosed with parasitic infection(s), 49% having S. mansoni. No significant negative association was observed between HRQoL and S. mansoni infection status/intensity. However, severity of pain urinating (ß = -0.106; s.e. = 0.043) and body swelling (ß = -0.326; s.e. = 0.005), increasing age (ß = -0.016; s.e. = 0.033), reduced socio-economic status (ß = 0.128; s.e. = 0.032), and being unemployed predicted lower HRQoL. Symptom severity and socio-economic status were better predictors of short-term HRQoL than current S. mansoni infection status/intensity. This is key to disentangling the link between infection(s) and short-term health outcomes, and highlights the complexity of correlating current infection(s) with long-term morbidity. Further evidence is needed on long-term schistosomiasis-associated HRQoL, health and economic outcomes to inform the case for upfront investments in schistosomiasis interventions.

The Madrid Posterior Component Separation: An Anatomical Approach for Effective Reconstruction of Complex Midline Hernias.

Introduction: In recent years, Posterior Component Separation (PCS) with the Madrid modification (Madrid PCS) has emerged as a surgical technique. This modification is believed to enhance the dissection of anatomical structures, offering several advantages. The study aims to present a detailed description of this surgical technique and to analyse the outcomes in a large cohort of patients. Materials and Methods: This study included all patients who underwent the repair of midline incisional hernias, with or without other abdominal wall defects. Data from patients at three different centres specialising in abdominal wall reconstruction was analysed. All patients underwent the Madrid PCS, and several variables, such as demographics, perioperative details, postoperative complications, and recurrences, were assessed. Results: Between January 2015 and June 2023, a total of 223 patients underwent the Madrid PCS. The mean age was 63.4 years, with a mean BMI of 33.3 kg/m2 (range 23-40). According to the EHS classification, 139 patients had a midline incisional hernia, and 84 had a midline incisional hernia with a concomitant lateral incisional hernia. According to the Ventral Hernia Working Group (VHWG) classification, 177 (79.4%) patients had grade 2 and 3 hernias. In total, 201 patients (90.1%) were ASA II and III. The Carolinas Equation for Determining Associated Risks (CeDAR) was calculated preoperatively, resulting in 150 (67.3%) patients with a score between 30% and 60%. A total of 105 patients (48.4%) had previously undergone abdominal wall repair surgery. There were 93 (41.7%) surgical site occurrences (SSO), 36 (16.1%) surgical site infections (SSI), including 23 (10.3%) superficial and 7 (3.1%) deep infections, and 6 (2.7%) organ/space infections. Four (1.9%) recurrences were assessed by CT scan with an average follow-up of 23.9 months (range 6-74). Conclusion: The Madrid PCS appears to be safe and effective, yielding excellent long-term results despite the complexity of abdominal wall defects. A profound understanding of the anatomy is crucial for optimal outcomes. The Madrid modification contributes to facilitating a complete retromuscular preperitoneal repair without incision of the transversus abdominis. The extensive abdominal wall retromuscular dissection obtained enables the placement of very large meshes with minimal fixation.

Dairy goat performance in two grazing regimes: silvopastoral rangeland or abandoned agricultural land, and two supplementation treatments in central Mexico.

Twenty Saanen third parturition dairy goats were used in an on-farm 2 × 2 factorial arrangement that ran for 12 weeks, with two grazing regimes and two concentrate types. The grazing regimes evaluated were an extensive silvopastoral native rangeland (SPR) and grazing in an abandoned agricultural land (AAL). Grazing happened between 9:00 and 17:00 h. The two types of concentrate supplement were a high protein concentrate (HP = 180 g CP/kg DM and 13 MJ ME/kg DM) or high energy concentrate (HE = 110  g CP/kg DM and 14.3 MJ ME/kg DM). Goats were milked once a day, providing 250 g of concentrate supplement per goat and day. Animal variables were fat and protein corrected milk yield recorded every day, and milk composition determined for two consecutive days at the end of each experimental week. Flora in the experimental paddocks was characerised and sampled, including grasses, shrubs, trees, legumes and cacti. The data was analysed with the R software using a mixed model with day nested in period as random effect and goat as repeated measure. The SPR had greater (P = 0.002) fat and protein corrected milk yield than AAL, with no differences between concentrate type and no interaction (P > 0.05). There was an interaction (P < 0.01) between grazing regime and concentrate type for fat content in milk, where a reduction in fat content was notorious in the SPR regime. Protein content of milk was greater (P < 0.01) in SPR with no significant effects of concentrate type or the interaction. The number of plant species in SPR was greater. The native silvopastoral system supplemented with the high energy concentrate was the strategy with higher milk yield, and protein and milk fat content, although the interaction between grazing regime and supplement was significant only for milk fat content.

