Specialist physiotherapy for functional motor disorder in England and Scotland (Physio4FMD): a pragmatic, multicentre, phase 3 randomised controlled trial.

BACKGROUND: Functional motor disorder-the motor variant of functional neurological disorder-is a disabling condition that is commonly associated with poor health outcomes. Pathophysiological models have inspired new treatment approaches such as specialist physiotherapy, although evidence from large randomised controlled trials is absent. We aimed to assess the clinical effectiveness of a specialist physiotherapy intervention for functional motor disorder compared with treatment as usual. METHODS: In this pragmatic, multicentre, phase 3 randomised controlled trial at 11 hospitals in England and Scotland, adults with a clinically definite diagnosis of functional motor disorder, diagnosed by a neurologist, were included. Participants were randomly assigned (1:1, stratified by site) using a remote web-based application to either specialist physiotherapy (a protocolised intervention of nine sessions plus follow-up) or treatment as usual (referral to local community neurological physiotherapy). Individuals working on data collection and analysis were masked to treatment allocation. The primary outcome was the physical functioning domain of the 36-item short form health questionnaire (SF36) at 12 months after randomisation. The primary analysis followed a modified intention-to-treat principle, using a complete case approach; participants who were unable to receive their randomised treatment due to the suspension of health-care services during the COVID-19 pandemic were excluded from the primary analysis. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN56136713, and is completed. FINDINGS: Recruitment occurred between Oct 19, 2018, and March 11, 2020, pausing during the COVID-19 lockdown, and resuming from Aug 3, 2021, to Jan 31, 2022. Of 355 participants who were enrolled, 179 were randomly assigned to specialist physiotherapy and 176 to treatment as usual. 89 participants were excluded from the primary analysis due to COVID-19 interruption to treatment (27 were assigned to specialist physiotherapy and 62 to treatment as usual). After accounting for withdrawals (n=11) and loss to follow-up (n=14), the primary analysis included data from 241 participants (138 [91%] assigned specialist physiotherapy and 103 [90%] assigned treatment as usual). Physical functioning, as assessed by SF36, did not differ significantly between groups (adjusted mean difference 3·5, 95% CI -2·3 to 9·3; p=0·23). There were no serious adverse events related to the trial interventions. 35 serious adverse events were recorded in the specialist physiotherapy group by 24 participants (17·0%), and 24 serious adverse events were recorded in the treatment as usual group by 18 participants (17·0%); one death occurred in the specialist physiotherapy group (cause of death was recorded as suicide). All were considered unrelated to specialist physiotherapy. INTERPRETATION: Although more participants who were assigned specialist physiotherapy self-rated their motor symptoms as improved and had better scores on subjective measures of mental health, the intervention did not result in better self-reported physical functioning at 12 months. Both the specialist and community neurological physiotherapy appeared to be a safe and a valued treatment for selected patients with functional motor disorder. Future research should continue to refine interventions for people with functional motor disorder and develop evidence-based methods to guide treatment triage decisions. FUNDING: National Institute for Health and Care Research and Health Technology Assessment Programme.

Power of Light: Raman Spectroscopy and Machine Learning for the Detection of Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, emphasizing the urgent need for reliable and efficient diagnostic methods. Conventional approaches often involve invasive procedures and can be time-consuming and costly, thereby delaying the effective treatment. The current study explores the potential of Raman spectroscopy, as a promising noninvasive technique, by analyzing human blood plasma samples from lung cancer patients and healthy controls. In a benchmark study, 16 machine learning models were evaluated by employing four strategies: the combination of dimensionality reduction with classifiers; application of feature selection prior to classification; stand-alone classifiers; and a unified predictive model. The models showed different performances due to the inherent complexity of the data, achieving accuracies from 0.77 to 0.85 and areas under the curve for receiver operating characteristics from 0.85 to 0.94. Hybrid methods incorporating dimensionality reduction and feature selection algorithms present the highest figures of merit. Nevertheless, all machine learning models deliver creditable scores and demonstrate that Raman spectroscopy represents a powerful method for future in vitro diagnostics of lung cancer.

Mediterranean diet-based intervention to improve depressive symptoms: analysis of the PREDIDEP randomized trial.

