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Abstract Numerous genetic studies have contributed to reconstructing the human history of the Canary Islands population. The recent use of new ancient DNA targeted enrichment and next-generation sequencing techniques on new Canary Islands samples have greatly improved these molecular results. However, the bulk of the available data is still provided by the classic mitochondrial DNA phylogenetic and phylogeographic studies carried out on the indigenous, historical, and extant human populations of the Canary Islands. In the present study, making use of all the accumulated mitochondrial information, the existence of DNA contamination and archaeological sample misidentification in those samples is evidenced. Following a thorough review of these cases, the new phylogeographic analysis revealed the existence of a heterogeneous indigenous Canarian population, asymmetrically distributed across the various islands, which most likely descended from a unique mainland settlement. These new results and new proposed coalescent ages are compatible with a Roman-mediated arrival driven by the exploitation of the purple dye manufacture in the Canary Islands.

Active Bilingual Learners/Users of English (ABLE) represent a student population underserved by research even when ABLEs currently represent 10% of public-school enrollments, 78% of which speak Spanish as their native language. In Texas, the overall representation of ABLE Latinx students is 17%, and is expected to grow considerably over the next 10 years. Unfortunately, there is limited research that explores the experiences of Latinx ABLE college students (Núñez, et al., 2016) and the role that Spanish language plays in the creation of identity-affirming institutional practices. Thus, the proliferation of Latinx students at Predominantly White Institutions (PWIs) that are now Hispanic-Serving Institutions (HSIs) as well, for example, requires a deeper interrogation of institutional practices and student experiences. As a result, this study explores the experiences of 15 Spanish Native-Speaking ABLEs at an HSI in the south, called Southwestern University. We use the Nuñez’ conceptual framework of intersectionality work, to better understand the contextual influences that impact Spanish Native-Speaking ABLE’s academic experiences. We also apply a case-study methodology approach to examine Latinx student experiences at an HSI. [ABSTRACT FROM AUTHOR]

This Perspective explores the potential of nonpsychoactive cannabinoids (NPCs) such as CBD, CBG, CBC, and CBN in developing innovative biomaterials for biomedical and sports applications. It examines their physicochemical properties, anti-inflammatory, analgesic, and neuroprotective effects, and their integration into various biomaterials such as hydrogels, sponges, films, and scaffolds. It also discusses the current challenges in standardizing formulations, understanding long-term effects, and understanding their intrinsical regulatory landscapes. Further, it discusses the promising applications of NPC-loaded materials in bone regeneration, wound management, and drug delivery systems, emphasizing their improved biocompatibility, mechanical properties, and therapeutic efficacy demonstrated in vitro and in vivo . The review also addresses innovative approaches to enhance NPC delivery including the use of computational tools and explores their potential in both biomedical and sports science contexts. By providing a comprehensive overview of the current state of research, this review aims to outline future directions, emphasizing the potential of NPCs in biomaterial science and regenerative medicine.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a wide variety of symptoms, including frequent neurological and psychiatric symptomatology. Psychiatric symptoms encountered in SLE are frequent, between 37 and 95% of SLE patients present them, can appear at any point in the course of the disease and may include almost any type of disorder. We present the case of a 32-year-old woman who presented an SLE debut with catatonic symptoms without previous psychiatric history, representing a diagnostic and therapeutic challenge given that the diagnosis was initially wrongly filtered out and required up to three hospital admissions in a row to reach a proper diagnosis and treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Type I Alexander disease (AxD) presents with paroxysmal neurodegeneration, refractory epilepsy, and encephalopathy in the first years of life and is associated with a poor prognosis. Although there is no treatment, mild symptomatic improvement has been reported in one case of adult Alexander treated with ceftriaxone, given its interaction with the mutant glial fibrillary acid protein (GFAP) responsible for the disease's pathogenesis. We describe a patient presenting with irritability starting at 2 months of age, initially attributed to gastroesophageal reflux. A ventriculoperitoneal shunt was placed at 3 months of age due to hydrocephalus secondary to aqueduct stenosis detected through an MRI scan, but the irritability persisted. At 5 months, a new brain MRI was performed due to irritability worsening, onset of abnormal ocular movements and seizures. In addition genetic testing was performed. AxD was diagnosed due to the mutation c.716G>A (p.Arg239His) in GFAP. Since irritability had worsened and had not responded to levomepromazine, treatment with amoxicillin (80 mg/kg/day) was attempted to modulate glutamate levels. The patient showed a striking improvement of irritability in 48 h that persisted over the next months. The patient had frequent daily seizures which did not respond to valproate, clonazepam, or phenobarbital. Perampanel, a postsynaptic AMPA receptor antagonist, was added to phenobarbital and he was seizure free for more than 3 months. Drugs modulating glutamate levels in the central nervous system, including β-lactam antibiotics and perampanel, may have an important role in the symptomatic treatment of AxD and other neurodegenerative diseases where glutamatergic excitotoxicity is a pathogenic determinant. PLAIN LANGUAGE SUMMARY: Alexander disease is a rare and serious