Subnational Projections of Lymphatic Filariasis Elimination Targets in Ethiopia to Support National Level Policy.

BACKGROUND: Lymphatic filariasis (LF) is a debilitating, poverty-promoting, neglected tropical disease (NTD) targeted for worldwide elimination as a public health problem (EPHP) by 2030. Evaluating progress towards this target for national programmes is challenging, due to differences in disease transmission and interventions at the subnational level. Mathematical models can help address these challenges by capturing spatial heterogeneities and evaluating progress towards LF elimination and how different interventions could be leveraged to achieve elimination by 2030. METHODS: Here we used a novel approach to combine historical geo-spatial disease prevalence maps of LF in Ethiopia with 3 contemporary disease transmission models to project trends in infection under different intervention scenarios at subnational level. RESULTS: Our findings show that local context, particularly the coverage of interventions, is an important determinant for the success of control and elimination programmes. Furthermore, although current strategies seem sufficient to achieve LF elimination by 2030, some areas may benefit from the implementation of alternative strategies, such as using enhanced coverage or increased frequency, to accelerate progress towards the 2030 targets. CONCLUSIONS: The combination of geospatial disease prevalence maps of LF with transmission models and intervention histories enables the projection of trends in infection at the subnational level under different control scenarios in Ethiopia. This approach, which adapts transmission models to local settings, may be useful to inform the design of optimal interventions at the subnational level in other LF endemic regions.

An Ensemble Framework for Projecting the Impact of Lymphatic Filariasis Interventions Across Sub-Saharan Africa at a Fine Spatial Scale.

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease targeted for elimination as a public health problem by 2030. Although mass treatments have led to huge reductions in LF prevalence, some countries or regions may find it difficult to achieve elimination by 2030 owing to various factors, including local differences in transmission. Subnational projections of intervention impact are a useful tool in understanding these dynamics, but correctly characterizing their uncertainty is challenging. METHODS: We developed a computationally feasible framework for providing subnational projections for LF across 44 sub-Saharan African countries using ensemble models, guided by historical control data, to allow assessment of the role of subnational heterogeneities in global goal achievement. Projected scenarios include ongoing annual treatment from 2018 to 2030, enhanced coverage, and biannual treatment. RESULTS: Our projections suggest that progress is likely to continue well. However, highly endemic locations currently deploying strategies with the lower World Health Organization recommended coverage (65%) and frequency (annual) are expected to have slow decreases in prevalence. Increasing intervention frequency or coverage can accelerate progress by up to 5 or 6 years, respectively. CONCLUSIONS: While projections based on baseline data have limitations, our methodological advancements provide assessments of potential bottlenecks for the global goals for LF arising from subnational heterogeneities. In particular, areas with high baseline prevalence may face challenges in achieving the 2030 goals, extending the "tail" of interventions. Enhancing intervention frequency and/or coverage will accelerate progress. Our approach facilitates preimplementation assessments of the impact of local interventions and is applicable to other regions and neglected tropical diseases.

Socioeconomic status, loneliness, and depression among older adults: a cross-sectional study in Spain.

BACKGROUND: The association between socioeconomic status and depression is weaker in older adults than in younger populations. Loneliness may play a significant role in this relationship, explaining (at least partially) the attenuation of the social gradient in depression. The current study examined the relationship between socioeconomic status and depression and whether the association was affected by loneliness. METHODS: A cross-sectional design involving dwelling and nursing homes residents was used. A total of 887 Spanish residents aged over 64 years took part in the study. Measures of Depression (GDS-5 Scale), Loneliness (De Jong-Gierveld Loneliness Scale), Socioeconomic Status (Education and Economic Hardship), and sociodemographic parameters were used. The study employed bivariate association tests (chi-square and Pearson's r) and logistic regression analyses. RESULTS: The percentage of participants at risk of suffering depression was significantly higher among those who had not completed primary education (45.5%) and significantly lower among those with university qualifications (16.4%) (X2 = 40.25;p <.001), and respondents who could not make ends meet in financial terms faced a higher risk of depression (X2 = 23.62;p <.001). In terms of the respondents who experienced loneliness, 57.5% were at risk of depression, compared to 19% of those who did not report loneliness (X2 = 120.04;p <.001). The logistic regression analyses showed that having university qualifications meant a 47% reduction in the risk of depression. This risk was 86% higher among respondents experiencing financial difficulties. However, when scores for the loneliness measure were incorporated, the coefficients relating to education and economic hardships ceased to be significant or were significantly reduced. CONCLUSION: Loneliness can contribute to explaining the role played by socioeconomic inequalities in depression among older adults.