BACKGROUND: The effect of an intervention based on Mediterranean diet on reducing recurrence risk or subsyndromal depressive symptoms in recovered depressed patients has not been explored. METHODS: The PREDIDEP study was a two-year randomized trial designed to assess the effect of the Mediterranean Diet enriched with extra virgin olive oil on depression recurrence. At baseline and at four, eight, 16, 20, and 24 months of follow-up, depressive symptoms were evaluated through the Beck Depression inventory. Cox regression analysis was fitted to assess the role of dietary intervention on the risk of depression recurrence. Mixed effects linear models were used to assess changes in depressive subsyndromal symptoms according to the intervention. RESULTS: After two years of intervention, the dietary intervention group (n = 103) compared to the control group (n = 93) showed no differences regarding depression recurrence risk as main outcome. As secondary outcomes, an improvement of depressive symptoms was yielded at four (-2.15; 95% CI = -4.00 to -0.29) and eight months (-2.42; 95% CI = -4.17 to -0.67) in the intervention group, with no changes in control group. Moreover, at 20 months, significant differences were found between groups (-3.35; 95% CI = -6.08 to -0.61). CONCLUSIONS: An intervention with Mediterranean diet in patients with previous depressive episodes might contribute to the reduction of depressive subsyndromal symptoms.

An initial characterisation of the Unfolded Protein Response pathway in haematopoietic canine cancer cell lines - a necessary step for the future development of new therapies in dogs with neoplasia.

Introduction: New and more effective therapies for canine cancer patients are urgently required and this necessitates advanced experimental research. Dogs are good models for studies in comparative oncology; however, canine cancer cell biology research is currently limited by low availability of validated antibody reagents and techniques. This study characterises the expression of key components of the unfolded protein response (UPR) in a panel of haematopoietic canine cancer cell lines using commercially available antibodies, and validates the methods used to study this pathway. Material and Methods: The CLBL-1 canine lymphoma cell line and the GL-1 canine leukaemia cell line sourced externally and two counterparts established in house (CNK-89 and CLB70) were used as models of different lymphoma and leukaemia canine cell lines for the study. The human U2OS cell line served as the control. Antibodies were selected for identifying UPR proteins according to known canine cell reactivity and canine-murine and canine-human homology. Endoplasmic reticulum stress was induced with thapsigargin and MG132 in the cell lines. Etoposide was used to induce DNA damage in the cells. The techniques used for this validation analysis were RNA sequencing to observe the expression of UPR components in canine cell lines, Western blot to observe changes of protein expression levels after inducing ER stress in the cells, and flow cytometry in order to study cell death. Results: Substantial variations in both the basic expression and agonist-induced activation of the UPR pathway were observed in canine cancer cell lines, although the biological significance of these differences requires further investigation. Conclusion: These findings will be a starting point for future studies on cancer biology in dogs. They will also contribute to developing novel anticancer therapies for canine patients and may provide new insights into human oncology.

Studying the DNA damage response pathway in hematopoietic canine cancer cell lines, a necessary step for finding targets to generate new therapies to treat cancer in dogs.

Background: Dogs present a significant opportunity for studies in comparative oncology. However, the study of cancer biology phenomena in canine cells is currently limited by restricted availability of validated antibody reagents and techniques. Here, we provide an initial characterization of the expression and activity of key components of the DNA Damage Response (DDR) in a panel of hematopoietic canine cancer cell lines, with the use of commercially available antibody reagents. Materials and methods: The techniques used for this validation analysis were western blot, qPCR, and DNA combing assay. Results: Substantial variations in both the basal expression (ATR, Claspin, Chk1, and Rad51) and agonist-induced activation (p-Chk1) of DDR components were observed in canine cancer cell lines. The expression was stronger in the CLBL-1 (B-cell lymphoma) and CLB70 (B-cell chronic lymphocytic leukemia) cell lines than in the GL-1 (B-cell leukemia) cell line, but the biological significance of these differences requires further investigation. We also validated methodologies for quantifying DNA replication dynamics in hematopoietic canine cancer cell lines, and found that the GL-1 cell line presented a higher replication fork speed than the CLBL-1 cell line, but that both showed a tendency to replication fork asymmetry. Conclusion: These findings will inform future studies on cancer biology, which will facilitate progress in developing novel anticancer therapies for canine patients. They can also provide new knowledge in human oncology.