condition that affects the brain, often leading to neurodegeneration (brain damage), seizures, and other problems in early childhood. The disease is caused by a mutation in a gene called GFAP. There is no cure, and current treatments mainly focus on relieving symptoms. This article discusses the case of a baby who showed signs of irritability and seizures from a young age. The baby was diagnosed with Alexander disease after brain scans and genetic testing. Despite treatment with various drugs, the baby continued to experience seizures and irritability. The doctors decided to try amoxicillin, a common antibiotic, because of its potential to help control the disease by affecting a brain chemical called glutamate. Surprisingly, the baby's irritability improved within 2 days of starting amoxicillin, and the improvement lasted for several months. However, the seizures persisted until another medication, perampanel, was added. This combination controlled the baby's seizures for over 3 months. Unfortunately, the baby passed away at 13 months due to complications from the disease. However, doctors believe that drugs like amoxicillin and perampanel could be promising treatments for managing symptoms of Alexander disease and other similar brain conditions in the future, especially where excess glutamate plays a role in the damage. This case suggests that these treatments may help control irritability and seizures, offering hope for better management of this challenging disease., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The treatment and prevention of delirium in the intensive care unit (ICU) have gained significant importance in patient care in recent years. Some studies have linked delirium with increased risks of mortality, prolonged hospital stay, and more days of mechanical ventilation. This study aims to analyze the use of psychotropic drugs initiated in the ICU and their continuation upon hospital discharge, as well as to evaluate their contribution to polypharmacy and associated adverse clinical effects., Method: A multicenter prospective observational case study was designed, focusing on patients over 18 years old admitted to the ICU and treated with psychotropic drugs. Data on demographics, variables related to admission and psychotropic drug treatment, as well as clinical outcomes and adverse effects, will be collected. Among other variables, the frequency of psychotropic treatments initiated in the ICU and continued upon discharge from the ICU and the hospital will be measured. Data collection will be performed through review of electronic medical records and prescription programs, and IBM SPSS 20.0 statistical package will be used for analysis., Discussion: Delirium is common in ICU patients and is associated with long-term negative consequences. Although antipsychotics are used to treat delirium, their prolonged use can have adverse effects, and their continuation after ICU discharge contributes to polypharmacy. This study aims to provide information on the use of psychotropic drugs initiated in the ICU and their continuation upon discharge, with the goal of identifying opportunities for intervention and reducing unnecessary use of these medications., (Copyright © 2024 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Variants in GBA1 result in dysregulated sphingolipids. We investigated five CSF d18:1 sphingolipid species in a longitudinal multicenter cohort comprising people with Parkinson's Disease and Dementia with Lewy bodies with and without GBA1 variants and healthy controls. We found no increase of sphingolipid species in heterozygous GBA1 variant participants and no effect on development of cognitive impairment. Thus, CSF d18:1 sphingolipids are not suitable as state markers in Parkinson's Disease., (© 2024. The Author(s).)

Background: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial., Patients and Methods: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety., Results: Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups., Conclusions: With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Generalism in resource use is commonly considered a critical driver of population success, species distribution and extinction risk. This idea can be questioned as generalism may be a result rather than the cause of species abundance and range size. We tested these contrasting causal hypotheses focusing on host use in three databases encompassing approximately 44,000 mutualistic (hummingbird-plant), commensalistic (lichen-plant) and parasitic (flea-mammal) interactions in 617 ecological communities across the Americas and Eurasia. Across all interaction types, our analyses indicated that range size and abundance influence the probability of encountering hosts and set the arena for species to express generalism potentials or adapt to new hosts. Hence, our findings support the hypothesis that generalism is a consequence of species ecological success. This highlights the importance of ecological opportunity in driving species characteristics considered key for their survival and conservation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The use of technological innovations in ST elevation myocardial infarction (STEMI) care networks has been shown to be effective in improving information flow and coordination, and thus reducing the time to reperfusion. We developed a smartphone application called ODISEA to improve our STEMI care network and evaluated the results of its use., Method: Quasi-experimental study that compared the outcomes of STEMI suspected patients with an alert and indication for transfer to a cath lab during a previous period and a period in which the ODISEA APP was used. The main objective was to examine differences in reperfusion time and the proportion of patients with a final diagnosis other than acute coronary syndrome., Results: A total of 699 patients were included (415 before and 284 during the ODISEA-APP period). No differences were observed in patient characteristics, infarct type, or acute complications. We observed a reduction in the time from diagnostic ECG to wire crossing with the use of the ODISEA APP (117 vs 102 min, p < 0.001) and a reduction in the percentage