Effect of Human Activity and Presence on the Behavior of Long-Tailed Macaques (Macaca fascicularis) in an Urban Tourism Site in Kuala Selangor, Malaysia.

The increasing overlap of resources between human and long-tailed macaque (Macaca fascicularis) (LTM) populations have escalated human-primate conflict. In Malaysia, LTMs are labeled as a 'pest' species due to the macaques' opportunistic nature. This study investigates the activity budget of LTMs in an urban tourism site and how human activities influence it. Observational data were collected from LTMs daily for a period of four months. The observed behaviors were compared across differing levels of human interaction, between different times of day, and between high, medium, and low human traffic zones. LTMs exhibited varying ecological behavior patterns when observed across zones of differing human traffic, e.g., higher inactivity when human presence is high. More concerning is the impact on these animals' welfare and group dynamics as the increase in interactions with humans takes place; we noted increased inactivity and reduced intra-group interaction. This study highlights the connection that LTMs make between human activity and sources of anthropogenic food. Only through understanding LTM interaction can the cause for human-primate conflict be better understood, and thus, more sustainable mitigation strategies can be generated.

Reinfection of farm dogs following praziquantel treatment in an endemic region of cystic echinococcosis in southeastern Iran.

Cystic Echinococcosis (CE) as a prevalent tapeworm infection of human and herbivorous animals worldwide, is caused by accidental ingestion of Echinococcus granulosus eggs excreted from infected dogs. CE is endemic in the Middle East and North Africa, and is considered as an important parasitic zoonosis in Iran. It is transmitted between dogs as the primary definitive host and different livestock species as the intermediate hosts. One of the most important measures for CE control is dog deworming with praziquantel. Due to the frequent reinfection of dogs, intensive deworming campaigns are critical for breaking CE transmission. Dog reinfection rate could be used as an indicator of the intensity of local CE transmission in endemic areas. However, our knowledge on the extent of reinfection in the endemic regions is poor. The purpose of the present study was to determine E. granulosus reinfection rate after praziquantel administration in a population of owned dogs in Kerman, Iran. A cohort of 150 owned dogs was recruited, with stool samples collected before praziquantel administration as a single oral dose of 5 mg/kg. The re-samplings of the owned dogs were performed at 2, 5 and 12 months following initial praziquantel administration. Stool samples were examined microscopically using Willis flotation method. Genomic DNA was extracted, and E. granulosus sensu lato-specific primers were used to PCR-amplify a 133-bp fragment of a repeat unit of the parasite genome. Survival analysis was performed using Kaplan-Meier method to calculate cumulative survival rates, which is used here to capture reinfection dynamics, and monthly incidence of infection, capturing also the spatial distribution of disease risk. Results of survival analysis showed 8, 12 and 17% total reinfection rates in 2, 5 and 12 months following initial praziquantel administration, respectively, indicating that 92, 88 and 83% of the dogs had no detectable infection in that same time periods. The monthly incidence of reinfection in total owned dog population was estimated at 1.5% (95% CI 1.0-2.1). The results showed that the prevalence of echinococcosis in owned dogs, using copro-PCR assay was 42.6%. However, using conventional microscopy, 8% of fecal samples were positive for taeniid eggs. Our results suggest that regular treatment of the dog population with praziquantel every 60 days is ideal, however the frequency of dog dosing faces major logistics and cost challenges, threatening the sustainability of control programs. Understanding the nature and extent of dog reinfection in the endemic areas is essential for successful implementation of control programs and understanding patterns of CE transmission.

First use of tissue exudate serology to identify Toxocara spp. infection in food animals.