Socialización de experiencias y logros en la salud pública y la Colaboración Médica Cubana desde las redes sociales. Venezuela 2021-2022

Introducción: Las redes sociales son formas de interacción social, que fomentan un intercambio dinámico entre personas, grupos e instituciones en contextos disímiles. Objetivo: Socializar la experiencia y los logros de la salud pública y la Colaboración Médica Cubana desde las redes sociales en Venezuela desde enero de 2021 hasta octubre de 2022. Métodos: Se realiza una investigación de tipo observacional descriptiva en el periodo comprendido desde enero de 2021 hasta octubre de 2022 y aplicado en la Misión Médica Cubana en Venezuela con una población de 14 213 profesionales de la salud dividida en 24 estados. Resultados: En el año 2021 se realizaron 21 tuitazos con un millón 876 898 tuits. Para el año 2022 Facebook se comportó con 32 489 seguidores, Twiter con 16 832, Instagram Cubacooperave, 3 905, Yotube.com/c/cubacooperave 2 830, Tiktok 890 y Telegram 371 suscriptores. Se realizaron 26 actividades nacionales, 11 Tuitazos y 15 Jornadas en las Redes, 144 en TV, 200 en Radio y 100 en la Prensa escrita. Conclusiones: El reto es utilizar la posibilidad que ofrece la tecnología para ampliar los horizontes del uso de las redes sociales, realizar acciones de alfabetización informacional dirigidas a los gestores y usuarios de las mismas en pos de una divulgación adecuada del trabajo en la Misión Médica Cubana en Venezuela.

Introduction: Social networks are forms of social interaction that foster a dynamic exchange among people, groups, and institutions in dissimilar contexts. Objective: To socialize the experience and achievements of public health and the Cuban Medical Collaboration in social networks in Venezuela from January 2021 to October 2022. Method: An observational descriptive research was conducted from January 2021 to October 2022 and applied to the Cuban Medical Mission in Venezuela in a population of 14 213 health professionals divided into 24 states. Results: In the year 2021, there was a total of 21 tweets with 1 876 898 tweets published. In 2022, the Facebook network had 32 489 followers; Twitter, 16 832; Instragram Cubacooperave, 3 905; the Yotube.com/c/Cubacooperave channel, 2 830; Tik Tok, 890; and Telegram had 371 subscribers. A total of 26 national activities such as 11 Tuits, 15 Network Events; 144 TV, 200 Radio, and 100 written Press activities were performed. Conclusions: The challenge is to use the possibility offered by technology to broaden the horizons of the use of social networks, as well as to establish information literacy actions directed towards the managers and users of these networks for the sake of an adequate dissemination of the work carried out by the Cuban Medical Mission in Venezuela.

Exposure to non-persistent pesticides and sexual maturation of Spanish adolescent males.

BACKGROUND: Several non-persistent pesticides are endocrine disrupting chemicals and may impact on sexual maturation. OBJECTIVE: To examine the association between urinary biomarkers of non-persistent pesticides and sexual maturation in adolescent males in the Environment and Childhood (INMA) Project. METHODS: The metabolites of several pesticides were measured in spot urine samples collected from 201 boys aged 14-17 years, including: 3,5,6-trichloro-2-pyridinol (TCPy), metabolite of chlorpyrifos; 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), metabolite of diazinon; malathion diacid (MDA), metabolite of malathion; diethyl thiophosphate (DETP) and diethyl dithiophosphate, non-specific metabolites of organophosphates; 3-phenoxybenzoic acid (3-PBA) and dimethyl cyclopropane carboxylic acid, metabolites of pyrethroids; 1-naphthol (1-NPL), metabolite of carbaryl; and ethylene thiourea (ETU), metabolite of dithiocarbamate fungicides. Sexual maturation was assessed using Tanner stages, self-reported Pubertal Development Scale, and testicular volume (TV). Multivariate logistic regression was employed to examine associations between urinary pesticide metabolites and the odds of being in Tanner stage 5 of genital development (G5) or pubic hair growth (PH5); stage ≥4 of overall pubertal development, gonadarche, and adrenarche; or having mature TV (≥25 mL). RESULTS: DETP concentrations>75th percentile (P75) were associated with lower odds of being in stage G5 (OR = 0.27; 95% CI = 0.10-0.70), detectable TCPy with lower odds of gonadal stage≥4 (OR = 0.50; 95% CI = 0.26-0.96), and intermediate detectable MDA concentrations (

Effect of a dietary intervention based on the Mediterranean diet on the quality of life of patients recovered from depression: Analysis of the PREDIDEP randomized trial.