of patients with a final diagnosis other than acute coronary syndrome (17.1% vs 9.5%, p = 0.004)., Conclusions: The use of the ODISEA APP in the management of patients with suspected STEMI may be useful for reducing the time from diagnostic ECG to wire crossing and the percentage of patients with a final diagnosis other than acute coronary syndrome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: To investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative study., Design: Pooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined., Setting: Children aged 0-18 years from 26 European birth cohorts., Participants: 136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood., Main Outcome Measure: Questionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV 1 ), FEV 1 /forced vital capacity) at age 6-18 years., Results: Questionnaire-based and accelerometry-based PA and sedentary behaviour at age 3-5 years was not associated with asthma at age 6-18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results., Conclusions: Reduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mutations in GBA1, encoding glucocerebrosidase beta 1 (GCase), are the most common genetic risk factor for Parkinson's disease (PD). GCase dysfunction leads to an accumulation of glucosylceramide (GluCer) substrates in different organs and fluids. Despite the challenges in quantifying GluCer isoforms in biological samples, their potential clinical interest as PD biomarkers justifies the development of robust assays. An extensively evaluated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for quantifying 14 GluCer and galactosylceramide (GalCer) isoforms in human cerebrospinal fluid (CSF) samples is presented. Sample pretreatment, HPLC, and MS/MS parameters were optimized. Evaluation was performed according to the recommendations of the Clinical and Laboratory Standards Institute and European Medicines Agency guidelines. Four 7-point calibration curves were generated, with a linearity interval from 2.5 to 200 nM ( R 2 ≥ 0.995). The limit of quantification was set at 5 nM. Between-run precision and accuracy were up to 12.5 and 9%, respectively. After method validation, we measured the levels of GluCer and GalCer isoforms in CSF human samples, including 6 healthy controls (HC), 22 idiopathic GBA1 wild-type PD (iPD) patients, and 5 GBA1-associated PD (PD-GBA) patients. GluCer/GalCer median ratios were found to be higher in the CSF of PD-GBA patients, particularly in severe GBA1 mutations, than those in iPD and HC. The observed trends in GluCer/GalCer ratios among groups provide novel information for the comprehensive analysis of sphingolipids as potential biomarkers of PD.

Objectives: This case series aims to evaluate the long-term outcomes of congenital cytomegalovirus (CMV) infection in a population treated with valaciclovir during pregnancy. The study focuses on assessing the prevalence of long-term sequelae in infants with confirmed CMV fetal infection., Methods: A retrospective analysis was conducted on 33 pregnancies corresponding to 34 fetus with confirmed CMV congenital infection. They were followed from November 2004 to December 2020. Valaciclovir treatment was initiated after confirmation of fetal infection, and fetal outcomes were monitored through serial ultrasounds, neurosonography, and fetal magnetic resonance imaging (MRI). Postnatal assessments included: PCR confirmation, symptoms evaluation at birth, and long-term follow-up protocols for visual, auditory, and neurodevelopmental assessment., Results: Therapy was started at a median gestational age of 24 weeks. Of the 34 newborns 79.4 % were asymptomatic at birth. Median follow-up time was 6 years and 32.35 % developed long-term sequelae. Neurosensorial hearing loss (SNHL) was the predominant sequelae. In the cases which developed sequelae 54.5 % had imaging findings, and all with major findings developed long-term sequelae., Conclusions: In our treated population we had a higher asymptomatic rate at birth comparing with a non-treated population, similar to those found in previous studies. We had a long-term sequelae rate of 32.35 %, similar to recent studies on non-treated population, although we registered a slightly lower rate of SNHL. A larger multicenter studies with a longer follow-up time, where treatment is started in the first trimester, is of the utmost importance, so we can truly understand the correlation between these imaging findings, therapy and long-term sequelae., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: In patients with clinically lymph node-negative (cN0) breast cancer, performing sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NACT) has been preferentially embraced in comparison to before NACT. However, survival outcomes associated with both strategies remain understudied. We aimed to compare the axillary lymphadenectomy (ALND) rate, disease-free survival (DFS), and overall survival (OS), between two strategies., Methods: We included 310 patients in a retrospective observational study. SNLB was performed before NACT from December 2006 to April 2014 (107 cases) and after NACT from May 2014 to May 2020 (203 patients). An inverse probability of treatment weighting (IPTW) method was applied to homogenize both groups. Hazard ratios (HR) and odd ratios (OR) are reported with 95% confidence intervals (95%CI)., Results: The lymphadenectomy rate was 29.9% before NACT and 7.4% after NACT (p < 0.001), with an OR of 5.35 95%CI (2.7-10.4); p = .002. After 4 years of follow-up, SLNB after NACT was associated with lower risk for DFS, HR 0.42 95%CI (0.17-1.06); p = 0.066 and better OS, HR 0.21 CI 95% (0.07-0.67); p = 0.009 than SLNB before NACT. After multivariate analysis, independent adverse prognostic factors for OS included SLNB before NACT, HR 3.095 95%CI (2.323-4.123), clinical nonresponse to NACT, HR 1.702 95% CI (1.012-2.861), and small tumors (cT1) with high proliferation index, HR 1.889 95% (1.195-2.985)., Conclusion: Performing SLNB before NACT results in more ALND and has no benefit for patient survival. These findings support discontinuing the practice of SLNB before NACT in patients with cN0 breast cancer., (© 2024. The Author(s).)