Toxocara canis and Toxocara cati are globally distributed, zoonotic roundworm parasites. Human infection can have serious clinical consequences including blindness and brain disorders. In addition to ingesting environmental eggs, humans can become infected by eating infective larvae in raw or undercooked meat products. To date, no studies have assessed the prevalence of Toxocara spp. larvae in meat from animals consumed as food in the UK or assessed tissue exudates for the presence of anti-Toxocara antibodies. This study aimed to assess the potential risk to consumers eating meat products from animals infected with Toxocara spp. Tissue samples were obtained from 155 different food producing animals in the south, southwest and east of England, UK. Tissue samples (n = 226), either muscle or liver, were processed by artificial digestion followed by microscopic sediment evaluation for Toxocara spp. larvae, and tissue exudate samples (n = 141) were tested for the presence of anti-Toxocara antibodies using a commercial ELISA kit. A logistic regression model was used to compare anti-Toxocara antibody prevalence by host species, tissue type and source. While no larvae were found by microscopic examination after tissue digestion, the overall prevalence of anti-Toxocara antibodies in tissue exudates was 27.7%. By species, 35.3% of cattle (n = 34), 15.0% of sheep (n = 60), 54.6% of goats (n = 11) and 61.1% of pigs (n = 18) had anti-Toxocara antibodies. Logistic regression analysis found pigs were more likely to be positive for anti-Toxocara antibodies (odds ration (OR) = 2.89, P = 0.0786) compared with the other species sampled but only at a 10% significance level. The high prevalence of anti-Toxocara antibodies in tissue exudates suggests that exposure of food animals to this parasite is common in England. Tissue exudate serology on meat products within the human food chain could be applied in support of food safety and to identify practices that increase risks of foodborne transmission of zoonotic toxocariasis.

Implementation of One Health surveillance systems: Opportunities and challenges - lessons learned from the OH-EpiCap application.

As the complexity of health systems has increased over time, there is an urgent need for developing multi-sectoral and multi-disciplinary collaborations within the domain of One Health (OH). Despite the efforts to promote collaboration in health surveillance and overcome professional silos, implementing OH surveillance systems in practice remains challenging for multiple reasons. In this study, we describe the lessons learned from the evaluation of OH surveillance using OH-EpiCap (an online evaluation tool for One Health epidemiological surveillance capacities and capabilities), the challenges identified with the implementation of OH surveillance, and the main barriers that contribute to its sub-optimal functioning, as well as possible solutions to address them. We conducted eleven case studies targeting the multi-sectoral surveillance systems for antimicrobial resistance in Portugal and France, Salmonella in France, Germany, and the Netherlands, Listeria in The Netherlands, Finland and Norway, Campylobacter in Norway and Sweden, and psittacosis in Denmark. These evaluations facilitated the identification of common strengths and weaknesses, focusing on the organization and functioning of existing collaborations and their impacts on the surveillance system. Lack of operational and shared leadership, adherence to FAIR data principles, sharing of techniques, and harmonized indicators led to poor organization and sub-optimal functioning of OH surveillance systems. In the majority of studied systems, the effectiveness, operational costs, behavioral changes, and population health outcomes brought by the OH surveillance over traditional surveillance (i.e. compartmentalized into sectors) have not been evaluated. To this end, the establishment of a formal governance body with representatives from each sector could assist in overcoming long-standing barriers. Moreover, demonstrating the impacts of OH-ness of surveillance may facilitate the implementation of OH surveillance systems.

The Positive Effect of Social Support in the Relationship Between Emotion and Motivation of People in Science.

This study explores the role of social support as a mediator in the relationship between self-emotional appraisal and motivation in people in science. It also examines the moderating role of self-deceptive enhancement in the relationship between self-emotional appraisal and social support. Survey responses from 6,943 people in science in Spain were analyzed (43% women), aged 20-96 (M = 48.8; SD = 9.94). Structural equation modeling was used to examine a moderated mediation model explaining the path between self-emotional appraisal and motivation. The analysis controlled for age, gender and organization type. The results show a positive link between self-emotional appraisal and motivation. Mediation by social support strengthens this link: For self-emotional appraisal to be effective, people in science need to feel others' support when tackling a problem. Moderation by self-deceptive enhancement strengthens the association of self-emotional appraisal with social support: The need to adapt one's self-image to others' expectations activates the pursuit of social support. The implications of self-emotional appraisal and social support for improving motivation are discussed, as is the role of self-deception in social support as perceived by people in science.

Neuroimaging abnormalities associated with immunotherapy responsiveness in Down syndrome regression disorder.

OBJECTIVE: To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses. METHODS: A multicenter, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities. RESULTS: In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p < 0.001, 95%CI: 2.18-7.63). T2/FLAIR signal abnormalities were not appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p = 0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p < 0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were localized to the frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly in the bilateral basal ganglia (94%, 49/52). Individuals with DSRD and the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p < 0.001, OR: 8.42. 95%CI: 3.78-18.76) and less likely to respond to benzodiazepines (p = 0.01, OR: 0.45, 95%CI: 0.25-0.83), antipsychotics (p < 0.001, OR: 0.28, 95%CI: 0.11-0.55), or electroconvulsive therapy (p < 0.001, OR: 0.12; 95%CI: 0.02-0.78) compared to individuals without these neuroimaging abnormalities. INTERPRETATION: This study indicates that in individuals diagnosed with DSRD, T2/FLAIR, and SWI signal abnormalities are more common than previously thought and predict response to immunotherapy.