INTRODUCTION: There is substantial evidence supporting that improving diet quality leads to improved health-related quality of life (HRQoL). Our major aim was to assess the effectiveness of a Mediterranean diet-based nutritional intervention to improve HRQoL in the context of a secondary prevention trial of depression. Secondarily to assess its effectiveness among adults aged 60 or more years. METHODS: The PREDIDEP study is a 2-year multicentre, randomized, single-blinded nutritional trial. At baseline and at 1-year and 2-year follow-up, SF-36 health survey questionnaire was collected to evaluate participants' HRQoL (total and specific range for each of the 8 dimensions: 0 to 100 points). Mixed effect linear models were used to assess changes in HRQoL according to adherence to the Mediterranean diet. The trial was registered at ClinicalTrials.govNCT03081065. RESULTS: After 2 years of intervention, the Mediterranean Diet intervention group compared to control group (without nutritional intervention, only usual clinical care) showed an improvement in some dimensions of HRQoL such as Mental Health (7.22; 95 % CI = 2.22-12.22) (between-group difference: 6.79; 95 % CI -0.14-13.73, p = 0.055); Vitality (9.51; 95 % CI = 4.00-15.03) (between-group difference: 9.00; 95 % CI 1.75-16.25, p = 0.020); Mental Summary Component (2.83; 95 % CI = 0.55-5.11) (between-group difference: 1.17; 95 % CI = -1.96-4.30, p = 0.462); and General Health (10.70; 95 % CI = 5.58-15.81) (between-group difference: 6.20; 95 % CI = -0.89-13.28, p = 0.086). Similar results were observed for participants aged 60 or more years. CONCLUSION: The intervention based on Mediterranean diet in patients with previous depression seems to be effective in improving HRQoL, especially the mental dimensions. This effect is also observed among participants aged 60 or more years.

Implementation of effect biomarkers in human biomonitoring studies: A systematic approach synergizing toxicological and epidemiological knowledge.

Human biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of validated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxicological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2'-deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU confirms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better understand the public health implications of human exposure to environmental chemicals.

Childhood exposure to non-persistent pesticides and pubertal development in Spanish girls and boys: Evidence from the INMA (Environment and Childhood) cohort.

This study assessed cross-sectional associations between urinary metabolites of non-persistent pesticides and pubertal development in boys and girls from urban and rural areas in Spain and examined effect modification by body mass index (BMI). Four metabolites of insecticides (TCPy, metabolite of chlorpyrifos; IMPy, metabolite of diazinon; DETP, non-specific metabolite of organophosphates; 3-PBA, metabolite of pyrethroids) and the metabolite of ethylene-bis-dithiocarbamate fungicides (ETU) were quantified in urine collected in 2010-2016 from 7 to 11-year-old children (606 girls, 933 boys) participating in the INMA Project. Pubertal development was ascertained by Tanner stages and/or parent-reported Pubertal Development Scale (PDS). Associations between pesticide metabolites and odds of being in stage 2+ for breast development (girls), genital development (boys), pubic hair growth (girls and boys), and/or overall puberty onset, gonadarche, and adrenarche (PDS for girls and boys) were examined by mixed-effect logistic regression. Effect modification by BMI was explored by interaction terms and stratified analysis. In girls, DETP and ETU concentrations>75th percentile (P75) were associated with higher odds of overall puberty development (OR [95%CI] = 1.86 [1.07-3.24] and 1.71 [1.03-2.83], respectively, for > P75 vs. undetected concentrations), while ETU > P75 was also associated with higher odds of breast development (OR [95%CI] = 5.55 [2.83-12.91]), particularly in girls with underweight/normal weight (OR [95%CI] = 10.08 [2.62-38.76]). In boys, detection of TCPy (40%) and 3-PBA (34%) was associated with higher odds of genital development (OR [95%CI] = 1.97 [1.08-3.57] and 2.08 [1.15-3.81], respectively), and the association with 3-PBA was observed in boys with overweight/obesity alone. In addition, ETU > P75 was associated with higher odds of genital development in boys with underweight/normal weight (OR [95%CI] = 2.89 [1.08-7.74]) but higher DETP with lower odds of puberty in boys with overweight/obesity (OR [95%CI] = 0.94 [0.89-0.99] per log-unit increase in concentration). Results suggest an association of childhood exposure to ETU and certain insecticides with earlier puberty in girls and boys that may be modified by child BMI.

