COVID-19 infection and 2-year mortality in nursing home residents who survived the first wave of the pandemic.

BACKGROUND: During the first COVID-19 pandemic wave (1st CoPW), nursing homes (NHs) experienced a high rate of COVID-19 infection and death. Residents who survived the COVID-19 infection may have become frailer. This study aimed to determine the predictive value of having a COVID-19 infection during the 1st CoPW for 2-year mortality in NH residents. METHODS: This was a retrospective study conducted in three NHs. Residents who had survived the 1st CoPW (March to May 2020) were included. The diagnosis of COVID-19 was based on the results of a positive reverse transcriptase-polymerase chain reaction test. The collected data also included age, sex, length of residence in the NH, disability status, legal guardianship status, nutritional status, need for texture-modified food, hospitalization or Emergency Department visits during lockdown and SARS-COV2 vaccination status during the follow-up. Non-adjusted and adjusted Cox models were used to analyse factors associated with 2-year post-1st CoPW mortality. RESULTS: Among the 315 CoPW1 survivors (72% female, mean age 88 years, 48% with severe disability), 35% presented with COVID-19. Having a history of COVID-19 was not associated with 2-year mortality: hazard ratio (HR) [95% confidence interval] = 0.96 [0.81-1.13], p = 0.62. The factors independently associated with 2-year mortality were older age (for each additional year, HR = 1.05 [1.03-1.08], p < 0.01), severe disability vs. moderate or no disability (HR = 1.35 [1.12-1.63], p < 0.01) and severe malnutrition vs. no malnutrition (HR = 1.29 [1.04-1.60], p = 0.02). Considering that vaccination campaign started during the follow-up, mortality was associated with severe malnutrition before and severe disability after the start of the campaign. Vaccination was independently associated with better survival (HR 0.71 [0.55-0.93], p = 0.02). CONCLUSIONS: Having survived a COVID-19 infection during the 1st CoPW did not affect subsequent 2-year survival in older adults living in NHs. Severe malnutrition and disability remained strong predictor of mortality in this population, whereas vaccination was associated to better survival.

Nanotopography Influences Host-Pathogen Quorum Sensing and Facilitates Selection of Bioactive Metabolites in Mesenchymal Stromal Cells and Pseudomonas aeruginosa Co-Cultures.

Orthopedic implant-related bacterial infections and resultant antibiotic-resistant biofilms hinder implant-tissue integration and failure. Biofilm quorum sensing (QS) communication determines the pathogen colonization success. However, it remains unclear how implant modifications and host cells are influenced by, or influence, QS. High aspect ratio nanotopographies have shown to reduce biofilm formation of Pseudomonas aeruginosa, a sepsis causing pathogen with well-defined QS molecules. Producing such nanotopographies in relevant orthopedic materials (i.e., titanium) allows for probing QS using mass spectrometry-based metabolomics. However, nanotopographies can reduce host cell adhesion and regeneration. Therefore, we developed a polymer (poly(ethyl acrylate), PEA) coating that organizes extracellular matrix proteins, promoting bioactivity to host cells such as human mesenchymal stromal cells (hMSCs), maintaining biofilm reduction. This allowed us to investigate how hMSCs, after winning the race for the surface against pathogenic cells, interact with the biofilm. Our approach revealed that nanotopographies reduced major virulence pathways, such as LasR. The enhanced hMSCs support provided by the coated nanotopographies was shown to suppress virulence pathways and biofilm formation. Finally, we selected bioactive metabolites and demonstrated that these could be used as adjuncts to the nanostructured surfaces to reduce biofilm formation and enhance hMSC activity. These surfaces make excellent models to study hMSC-pathogen interactions and could be envisaged for use in novel orthopedic implants.

An In Vitro Model of the Blood-Brain Barrier for the Investigation and Isolation of the Key Drivers of Barriergenesis.

