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Background: Despite evidence on their short-term effectiveness, the long-term effects of group-based parenting interventions are unclear, programs are hard to scale up, and effects on parents of infants and toddlers are mixed. Objective: We evaluate the impact of a parenting intervention, "Crianza Positiva," that combines 8 group sessions with a 6 months e-messaging component. The program targets parents of infants and toddlers, is designed to be scalable by using low-cost delivery formats and a structured framework, and relies on a "top up" module to sustain the effects. Methods: We analyze video-recordings of a free play activity to rate the quality of child-caregiver interaction. We compare outcomes across three arms: (a) workshop + messages, (b) workshop only, and (c) a weekly unstructured playgroup. Because assignment to treatment is not random, we use inverse probability weighting to address initial unbalances and differential attrition. Our sample includes 442 disadvantaged families with infants/toddlers enrolled in early childhood centers in Uruguay. Results: Results show significant and sustained benefits of the program on child-caregiver interaction quality, with medium effect sizes in the affective (d = 0.44) and teaching dimensions (d = 0.59). Conclusions: The data suggest that group parenting interventions may help improve the childrearing environment among parents of children aged 0-2. Due to its protocolized design and the low cost of integrating it into early-childhood centers, the program has a potential for widespread implementation. Still, definitive conclusions are precluded by the evaluation design. Future randomized designs are needed.

Abstract Background No clinical trials have evaluated the antimicrobial activity and substantivity of gel formulations containing chlorhexidine (CHX) and cymenol. Objective To compare the in situ antimicrobial effect and substantivity of a new 0.20% CHX + cymenol gel (test) with the current 0.20% CHX gel formulation (control) on salivary flora and dental plaque biofilm up to seven hours after a single application. Methods A randomised-crossover clinical trial was conducted with 29 orally healthy volunteers participating in the development of Experiments 1 (saliva) and 2 (dental plaque biofilm). All subjects participated in both experiments and were randomly assigned to receive either the test or control gels. Samples were collected at baseline and five minutes and one, three, five, and seven hours after a single application of the products. The specimens were processed using confocal laser scanning microscopy after staining with the LIVE/DEAD® BacLight™ solution. Bacterial viability (BV) was quantified in the saliva and biofilm samples. The BV was calculated using the DenTiUS Biofilm software. Results In Experiment 1, the mean baseline BV was significantly reduced five minutes after application in the test group (87.00% vs. 26.50%; p

Abstract Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.

Abstract Background Botulinum toxin type A is currently strongly recommended for the treatment of anal fissures (AFs). However, there is still no consensus on dosage or injection technique. This study provides further efficacy and safety evidence in a 2-year follow-up. Method Prospective, open-label, single-arm, single-center study carried out in adult patients with AFs non-responsive to previous treatments. Patients were treated with incobotulinumtoxinA (incoBoNT/A) injected in both laterals and posterior intersphincteric groove. Healing rate at 2 years was the primary endpoint. Secondary endpoints included internal anal sphincter pressures, incontinence, and safety. Results A total of 49 patients were treated with a mean incoBoNT/A dose of 40.5 U (spread across three locations). Healing rate at 2 years was 83.9% with a 24.5% of recurrence throughout the study. Only 7 patients (14.3%) reported adverse events (AEs) that were mild and temporary. Mean reduction in anal resting pressure was -9.1 mmHg at 3 months (p = 0.001). Mean reduction in voluntary squeeze pressure was -27.5 mmHg at 3 months (p

Rheumatoid arthritis (RA) is an autoimmune disease characterised by persistent inflammation of the synovial joints as well as other tissues and organs. Left untreated, it can lead to joint damage, disability and even increased mortality. The disease is driven by inflammatory cytokines that contribute to the chronic inflammation seen in RA. Interleukin-6 (IL-6) is a key pathological cytokine and a target for treatments aiming to alleviate local and systemic inflammation. Despite advances in understanding RA and the introduction of new treatments, achieving sustained remission remains challenging. This review explores the role of IL-6 in RA pathogenesis, its potential as a treatment target and the significance of personalised medicine in RA management. IL-6 has a dual signalling mechanism, classical and trans-signalling, which influences various intracellular pathways. While several targeted therapies have emerged, no single mechanism-based therapy is universally effective due to the diversity and complexity of the disease. Different approaches to targeting IL-6 have been tested, including biologic blockade of receptors or ligands, and inhibition of IL-6 signalling. IL-6 receptor inhibitors have been validated as RA therapeutics, either alone or in combination with other treatments. Tocilizumab, the first approved IL-6 inhibitor, blocks both soluble and membrane-bound IL-6 receptors, reducing the inflammatory cascade. Clinical trials confirm the efficacy and safety of tocilizumab and its role as a treatment option for patients unresponsive to conventional therapies. The benefits of IL-6 inhibition extend beyond reduced joint inflammation to the amelioration of comorbidities like anaemia, cardiovascular disease, depression and osteoporosis. Tailoring treatment to patients’ profiles and comorbidities is essential for optimal outcomes. A ‘treat-to-profile’ approach, focusing on a holistic view of the patient, could improve personalised medicine strategies. Biosimilars – lower-cost alternatives to biologics – further enhance the accessibility and cost-effectiveness of treatment. IL-6 inhibitors present a valuable treatment option for RA management, particularly for patients with specific comorbidities.