'Effectiveness of a remote nutritional intervention to increase the adherence to the Mediterranean diet among recovered depression patients'.

BACKGROUND: There is substantial evidence supporting that remote interventions are useful to change dietary habits. However, the effect of a remote intervention based on Mediterranean diet (MD) in depressive patients has been less explored. OBJECTIVE: This study aims to assess the effectiveness of a remotely provided Mediterranean diet-based nutritional intervention in the context of a secondary prevention trial of depression. METHODS: The PREDIDEP study was a 2-year multicenter, randomized, single-blinded trial designed to assess the effect of the MD enriched with extra virgin olive oil (EVOO) on the prevention of depression recurrence. The intervention group received usual care for depressed patients and remote nutritional intervention every three months which included phone contacts and web-based interventions; and the control group, usual care. At baseline and at 1-year and 2-year follow-up, the 14-item MD Adherence Screener (MEDAS) questionnaire and a semiquantitative food frequency questionnaire (FFQ) were collected by a dietitian. Mixed effects linear models were used to assess changes in nutritional variables according to the group of intervention. The trial was registered at ClinicalTrials.gov NCT03081065. RESULTS: Compared with control group, the MD intervention group showed more adherence to MD (between-group difference: 2.76; 95% CI 2.13-3.39; p < 0.001); and a healthier diet pattern with a significant increase in the consumption of olive oil (p < 0.001), and a significant reduction in refined cereals (p = 0.031) after 2 years of intervention. CONCLUSIONS: The remote nutritional intervention increases adherence to the MD among recovered depression patients.Trial registration: ClinicalTrials.gov identifier: NCT03081065.

The use of metaphors by service users with diverse long-term conditions: a secondary qualitative data analysis.

Long-term conditions and accompanied co-morbidities now affect about a quarter of the UK population. Enabling patients and caregivers to communicate their experience of illness in their own words is vital to developing a shared understanding of the condition and its impact on patients' and caregivers' lives and in delivering person-centred care. Studies of patient language show how metaphors provide insight into the physical and emotional world of the patient, but such studies are often limited by their focus on a single illness. The authors of this study undertook a secondary qualitative data analysis of 25 interviews, comparing the metaphors used by patients and parents of patients with five longterm conditions. Analysis shows how similar metaphors can be used in empowering and disempowering ways as patients strive to accept illness in their daily lives and how metaphor use depends on the manifestation, diagnosis, and treatment of individual conditions. The study concludes with implications for how metaphorical expressions can be attended to by healthcare professionals as part of shared care planning.

Circulating MicroRNAs as Cancer Biomarkers in Liquid Biopsies.

Biological fluids such as blood, saliva, and urine offer a rich source of biomarkers that have the potential to change the paradigm of cancer management. By allowing routine noninvasive sampling that can offer new insights into cancer progression and response to treatment so-called liquid biopsies can play an important role in personalized medicine. MicroRNAs (miRNAs) are a particularly attractive class of biomarkers as they are not only resistant to the high levels of RNases found in biological fluids, but also able to confer clinically useful information about the disease relating to diagnosis, prognosis, and the response to treatment. Circulating miRNAs are either associated with proteins or extracellular vesicles (EV) and although their origin and implied functions as intracellular messengers remain somewhat controversial, they are implicated in the progression and the establishment of metastatic niches. In this chapter, we review the rapidly emerging field of circulating miRNA cancer biomarkers, their origin and function, techniques to detect these molecules, and the use of bioinformatic tools to derive implied regulatory function, as well as the challenges that lie ahead for their clinical implementation.