Background: Cancer patients often have weakened immune systems, resulting in a lower response to vaccines, especially those receiving immunosuppressive oncological treatment (OT). We aimed to assess the impact of OT on the humoral and T-cell response to the B.1 lineage and Omicron variant following COVID-19 vaccination in patients with solid and hematological neoplasms., Methods: We conducted a prospective study on cancer patients, stratified into OT and non-OT groups, who received a two-dose series of the COVID-19 mRNA vaccine and a booster six months later. The outcomes measured were the humoral (anti-SARS-CoV-2 S IgG titers and ACE2-S interaction inhibition capacity) and cellular (SARS-CoV-2 S-specific T-cell spots per million PBMCs) responses against the B.1 lineage and Omicron variant. These responses were evaluated four weeks after the second dose (n = 98) and eight weeks after the booster dose (n = 71)., Results: The humoral response after the second vaccine dose against the B.1 lineage and Omicron variant was significantly weaker in the OT group compared to the non-OT group (q-value<0.05). A booster dose of the mRNA-1273 vaccine significantly improved the humoral response in the OT group, making it comparable to the non-OT group. The mRNA-1273 vaccine, designed for the original Wuhan strain, elicited a weaker humoral response against the Omicron variant compared to the B.1 lineage, regardless of oncological treatment or vaccine dose. In contrast, T-cell responses against SARS-CoV-2, including the Omicron variant, were already present after the second vaccine dose and were not significantly affected by oncological treatments., Conclusions: Cancer patients, particularly those receiving immunosuppressive oncological treatments, should require booster doses and adapted COVID-19 vaccines for new SARS-CoV-2 variants like Omicron. Future studies should evaluate the durability of the immune response and the efficacy of individualized regimens., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: We aimed to assess IgG antibodies against the SARS-CoV-2 spike protein (anti-SARS-CoV-2 S IgG) in vaccinated mothers and their infants at delivery and 2-3 months of age., Methods: We conducted a prospective study on mothers who received at least one dose of the COVID-19 vaccine (Pfizer-BNT162b2, Moderna mRNA-1273, or Oxford-AstraZeneca ChAdOx1-S) during pregnancy and on their infants. The baseline was at the time of delivery (n = 93), and the end of follow-up was 2 to 3 months post-partum (n = 53). Serum anti-SARS-CoV-2 S IgG titers and ACE2 binding inhibition levels were quantified by immunoassays., Results: Mothers and infants had high anti-SARS-CoV-2 S IgG titers against the B.1 lineage at birth. However, while antibody titers were maintained at 2-3 months post-partum in mothers, they decreased significantly in infants (p < 0.001). Positive and significant correlations were found between anti-SARS-CoV-2 S IgG titers and ACE2-binding inhibition levels in mothers and infants at birth and 2-3 months post-partum (r > 0.8, p < 0.001). Anti-S antibodies were also quantified for the Omicron variant at 2-3 months post-partum. The antibody titers against Omicron were significantly lower in mothers and infants than those against B.1 (p < 0.001). Again, a positive correlation was observed for Omicron between IgG titers and ACE2-binding inhibition both in mothers (r = 0.818, p < 0.001) and infants (r = 0.386, p < 0.005). Previous SARS-CoV-2 infection and COVID-19 vaccination near delivery positively impacted anti-SARS-CoV-2 S IgG levels., Conclusions: COVID-19 mRNA vaccines induce high anti-SARS-CoV-2 S titers in pregnant women, which can inhibit the binding of ACE2 to protein S and are efficiently transferred to the fetus. However, there was a rapid decrease in antibody levels at 2 to 3 months post-partum, particularly in infants., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Early life environmental stressors play an important role in the development of multiple chronic disorders. Previous studies that used environmental risk scores (ERS) to assess the cumulative impact of environmental exposures on health are limited by the diversity of exposures included, especially for early life determinants. We used machine learning methods to build early life exposome risk scores for three health outcomes using environmental, molecular, and clinical data., Methods: In this study, we analyzed data from 1622 mother-child pairs from the HELIX European birth cohorts, using over 300 environmental, 100 child peripheral, and 18 mother-child clinical markers to compute environmental-clinical risk scores (ECRS) for child behavioral difficulties, metabolic syndrome, and lung function. ECRS were computed using LASSO, Random Forest and XGBoost. XGBoost ECRS were selected to extract local feature contributions using Shapley values and derive feature importance and interactions., Results: ECRS captured 13%, 50% and 4% of the variance in mental, cardiometabolic, and respiratory health, respectively. We observed no significant differences in predictive performances between the above-mentioned methods.The most important predictive features were maternal stress, noise, and lifestyle exposures for mental health; proteome (mainly IL1B) and metabolome features for cardiometabolic health; child BMI and urine metabolites for respiratory health., Conclusions: Besides their usefulness for epidemiological research, our risk scores show great potential to capture holistic individual level non-hereditary risk associations that can inform practitioners about actionable factors of high-risk children. As in the post-genetic era personalized prevention medicine will focus more and more on modifiable factors, we believe that such integrative approaches will be instrumental in shaping future healthcare paradigms., (© 2024. The Author(s).)

This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention-deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population-based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome-wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age-related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3-way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability., (© 2024 The Authors. Developmental Psychobiology published by Wiley Periodicals LLC.)