BackgroundThe EXXELERATE study revealed poorer clinical outcomes in patients treated with adalimumab (ADL) and baseline rheumatoid factor (RF) above 203 IU/mL. However, responses were similar in patients treated with certolizumab pegol (CZP) regardless of RF levels.ObjectivesThis study investigated the impact of RF levels >203 IU/mL on TNF inhibitors (TNFi) serum levels and the association with secondary nonresponse in RA patients treated with TNFi.MethodsWe performed an observational ambispective study with RA patients treated with infliximab (IFX), ADL, or CZP. Patients were stratified according to baseline RF levels: ≤ or >203 IU/mL. After 6 months, serum drug levels and antidrug antibodies were measured, and reasons for discontinuation were collected.ResultsWe included 170 RA patients: 90 (53%) received IFX, 48 (28%) ADL, and 32 (19%) CZP. While CZP serum levels did not differ between RF groups at 6 months (p = 0.6), RF levels >203 IU/mL were linked to lower serum drug levels in patients treated with IFX (p = 0.09) or ADL (p = 0.02). Secondary nonresponse was 3.6 times higher in patients with high versus low RF levels in patients under IFX or ADL. However, the reasons for withdrawal were not affected by RF levels in patients treated with CZP.ConclusionBaseline RF above 203 IU/mL is associated with lower serum drug levels and an increased risk of discontinuation due to secondary nonresponse in patients treated with IFX or ADL. In contrast, drug levels and clinical outcomes are not significantly impacted by baseline RF levels in patients under CZP.

Legionellers’ desease accounts for 1–8 % of cases of severe community-acquired pneumonia (CAP). Legionella spp. Is the causative organism that can result in respiratory failure, multi-organ dysfunction, sepsis, and death. Therefore, rapid diagnosis and efficient treatment are crucial. We report the clinical and microbiology study of a patient with community-acquired pneumonia caused by Legionella pneumophila, with fatal outcome. After death, the strain causing the infection was identified as Legionella pneumophila serogroup 1, Olda OLDA phenotype and sequence-type 1. This is the first reported case of septic shock and death associated with an isolate of these characteristics.

Abstract Background The selection of primer pairs in sequencing-based research can greatly influence the results, highlighting the need for a tool capable of analysing their performance in-silico prior to the sequencing process. We therefore propose PrimerEvalPy, a Python-based package designed to test the performance of any primer or primer pair against any sequencing database. The package calculates a coverage metric and returns the amplicon sequences found, along with information such as their average start and end positions. It also allows the analysis of coverage for different taxonomic levels. Results As a case study, PrimerEvalPy was used to test the most commonly used primers in the literature against two oral 16S rRNA gene databases containing bacteria and archaea. The results showed that the most commonly used primer pairs in the oral cavity did not match those with the highest coverage. The best performing primer pairs were found for the detection of oral bacteria and archaea. Conclusions This demonstrates the importance of a coverage analysis tool such as PrimerEvalPy to find the best primer pairs for specific niches. The software is available under the MIT licence at https://gitlab.citius.usc.es/lara.vazquez/PrimerEvalPy .