Maternal urinary concentrations of bisphenol A during pregnancy are associated with global DNA methylation in cord blood of newborns in the "NELA" birth cohort.

Endocrine disrupting chemicals (EDCs) set a public health risk through disruption of normal physiological processes. The toxicoepigenetic mechanisms of developmental exposure to common EDCs, such as bisphenol A (BPA), are poorly known. The present study aimed to evaluate associations between perinatal maternal urinary concentrations of BPA, bisphenol S (BPS) and bisphenol F (BPF) and LINE-1 (long interspersed nuclear elements) and Alu (short interspersed nuclear elements, SINEs) DNA methylation levels in newborns, as surrogate markers of global DNA methylation. Data come from 318 mother-child pairs of the `Nutrition in Early Life and Asthma´ (NELA) birth cohort. Urinary bisphenol concentration was measured by dispersive liquid-liquid microextraction and ultrahigh performance liquid chromatography with tandem mass spectrometry detection. DNA methylation was quantitatively assessed by bisulphite pyrosequencing on 3 LINEs and 5 SINEs. Unadjusted linear regression analyses showed that higher concentration of maternal urinary BPA in 24th week's pregnancy was associated with an increase in LINE-1 methylation in all newborns (p = 0.01) and, particularly, in male newborns (p = 0.03). These associations remained in full adjusted models [beta = 0.09 (95 % CI = 0.03; 0.14) for all newborns; and beta = 0.10 (95 % CI = 0.03; 0.17) for males], including a non-linear association for female newborns as well (p-trend = 0.003). No associations were found between maternal concentrations of bisphenol and Alu sequences. Our results suggest that exposure to environmental levels of BPA may be associated with a modest increase in LINE-1 methylation -as a relevant marker of epigenomic stability- during human fetal development. However, any effects on global DNA methylation are likely to be small, and of uncertain biological significance.

Genetic Variants of APOL1 Are Major Determinants of Kidney Failure in People of African Ancestry With HIV.

Introduction: Variants of the APOL1 gene are associated with chronic kidney disease (CKD) in people of African ancestry, although evidence for their impact in people with HIV are sparse. Methods: We conducted a cross-sectional study investigating the association between APOL1 renal risk alleles and kidney disease in people of African ancestry with HIV in the UK. The primary outcome was end-stage kidney disease (ESKD; estimated glomerular filtration rate [eGFR] of <15 ml/min per 1.73 m2, chronic dialysis, or having received a kidney transplant). The secondary outcomes included renal impairment (eGFR <60 ml/min per 1.73 m2), albuminuria (albumin-to-creatinine ratio [ACR] >30 mg/mmol), and biopsy-proven HIV-associated nephropathy (HIVAN). Multivariable logistic regression was used to estimate the associations between APOL1 high-risk genotypes (G1/G1, G1/G2, G2/G2) and kidney disease outcomes. Results: A total of 2864 participants (mean age 48.1 [SD 10.3], 57.3% female) were genotyped, of whom, 354 (12.4%) had APOL1 high-risk genotypes, and 99 (3.5%) had ESKD. After adjusting for demographic, HIV, and renal risk factors, individuals with APOL1 high-risk genotypes were at increased odds of ESKD (odds ratio [OR] 10.58, 95% CI 6.22-17.99), renal impairment (OR 5.50, 95% CI 3.81-7.95), albuminuria (OR 3.34, 95% CI 2.00-5.56), and HIVAN (OR 30.16, 95% CI 12.48-72.88). An estimated 49% of ESKD was attributable to APOL1 high-risk genotypes. Conclusion: APOL1 high-risk genotypes were strongly associated with kidney disease in people of African ancestry with HIV and accounted for approximately half of ESKD cases in this cohort.

CA 15-3 prognostic biomarker in SARS-CoV-2 pneumonia.