Lemon verbena has been shown to ameliorate obesity-related oxidative stress, but the intracellular final effectors underlying its antioxidant activity are still unknown. The purpose of this study was to correlate the antioxidant capacity of plasma metabolites of lemon verbena (verbascoside, isoverbascoside, hydroxytyrosol, caffeic acid, ferulic acid, homoprotocatechuic acid, and luteolin-7-diglucuronide) with their uptake and intracellular metabolism in hypertrophic adipocytes under glucotoxic conditions. To this end, intracellular ROS levels were measured, and the intracellular metabolites were identified and quantified by high-performance liquid chromatography with a diode array detector coupled to mass spectrometry (HPLC-DAD-MS). The results showed that the plasma metabolites of lemon verbena are absorbed by adipocytes and metabolized through phase II reactions and that the intracellular appearance of these metabolites correlates with the decrease in the level of glucotoxicity-induced oxidative stress. It is postulated that the biotransformation and accumulation of these metabolites in adipocytes contribute to the long-term antioxidant activity of the extract.

Introduction: Outcomes for silver coated megaprostheses (SC-MP) used in cases of end-stage periprosthetic joint infection (PJI) have not been clearly defined. Although attractive, concerns over implant longevity and the risk of infection relapse exist among the scientific community. Therefore, we sought to investigate the effect of silver coating in lower-extremity MPs used in such difficult-to-treat scenarios. The study's primary hypothesis was that the periprosthetic infection control rate would be higher in patients with silver-coated implants., Materials and Methods: Non-interventional retrospective study with a historical comparison group. We identified all consecutive end-stage hip and knee PJI cases at our center managed with exchange arthroplasty using a silver-coated megaprosthesis from January 2016 to March 2021, these cases were compared with a historical cohort of end-stage PJI cases managed with uncoated megaprostheses. The main outcome studied was infection control rate. Secondarily, we analyzed the short-to-medium-term survivorship of this type of silver-coated implant., Results: Fifty-nine megaprostheses used in cases of end-stage PJI were included in this study. We identified 30 cases of chronic hip or knee PJI in which a silver-coated modular megaprosthesis was implanted. Our non-coated megaprosthesis (NC-MP) historical group included 29 patients. Both groups had similar demographic characteristics. We found no statistically significant differences in infection control rate (80% vs. 82.8%, p = 0.47) or implant survivorship (90% vs. 89.65%, p = 1) after a mean follow-up for SC-MP of 46.43 months, and 48 months for the non-coated MP group. In relapsed cases, there were no differences in infection eradication after DAIR (66% SC-MP vs. 60% NC-MP success rate, p = 1). During the follow-up we observed one case of skin argyria without further repercussion., Conclusion: We were unable to confirm our initial hypothesis that use of silver-coated implants in end-stage PJI scenarios may be associated with better outcomes in terms of infection control or implant survivorship., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Zebrafish larvae have emerged as a valuable model for studying heart physiology and pathophysiology, as well as for drug discovery, in part thanks to its transparency, which simplifies microscopy. However, in fluorescence-based optical mapping, the beating of the heart results in motion artifacts. Two approaches have been employed to eliminate heart motion during calcium or voltage mapping in zebrafish larvae: the knockdown of cardiac troponin T2A and the use of myosin inhibitors. However, these methods disrupt the mechano-electric and mechano-mechanic coupling mechanisms. We have used ratiometric genetically encoded biosensors to image calcium in the beating heart of intact zebrafish larvae because ratiometric quantification corrects for motion artifacts. In this study, we found that halting heart motion by genetic means (injection of tnnt2a morpholino) or chemical tools (incubation with para -aminoblebbistatin) leads to bradycardia, and increases calcium levels and the size of the calcium transients, likely by abolishing a feedback mechanism that connects contraction with calcium regulation. These outcomes were not influenced by the calcium-binding domain of the gene-encoded biosensors employed, as biosensors with a modified troponin C (Twitch-4), calmodulin (mCyRFP1-GCaMP6f), or the photoprotein aequorin (GFP-aequorin) all yielded similar results. Cardiac contraction appears to be an important regulator of systolic and diastolic Ca 2+ levels, and of the heart rate.