IntroductionMicrobiome-based clinical applications that improve diagnosis related to oral health are of great interest to precision dentistry. Predictive studies on the salivary microbiome are scarce and of low methodological quality (low sample sizes, lack of biological heterogeneity, and absence of a validation process). None of them evaluates the impact of confounding factors as batch effects (BEs). This is the first 16S multi-batch study to analyze the salivary microbiome at the amplicon sequence variant (ASV) level in terms of differential abundance and machine learning models. This is done in periodontally healthy and periodontitis patients before and after removing BEs.MethodsSaliva was collected from 124 patients (50 healthy, 74 periodontitis) in our setting. Sequencing of the V3-V4 16S rRNA gene region was performed in Illumina MiSeq. In parallel, searches were conducted on four databases to identify previous Illumina V3-V4 sequencing studies on the salivary microbiome. Investigations that met predefined criteria were included in the analysis, and the own and external sequences were processed using the same bioinformatics protocol. The statistical analysis was performed in the R-Bioconductor environment.ResultsThe elimination of BEs reduced the number of ASVs with differential abundance between the groups by approximately one-third (Before=265; After=190). Before removing BEs, the model constructed using all study samples (796) comprised 16 ASVs (0.16%) and had an area under the curve (AUC) of 0.944, sensitivity of 90.73%, and specificity of 87.16%. The model built using two-thirds of the specimens (training=531) comprised 35 ASVs (0.36%) and had an AUC of 0.955, sensitivity of 86.54%, and specificity of 90.06% after being validated in the remaining one-third (test=265). After removing BEs, the models required more ASVs (all samples=200–2.03%; training=100–1.01%) to obtain slightly lower AUC (all=0.935; test=0.947), lower sensitivity (all=81.79%; test=78.85%), and similar specificity (all=91.51%; test=90.68%).ConclusionsThe removal of BEs controls false positive ASVs in the differential abundance analysis. However, their elimination implies a significantly larger number of predictor taxa to achieve optimal performance, creating less robust classifiers. As all the provided models can accurately discriminate health from periodontitis, implying good/excellent sensitivities/specificities, the salivary microbiome demonstrates potential clinical applicability as a precision diagnostic tool for periodontitis.

Background: Human T-lymphotropic viruses (HTLV)-1 infection is endemic in many countries of Central and South America and Caribbean (CSA&C). Neither screening nor surveillance programs exist for HTLV-1/2 infection among pregnant women in this region. Neither in Western nations with large migrant flows from HTLV-1/2 endemic regions. Methods: Systematic review and meta-analysis of the prevalence of HTLV-1/2 infection among CSA&C pregnant women. We included studies searching EMBASE, PubMed/MEDLINE, Scopus, and Web of Science from inception to February 15, 2023. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Results: We identified a total of 620 studies. Only 41 were finally included in the meta-analysis. Most studies (61.0%) were from Brazil and Peru (14.6%). The total number of participants was 343,707. The pooled prevalence of HTLV-1/2 infection among CSA&C pregnant women was 1.30% (95% CI: 0.96-1.69) using anti-HTLV-1/2 antibody screening tests. There was a high heterogeneity (I2 = 98.6%). Confirmatory tests gave an HTLV-1 infection rate of 1.02% (95% CI: 0.75-1.33). Conclusions: The prevalence of HTLV-1/2 infection among CSA&C pregnant women is 1.3%, most cases being HTLV-1. This rate is greater than for other microbial agents regularly checked as part of antenatal screening (such as HIV, hepatitis B, or syphilis). Thus, HTLV-1/2 antenatal testing should be mandatory among CSA&C pregnant women everywhere.

Abstract Background In Spain, the risk of imported malaria has increased in recent years due to the rise in international travel and migration. Little is known about the knowledge, information sources, clinical practice, and specific needs of primary care physicians (PCPs) concerning malaria despite the pivotal role played by these professionals in managing the health of tourists. The objective of this study was to assess the knowledge, attitudes, and practices of PCPs in Spain regarding malaria. Methods This research analyses data from (1) a cross-sectional nationwide survey assessing the knowledge and attitudes of PCPs regarding malaria, and (2) a retrospective review of 373 malaria cases appearing in primary care medical records (PCMRs) in the Madrid area over the past 15 years to determine how cases were documented, managed, or characterized in the primary care setting. Results The survey findings reveal a modest level of self-perceived familiarity with malaria (221/360, 57.6%), even though 32.8% of the practitioners reported having delivered care for confirmed or suspected cases of the disease, these practitioners had greater knowledge of malaria (80.4%) compared to physicians who reported not having delivered care for malaria (19.6%, p

Abstract Tryptophan metabolism through the kynurenine pathway influences molecular processes critical to healthy aging including immune signaling, redox homeostasis, and energy production. Aberrant kynurenine metabolism occurs during normal aging and is implicated in many age-associated pathologies including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. We and others previously identified three kynurenine pathway genes—tdo-2, kynu-1, and acsd-1—for which decreasing expression extends lifespan in invertebrates. Here we report that knockdown of haao-1, a fourth gene encoding the enzyme 3-hydroxyanthranilic acid (3HAA) dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated health decline in Caenorhabditis elegans. Lifespan extension is mediated by increased physiological levels of the HAAO substrate 3HAA. 3HAA increases oxidative stress resistance and activates the Nrf2/SKN-1 oxidative stress response. In pilot studies, female Haao knockout mice or aging wild type male mice fed 3HAA supplemented diet were also long-lived. HAAO and 3HAA represent potential therapeutic targets for aging and age-associated disease.