The severity of lung involvement is the main prognostic factor in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Carbohydrate antigen 15-3 (CA 15-3), a marker of lung damage and fibrosis, could help predict the prognosis of SARS-CoV-2 pneumonia. This was a retrospective and observational study. CA 15-3 was analyzed in the blood samples of patients consecutively admitted for SARS-CoV-2 pneumonia and whose blood samples were available in the biobank. Other prognostic markers were also measured (interleukin 6 [IL6], C-reactive protein [CRP], D-dimer, troponin T, and NT-ProBNP). The occurrence of in-hospital complications was registered, including death, the need for medical intensive care, and oxygen therapy at discharge. In this study, 539 patients were recruited (54.9% men, mean age: 59.6 ± 16.4 years). At admission, the mean concentrations of CA 15-3 was 20.5 ± 15.8 U/mL, and the concentration was correlated with male sex, older age, and other severity markers of coronavirus disease of 2019 (COVID-19) (IL6, CRP, D-dimer, troponine T, and NT-ProBNP). CA 15-3 levels were higher in patients who died (n = 56, 10.4%) (35.33 ± 30.45 vs. 18.8 ± 12.11, p < 0.001), who required intensive medical support (n = 78, 14.4%; 31.17 ± 27.83 vs. 18.68 ± 11.83; p < 0.001), and who were discharged with supplemental oxygen (n = 64, 13.3%; 22.65 ± 14.41 vs. 18.2 ± 11.7; p = 0.011). Elevated CA 15-3 levels (above 34.5 U/mL) were a strong predictor of a complicated in-hospital course, in terms of a higher risk of death (adjusted odds ratio [OR] 3.74, 95% confidence interval [CI]: 1.22-11.9, p = 0.022) and need for intensive care (adjusted OR 4.56, 95% CI: 1.37-15.8) after adjusting for all other risk factors. The degree of lung damage and fibrosis evaluated in terms of CA 15-3 concentrations may allow early identification of the increased risk of complications in patients with SARS-CoV-2 pneumonia.

Exposure to non-persistent pesticides, BDNF, and behavioral function in adolescent males: Exploring a novel effect biomarker approach.

BACKGROUND: Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological function that could help to understand the biological responses of some environmental exposures. OBJECTIVES: To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents. METHODS: The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide carbaryl 1-naphthol (1-N), and the metabolite of ethylene-bis-dithiocarbamate fungicides ethylene thiourea (ETU) were measured in spot urine samples, as well as serum BDNF protein levels and blood DNA methylation of Exon IV of BDNF gene in 15-17-year-old boys from the INMA-Granada cohort in Spain. Adolescents' behavior was reported by parents using the Child Behavior Check List (CBCL/6-18). This study included 140 adolescents of whom 118 had data on BDNF gene DNA methylation. Multivariable linear regression, weighted quantile sum (WQS) for mixture effects, and mediation models were fit. RESULTS: IMPy, MDA, DCCA, and ETU were detected in more than 70% of urine samples, DETP in 53%, and TCPy, 3-PBA, and 1-N in less than 50% of samples. Higher levels of IMPy, TCPy, and ETU were significantly associated with more behavioral problems as social, thought problems, and rule-breaking symptoms. IMPy, MDA, DETP, and 1-N were significantly associated with decreased serum BDNF levels, while MDA, 3-PBA, and ETU were associated with higher DNA methylation percentages at several CpGs. WQS models suggest a mixture effect on more behavioral problems and BDNF DNA methylation at several CpGs. A mediated effect of serum BDNF within IMPy-thought and IMPy-rule breaking associations was suggested. CONCLUSION: BDNF biomarkers measured at different levels of biological complexity provided novel information regarding the potential disruption of behavioral function due to contemporary pesticides, highlighting exposure to diazinon (IMPy) and the combined effect of IMPy, MDA, DCCA, and ETU. However, further research is warranted.

Sickle Cell Trait and Kidney Disease in People of African Ancestry With HIV.