Objective: To investigate intermediate-term clinical results in patients with concomitant anterior cruciate ligament (ACL) reconstruction and chondral defect treated with high-density autologous chondrocyte implantation (HD-ACI) compared to patients without ACL tear but with a chondral lesion and HD-ACI treatment., Design: Forty-eight patients with focal chondral lesions underwent HD-ACI (24 with ACL reconstruction after an ACL injury and 24 with an intact ACL). Follow-up assessments occurred at 6, 12, and 24 months. Patient-reported knee function and symptoms were assessed using the International Knee Documentation Committee (IKDC) questionnaire, pain was measured using the Visual Analog Scale (VAS), and adverse events were monitored. Physical activity was assessed using the Tegner Activity Level Scale, and cartilage healing was evaluated with the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score., Results: No significant adverse events occurred during follow-up. Both groups showed significant improvements at 2 years compared to baseline (VAS: 8.0 ± 1.3 to 1.4 ± 2.0 [normal ACL]; 7.4 ± 2.3 to 2.1 ± 2.3 [ACL reconstruction]; IKDC: 39.2 ± 10.6 to 76.1 ± 22.0 [intact ACL]; 35.6 ± 12.1 to 74.6 ± 20.9 [ACL reconstruction]). Patients in both groups exceeded the minimal clinically important difference (MCID) for IKDC scores. The Tegner Activity Level Scale decreased immediately after surgery and increased after 2 years, with 70.6% (normal ACL) and 89.5% (ACL reconstruction) returning to their preinjury activity levels. No significant differences in the MOCART score were observed between the groups., Conclusions: ACL reconstruction does not appear to reduce the outcomes (at 2 years) of HD-ACI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: New drugs developed for SARS-CoV-2 infection, such as nirmatrelvir/ritonavir (NMV/r), represent a potential for oncohematology patients, but also pose a challenge in managing the potential clinically relevant drug-drug interactions (pDDIs) that may arise. The aim of this study is to assess the frequency, severity, and pharmacist detection of pDDIs., Methods: This prospective, observational, study spanned 8 months, involving 42 oncohematology patients prescribed NMV/r in a tertiary-level hospital. A Board Certified oncology pharmacist assessed pDDIs using three databases and made recommendations to prescribing physicians. Linear and logistic regression analyses were employed to explore the relationship between prescribed drugs and pDDIs., Results: Clinically relevant pDDIs were detected in 76.2% of patients, with 18.1% of all medications involved in drug-drug interactions (DDIs). The most common drugs implicated were atorvastatin and imatinib. Micromedex® identified 63.3% of interactions as major severity, while Lexicomp® and University of Liverpool classifications were less restrictive. Pharmacists prevented most DDIs from reaching patients through different interventions, including treatment monitoring (44.2%), discontinuation (36.5%), and dose reduction (17.3%)., Conclusion: This study highlights the high prevalence of clinically significant pDDIs in oncohematology patients receiving NMV/r for COVID-19. Pharmacists, as integral members of the healthcare team, played a crucial role in detecting, categorizing, and mitigating these interactions. The results underscore the need for comprehensive studies to evaluate the impact of pharmacist-led interventions in optimizing drug therapy and enhancing patient safety in this vulnerable population., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Chemical exposures often occur in mixtures and exposures during pregnancy may lead to adverse effects on the fetal brain, potentially reducing lower cognitive abilities and fine motor function of the child. We investigated the association of motheŕs exposure to a mixture of chemicals during pregnancy (i.e., organochlorine compounds, per- and polyfluoroalkyl substances, phenols, phthalates, organophosphate pesticides) with cognitive abilties and fine motor function in their children. We studied 1097 mother-child pairs from five European cohorts participating in the Human Early Life Exposome study (HELIX). Measurement of 26 biomarkers of exposure to chemicals was performed on urine or blood samples of pregnant women (mean age 31 years). Cognitive abilities and fine motor function were assessed in their children (mean age 8 years) with a battery of computerized tests administered in person (Raveńs Coloured Progressive Matrices, Attention Network Test, N-back Test, Trail Making Test, Finger Tapping Test). We estimated the joint effect of prenatal exposure to chemicals on cognitive abilities and fine motor function using the quantile-based g-computation method, adjusting for sociodemographic characteristics. A quartile increase in all the chemicals in the overall mixture was associated with worse fine motor function, specifically lower scores in the Finger Tapping Test [-8.5 points, 95 % confidence interval (CI) -13.6 to -3.4; -14.5 points, 95 % CI -22.4 to -6.6, and -18.0 points, 95 % CI -28.6 to -7.4) for the second, third and fourth quartile of the overal mixture, respectively, when compared to the first quartile]. Organochlorine compounds, phthalates, and per- and polyfluoroalkyl substances contributed most to this association. We did not find a relationship with cognitive abilities. We conclude that exposure to chemical mixtures during pregnancy may influence neurodevelopment, impacting fine motor function of the offspring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: Nirmatrelvir/ritonavir may cause a clinically relevant drug-drug interaction (DDI) with immunosuppressive drugs, such as tacrolimus, which may condition the use of this antiviral in transplant patients. We aimed to describe the management of this interaction., Methods: Descriptive study in which renal transplant patients in treatment with nirmatrelvir/ritonavir and tacrolimus were included. They suspended tacrolimus the day before starting the antiviral treatment, and the decision to restart it was made based on their tacrolimus