Cardiopulmonary Phenotypes and Protein Signatures in Children With Down Syndrome.

Pulmonary disease, lower respiratory tract infection, and pneumonia are the largest causes of morbidity and mortality in individuals with Down syndrome (DS), but whether pulmonary diagnoses in children with DS are common and occur independently of cardiac disease and pulmonary hypertension (PH) is unknown. Cardiopulmonary phenotypes were examined in a cohort of 1248 children with DS. Aptamer-based proteomic analysis of blood was performed in a subset (n = 120) of these children. By the age of 10 years, half of the patients in this cohort (n = 634, 50.8%) had co-occurring pulmonary diagnoses. That proteins and related pathways were distinct between children with pulmonary diagnoses and those with cardiac disease and/or PH may indicate that pulmonary diagnoses appear to occur independently of cardiac disease and PH. Heparin sulfate-glycosaminoglycandegradation, nicotinate metabolism, and elastic fiber formation were ranked highest in the group with pulmonary diagnoses.

Assessing Dietary Salt Intake and Pilot-Testing a Home-Based Intervention to Lower Salt Intake Among Filipino College Students.

PURPOSE: To assess the knowledge, attitude, and behaviors related to dietary salt intake and develop a home-based intervention that helps lower salt intake among Filipino college students. DESIGN: Two-phase program development study utilizing descriptive and quasi-experimental design. METHODS: Phase 1 determined the knowledge, attitude, and behaviors alongside the frequency of dietary salt intake of a consecutive sample (n = 118). Phase 2 involved the development and pilot-testing of a home-based intervention wherein a random sample (n = 35) selected from Phase 1 joined for pilot-testing. The study was conducted from October - November 2021 and utilized valid and reliable measures to test the knowledge, attitude, and behavior of the participants. FINDINGS: Initial assessment showed knowledge regarding health risks of high salt intake and positive attitude toward health-promoting behaviors. Post-intervention showed improvement in attitude (p = 0.0004) and behavior (p = 0.001) related to dietary salt intake alongside health literacy (p = 0.036). There was no significant change in knowledge (p = 0.054). CONCLUSION: The home-based intervention involving the use of health education materials is successful in improving dietary salt intake patterns. CLINICAL EVIDENCE: Community health nurses may utilize home-based interventions to help develop health-promoting behaviors among young adults.

Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach.

Alzheimer's disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (n = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results.

Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions.

The design, synthesis, and evaluation of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are big challenges today. In this work, two 5-acetamido-2-hydroxy benzoic acid derivatives were proposed, increasing the alkyl position (methyl) in an acetamide moiety, and synthesized, and their structural elucidation was performed using 1H NMR and 13C NMR. The changes in methyl in larger groups such as phenyl and benzyl aim to increase their selectivity over cyclooxygenase 2 (COX-2). These 5-acetamido-2-hydroxy benzoic acid derivatives were prepared using classic methods of acylation reactions with anhydride or acyl chloride. Pharmacokinetics and toxicological properties were predicted using computational tools, and their binding affinity (kcal/mol) with COX-2 receptors (Mus musculus and Homo sapiens) was analyzed using docking studies (PDB ID 4PH9, 5KIR, 1PXX and 5F1A). An in-silico study showed that 5-acetamido-2-hydroxy benzoic acid derivates have a better bioavailability and binding affinity with the COX-2 receptor, and in-vivo anti-nociceptive activity was investigated by means of a writhing test induced by acetic acid and a hot plate. PS3, at doses of 20 and 50 mg/kg, reduced painful activity by 74% and 75%, respectively, when compared to the control group (20 mg/kg). Regarding the anti-nociceptive activity, the benzyl showed reductions in painful activity when compared to acetaminophen and 5-acetamido-2-hydroxy benzoic acid. However, the proposed derivatives are potentially more active than 5-acetamido-2-hydroxy benzoic acid and they support the design of novel and safer derivative candidates. Consequently, more studies need to be conducted to evaluate the different pharmacological actions, the toxicity of possible metabolites that can be generated, and their potential use in inflammation and pain therapy.

Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.