Introduction: Sickle cell trait (SCT) has been associated with chronic kidney disease (CKD) in African Americans, although evidence for its impact in Africans and people with HIV is currently lacking. We conducted a cross-sectional study investigating the association between SCT and kidney disease in people of African ancestry with HIV in the UK. Methods: The primary outcome was estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. Secondary outcomes were eGFR <90 ml/min per 1.73 m2, end-stage kidney disease (ESKD; eGFR <15 ml/min per 1.73 m2, chronic dialysis, or having received a kidney transplant), proteinuria (protein-to-creatinine ratio >50 mg/mmol), and albuminuria (albumin-to-creatinine ratio >3 mg/mmol). Multivariable logistic regression was used to estimate the associations between SCT and kidney disease outcomes. Results: A total of 2895 participants (mean age 48.1 [SD 10.3], 57.2% female) were included, of whom 335 (11.6%) had SCT and 352 (12.2%) had eGFR <60 ml/min per 1.73 m2. After adjusting for demographic, HIV, and kidney risk factors including APOL1 high-risk genotype status, individuals with SCT were more likely to have eGFR <60 ml/min per 1.73 m2 (odds ratio 1.62 [95% CI 1.14-2.32]), eGFR <90 ml/min per 1.73 m2 (1.50 [1.14-1.97]), and albuminuria (1.50 [1.09-2.05]). Stratified by APOL1 status, significant associations between SCT and GFR <60 ml/min per 1.73 m2, eGFR <90 ml/min per 1.73 m2, proteinuria, and albuminuria were observed for those with APOL1 low-risk genotypes. Conclusion: Our results extend previously reported associations between SCT and kidney disease to people with HIV. In people of African ancestry with HIV, these associations were largely restricted to those with APOL1 low-risk genotypes.

DNA damage response proteins in canine cancer as potential research targets in comparative oncology.

The DNA damage response (DDR) is a complex signal transduction network that is activated when endogenous or exogenous genotoxins damage or interfere with the replication of genomic DNA. Under such conditions, the DDR promotes DNA repair and ensures accurate replication and division of the genome. High levels of genomic instability are frequently observed in cancers and can stem from germline loss-of-function mutations in certain DDR genes, such as BRCA1, BRCA2, and p53, that form the basis of human cancer predisposition syndromes. In addition, mutation and/or aberrant expression of multiple DDR genes are frequently observed in sporadic human cancers. As a result, the DDR is considered to represent a viable target for cancer therapy in humans and a variety of strategies are under investigation. Cancer is also a significant cause of mortality in dogs, a species that offers certain advantages for experimental oncology. Domestic dogs present numerous inbred lines, many of which display predisposition to specific forms of cancer and the study of which may provide insight into the biological basis of this susceptibility. In addition, clinical trials are possible in dogs and may lead to therapeutic insights that could ultimately be extended to humans. Here we review what is known specifically about the DDR in dogs and discuss how this knowledge could be extended and exploited to advance experimental oncology in this species.

Development and validation of brain-derived neurotrophic factor measurement in human urine samples as a non-invasive effect biomarker.

Background: Brain-derived neurotrophic factor (BDNF), a neurotrophic growth factor mainly expressed in the brain, has been proposed as a potential effect biomarker; that is, as a measurable biomarker whose values could be associated with several diseases, including neurological impairments. The European Human Biomonitoring Initiative (HBM4EU) has also recognized effect biomarkers as a useful tool for establishing link between exposure to environmental pollutants and human health. Despite the well-establish protocol for measuring serum BDNF, there is a need to validate its assessment in urine, a non-invasive sample that can be easily repeated over time. The aim of this study was to develop, standardize and validate a methodology to quantify BDNF protein levels in urine samples before its implementation in biomonitoring studies. Methods: Different experimental conditions and non-competitive commercial enzyme-linked immunosorbent assay (ELISA) kits were tested to determine the optimal analytical procedure, trying to minimize the shortcomings of ELISA kits. The fine-tune protocol was validated in a pilot study using both upon awakening (n = 150) and prior to sleeping (n = 106) urine samples from the same Spanish adolescent males in a well-characterized study population (the Spanish INMA-Granada cohort). Results: The best results were obtained in 0.6 ml of urine after the acidification and extraction (pre-concentration) of samples. The highest reproducibility was obtained with the ELISA kit from Raybiotech. Urinary BDNF concentrations of adolescent males were within the previously reported range (morning = 0.047-6.801 ng/ml and night = 0.047-7.404 ng/ml). Urinary BDNF levels in the awakening and pre-sleep samples did not follow a normal distribution and were not correlated. Conclusion: The developed methodology offers good sensitivity and reproducibility. Having reliable markers in urine may facilitate both diagnosis and monitoring possible diseases (and treatment). Further studies are needed to implement urinary BDNF in biomonitoring studies to further elucidate its usefulness and biological significance for neurological impairments.