blood levels. Main variables studied to measure this DDI were tacrolimus blood concentration, dose adjustment and serum creatinine., Results: Three patients were included. During the study, tacrolimus levels elevation did not have repercussion in the serum creatinine, that remained stable in all patients. No patient required hospitalisation or showed signs of rejection., Conclusions: Our experience provides further evidence that this interaction should not be a contraindication to treatment with nirmatrelvir/ritonavir, and can be managed with close monitoring of tacrolimus levels., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In April 2022, after a year of COVID-19 vaccination, there were large differences in coverage between urban and rural areas in Guatemala. To address barriers in rural communities, the "Health on Wheels" (HoW) strategy was implemented. The strategy deployed mobile brigades with a dedicated team of health workers and a culturally sensitive health promotion plan in selected communities in 15 districts in Alta Verapaz, a health area with low COVID-19 vaccination uptake and a high-level of COVID-19 vaccine hesitancy. This study evaluates the impact of the HoW strategy., Methods: We measured the relative increase in COVID-19 doses administered prior and during the HoW implementation period in the 190 intervened communities and compared to 188 communities without the intervention. Communities were grouped by health district and the impact analyses were stratified by number of COVID-19 vaccine dose (1st, 2nd, and 3rd doses) and history of vaccine hesitancy., Results: The increase in 1st, 2nd, and 3rd dose-COVID-19 vaccination coverage between before and during HoW implementation was 2.4, 2.2 and 2.6 times higher in intervened communities (20 %, 21 % and 37 % increase in 1st, 2nd and 3rd dose, respectively) than in non-intervened communities (8 %, 10 % and 14 % increase in 1st, 2nd and 3rd dose respectively). For the 1st dose, increase in dose administration was 2.9 times higher in intervened communities (n = 24) with hesitancy (24 % increase) compared to non-intervened communities (n = 188) without hesitancy (8 % increase)., Conclusion: The deployment of mobile brigades with a dedicated team of vaccinators and culturally sensitive health promotion through the HoW strategy successfully accelerated the increase in COVID-19 vaccination coverage in rural communities in Guatemala., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) stand as the prevailing sources of neurodegenerative dementia, impacting over 55 million individuals across the globe. Patients with AD and DLB exhibit a higher prevalence of epileptic activity compared to those with other forms of dementia. Seizures can accompany AD and DLB in early stages, and the associated epileptic activity can contribute to cognitive symptoms and exacerbate cognitive decline. Aberrant neuronal activity in AD and DLB may be caused by several mechanisms that are not yet understood. Hyperexcitability could be a biomarker for early detection of AD or DLB before the onset of dementia. In this review, we compare and contrast mechanisms of network hyperexcitability in AD and DLB. We examine the contributions of genetic risk factors, Ca 2+ dysregulation, glutamate, AMPA and NMDA receptors, mTOR, pathological amyloid beta, tau and α-synuclein, altered microglial and astrocytic activity, and impaired inhibitory interneuron function. By gaining a deeper understanding of the molecular mechanisms that cause neuronal hyperexcitability, we might uncover therapeutic approaches to effectively ease symptoms and slow down the advancement of AD and DLB., 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 Vicente, Addo-Osafo and Vossel.)

The Sepetiba Bay (Southeast Brazil) is a known Cd- and Zn-contaminated site that received spills of a large slag pile leachate from a Zn smelter. With important harbors, Sepetiba Bay demands periodic dredging operations which affect the mobility of the metals. The main goal of this work was to assess metal mobility in sediments and its associated toxicity in a fictive dredging area, to evaluate the risks of the operation. To achieve this goal, 18 superficial sediment samples were collected and characterized for pH and Eh. Sediments were analyzed for grain size, organic carbon, and total nitrogen, and metal mobility was evaluated with a sequential extraction procedure, proposed by the European Community Bureau of Reference (BCR). The results demonstrate that Cd and Zn are mainly associated with the exchangeable fraction (mean concentrations 1.4 mg kg -1 and 149.4 mg kg -1 , respectively) and reducible fractions (mean concentrations 0.3 mg kg -1 and 65.5 mg kg -1 , respectively), while Fe, Cr, Cu, Ni, and Al were associated with the residual fraction. Metals in the residual fraction are probably associated with the mineral lattice of the sediment and should not represent an environmental risk for the biota. The application of the enrichment factor and three risk assessment indexes (Risk Assessment Code, Risky Pollution Index, and Bioavailability Risk Assessment Index) show that the sediments are considerably enriched in metals that constitute a relevant risk for the sediment biota. In the case of dredging operations, Cd and Zn should be released to the overlying waters and be available to organisms, threatening the whole ecosystem. The proposed approach was shown to be much more precise than what is frequently presented in the Environmental Impact Assessments that only consider the threshold limits of the legislation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Bradyarrhythmias result from inhibition of automaticity, prolonged repolarization, or slow conduction in the heart. The ERG channels mediate the repolarizing current I Kr in the cardiac action potential, whereas T-type calcium channels (TTCC) are involved in the sinoatrial pacemaker and atrioventricular conduction in mammals. Zebrafish have become a valuable research model for human cardiac electrophysiology and disease. Here, we investigate the contribution of ERG channels and TTCCs to the pacemaker and atrioventricular conduction in zebrafish larvae and determine the mechanisms causing atrioventricular block., Methods: Zebrafish larvae expressing ratiometric fluorescent Ca 2+ biosensors in the heart were used to measure Ca 2+ levels and rhythm in beating hearts in vivo, concurrently with contraction and hemodynamics. The atrioventricular delay (the time between the start of atrial and ventricular Ca 2+ transients) was used to measure impulse conduction velocity and distinguished between slow conduction and prolonged refractoriness as the cause of the conduction block., Results: ERG blockers caused bradycardia and atrioventricular block by prolonging the refractory period in the atrioventricular canal and in working ventricular myocytes. In contrast, inhibition of TTCCs caused bradycardia and second-degree block (Mobitz type I) by slowing atrioventricular conduction. TTCC block did not affect ventricular contractility, despite being highly expressed in cardiomyocytes. Concomitant measurement of Ca 2+ levels and ventricular size showed mechano-mechanical coupling: increased preload resulted in a stronger heart contraction in vivo., Conclusion: ERG channels and TTCCs influence the heart rate and atrioventricular conduction in zebrafish larvae. The zebrafish lines expressing Ca 2+ biosensors in the heart allow us to investigate physiological feedback mechanisms and complex arrhythmias., (© 2023 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Purpose: To assess whether erythropoiesis-stimulating agents (ESA) administration impacts the outcomes of patients with HER2-positive early breast cancer (EBC)., Methods: ALTTO (NCT00490139) patients were categorized by ESA use during adjuvant anti-HER2 treatment. Disease-free-survival (DFS), overall survival (OS), and time-to-distant recurrence (TTDR) were analyzed by ESA administration, with subgroup analyses according to prognostic factors. Log-rank tests and Cox modeling were performed. Adverse events (AEs) of ESA-interest were compared., Results: Among 8381 patients recruited in ALTTO, 123 (1.5%) received ESA concomitantly with study treatment. The median age of patients receiving ESA was 54 years, 39.0% premenopausal, most had tumor size > 2 cm (56.9%), node-positive (58.5%), and positive estrogen receptor expression (61.8%). Median follow-up was shorter in the ESA group [6.1 years (IQR 5.3-7.0) vs. 6.9 years (6.0-7.1); p < 0.001]. There was no DFS difference by ESA administration (log-rank p = 0.70), with 3- and 7-year DFS of 89.2% (95% CI 81.8-93.8%) and 81.6% (71.4-88.5%) in ESA group vs. 88.3% (87.6-89.0%) and 80.0% (79.1-80.9%) in No-ESA group. In subgroup analyses, the interaction of ESA administration with menopausal status was statistically significant (unadjusted p = 0.024; stratified p = 0.033), favoring premenopausal women receiving ESA. We observed no significant association of ESA administration with OS (log-rank p = 0.57; 7-year OS in ESA 88.6% vs. 90.0% in non-ESA) or TTDR. ESA-interest AEs were experienced by eight (6.5%) patients receiving ESA and 417 (5.1%) in the No-ESA group (p = 0.41)., Conclusion: ESA administration to patients receiving adjuvant anti-HER2 treatment for HER2-positive EBC was safe and not associated with a negative impact on survival outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Around 57,000 people in Spain and Portugal currently living with HIV or chronic hepatitis C are unaware of their infection. The COVID-19 pandemic severely disrupted screening efforts for these infections. We designed an intervention to increase and sustain opportunistic blood-borne virus (BBV) screening and linkage to care (SLTC) by implementing the TEST model., Methods: The Plan Do Study Act (PDSA) method of quality improvement (QI) was implemented in 8 healthcare organizations (HCOs), including four hospitals, two clusters of community health centers, and two community-based organizations (CBOs). Baseline assessment included a review of BBV SLTC practices, testing volume, and results 12 months before the intervention. Changes in BBV testing rates over time were measured before, during, and after the COVID-19 lockdowns in 2020. A mixed ANOVA model was used to analyze the possible effect on testing volumes among HCOs over the three study periods., Intervention: BBV testing was integrated into normal clinical flow in all HCOs using existing clinical infrastructure and staff. Electronic health record (EHR) systems were modified whenever possible to streamline screening processes, implement systemic institutional policy changes, and promote QI., Results: Two years after the launch of the intervention in screening practices, testing volumes increased by 116%, with formal healthcare settings recording larger increases than CBOs. The start of the COVID-19 lockdowns was accompanied by a global 60% decrease in testing in all HCOs. Screening emergency department patients or using EHR systems to automate screening showed the highest resilience and lowest reduction in testing. HCOs recovered 77% of their testing volume once the lockdowns were lifted, with CBOs making the fullest recovery. Globally, enhanced screening techniques enabled HCOs to diagnose a total of 1,860 individuals over the research period., Conclusions: Implementation of the TEST model enabled HCOs to increase and sustain BBV screening, even during COVID-19 lockdowns. Although improvement in screening was noted in all HCOs, additional work is needed to develop strong patient linkage to care models in challenging times, such as global pandemics., Competing Interests: DM owns stock in and is an employee of Gilead Sciences. Data collection and management were conducted independently, with additional oversight of independent data monitoring agencies. The remaining 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 Vaz-Pinto, Ortega, Chivite, Butí, Turnes-Vázquez, Magno-Pereira, Rocha, Garrido, Esteves-Santos, Guimaraes, Mourão, Martínez Roma, Guilera, Llaneras-Artigues, Barreira-Díaz, Pérez Cachafeiro, Daponte Angueira, Xavier, Vicente, Garrido, Heredia, Medina and García Deltoro.)