The blood-brain barrier (BBB) tightly regulates substance transport between the bloodstream and the brain. Models for the study of the physiological processes affecting the BBB, as well as predicting the permeability of therapeutic substances for neurological and neurovascular pathologies, are highly desirable. Existing models, such as Transwell utilizing-models, do not mimic the extracellular environment of the BBB with their stiff, semipermeable, non-biodegradable membranes. To help overcome this, we engineered electrospun membranes from poly L-lactic acid in combination with a nanometric coating of poly(ethyl acrylate) (PEA) that drives fibrillogenesis of fibronectin, facilitating the synergistic presentation of both growth factors and integrin binding sites. Compared to commercial semi-porous membranes, these membranes significantly improve the expression of BBB-related proteins in brain endothelial cells. PEA-coated membranes in combination with different growth factors and extracellular protein coatings reveal nerve growth factor (NGF) and fibroblast growth factor (FGF-2) caused formation of better barriers in vitro. This BBB model offers a robust platform for studying key biochemical factors influencing barrier formation that marries the simplicity of the Transwell model with the highly tunable electrospun PEA-fibronectin membranes. This enables the generation of high-throughput drug permeability models without the need of complicated co-culture conditions.

Impact of the presence and type of cardiovascular disease on the risk of mortality in type 2 diabetic patients: The DIABET-IC trial.

INTRODUCTION: All-cause mortality and cardiovascular mortality (CVM) risk can be very high in adults with type 2 diabetes mellitus (DM2) with previous cardiovascular disease (CVD). Our objective was to determine this risk among the different clinical spectrum of CVD. MATERIAL AND METHODS: The DIABET-IC trial is a multicenter, prospective, observational, and analytical study. Consecutive subjects with DM2 attending our outpatients' clinics were recruited. Data on clinical features, lab test results, and echocardiographic measures were collected. Patients were categorized depending on the presence and type of CVD: heart failure (HF), coronary artery disease (CAD), cerebrovascular disease (CVD) and peripheral artery disease (PAD). All-cause mortality and CVM were the dependent variables analyzed. Mortality rate was expressed as deaths per 1000 patients-year. Cox proportional hazards regressions models were used to establish the mortality risk associated with every type of CVD. RESULTS: We studied a total of 1246 patients (mean age, 6.3 (SD, 9.9) years; 31.6%, female) with an initial prevalence of CVD of 59.3%. A total of 122 deaths (46 due to CVD) occurred at the 2.6-year follow-up. All-cause and MCV rates associated with the presence of PAD (85.6/1000 and 33.6/1000, respectively) and HF (72.9/1000 and 28.7/1000 respectively) were the most elevated of all. In multivariate analysis, HF increased all-cause mortality risk (HR, 1.63; CI 95% 1.03-2.58; P=.037) and the risk of CVM (HR, 3.41; 95% CI, 1.68-6.93; P=.001). CONCLUSIONS: Mortality among DM2 patients is highly increased in the presence of HF and PAD. This justifies the screening of these conditions to intensify therapeutic strategies.

Efficacy of physiotherapy treatment in medium and long term in adults with fibromyalgia: an umbrella of systematic reviews.

OBJECTIVES: To summarise the available evidence and assess the effectiveness of medium and long-term physiotherapy treatment in adults with fibromyalgia (FM). METHODS: This systematic review was registered in PROSPERO: CRD42023388356. The databases searched were MEDLINE, PEDro, Scopus, Cinhal, LatinIndex, and Cochrane, using the following keywords: "fibromyalgia", "physiotherapy", "treatment", "therapeutic exercise", "TENS", "laser therapy" and "manual therapy." The included articles analysed treatments with active or passive physiotherapy approaches in patients with FM. The variables included structural characteristics, such as: author, publication year, research question, and main outcome variables. The data on the findings of the articles comprised the following aspects: number of participants, intervention, follow-up, results, and principal conclusions. RESULTS: Thirty-three articles were analysed, with an overall PRISMA score of 18.63±3.36. The active treatment methods analysed were: movement and body awareness therapies (stretching, tai chi, yoga and Pilates); hydrotherapy; physical or aerobic exercise; and multidisciplinary therapy. The passive therapies analysed were: manual therapy; repetitive transcranial magnetic stimulation (rTMS); and other therapies (hyperbaric oxygen therapy, vibration therapy, virtual reality, transcutaneous electric nervous stimulation (TENS), pain neuroscience education, and acupuncture). Evidence was found on the positive effect of physiotherapy treatment on the signs and symptoms of fibromyalgia, such as pain, impairment of physical capacity and worse quality of life. CONCLUSIONS: The effectiveness of the active and passive therapies analysed in the management of the symptoms and signs of the disease was positive in most of the studies. However, more specific descriptions of the treatment protocol, frequency, intensity and treatment dose are required to reach a consensus, as well as primary studies for a more extended follow-up period to better evaluate long-term effects.

Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells.

Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via stem cell transplantation. The very low abundance of LT-HSCs and their rapid differentiation during in vitro culture hinders their clinical utility. Previous developments using stromal feeder layers, defined media cocktails, and bioengineering have enabled HSC expansion in culture, but of mostly short-term HSCs and progenitor populations at the expense of naive LT-HSCs. Here, we report the creation of a bioengineered LT-HSC maintenance niche that recreates physiological extracellular matrix organisation, using soft collagen type-I hydrogels to drive nestin expression in perivascular stromal cells (PerSCs). We demonstrate that nestin, which is expressed by HSC-supportive bone marrow stromal cells, is cytoprotective and, via regulation of metabolism, is important for HIF-1α expression in PerSCs. When CD34+ve HSCs were added to the bioengineered niches comprising nestin/HIF-1α expressing PerSCs, LT-HSC numbers were maintained with normal clonal and in vivo reconstitution potential, without media supplementation. We provide proof-of-concept that our bioengineered niches can support the survival of CRISPR edited HSCs. Successful editing of LT-HSCs ex vivo can have potential impact on the treatment of blood disorders.

Teratoma to Angiosarcoma: A Metamorphosis in the Mediastinum.

We describe a rare and remarkable transformation of an immature mediastinal teratoma into high-grade angiosarcoma in a 21-year-old male. Mediastinal teratomas, particularly immature ones, are exceedingly rare, representing a small fraction of germ cell tumors (GCTs). Our case describes the clinical journey of the patient, who initially presented with acute chest pain and was subsequently diagnosed with an immature teratoma following imaging studies and elevated tumor markers. Despite an initial positive response to cisplatin-based chemotherapy, surveillance imaging revealed liver masses, which a biopsy confirmed as angiosarcoma. This transformation underscores the aggressive nature of immature teratomas and the propensity for sarcomatous differentiation, particularly in the mediastinum. The case contributes valuable insight into the management and surveillance of mediastinal non-seminoma germ cell tumors (MNGCT), a subset of GCTs with limited literature. We believe this case is the first in the literature to describe a transformation from an immature teratoma in the mediastinum to a high-grade angiosarcoma.

Development and validation of a new questionnaire for the assessment of patients with diabetic foot disease: The Diabetic Foot Questionnaire (DiaFootQ).

BACKGROUND: The epidemiology data and global burden of diabetic foot disease underscores the need for effective prevention strategies, which requires an early diagnosis. Patient-reported outcome measures are instruments based on a simple format, which favours their application. Currently, there is an absence of instruments with a broad enough scope to capture the diverse aspects involved in diabetic foot disease. OBJECTIVES: To develop a questionnaire for the assessment of patients with diabetic foot disease and carry out an analysis of its validity and reliability. METHODS: The study was developed in two stages. Stage 1: the Delphi Panel was composed of 22 experts. The questionnaire is made up of 25 questions selected, after three rounds, from an initial sample of 68 questions. Stage 2: A validation study was performed. With a sample of 273 subjects, an exploratory factor analysis and an analysis of internal consistency, items response, and validity were carried out using the Diabetes Quality of Life, SF-12v2, Foot Function Index and EuroQol EQ5D questionnaires. Measurements of error and sensitivity to change were also analyzed. RESULTS: A 25-item questionnaire (DiaFootQ) was developed. It comprised two dimensions: 1) lifestyle and function; and 2) footwear and foot self-care. Sample (n=273) mean age was 69.77 years (±11.08). The internal consistency of DiafootQ was α=0.916, and item response values were ICC=0.862-0.998. External validity correlation levels ranged from r=0.386 to r=0.888. CONCLUSION: DiaFootQ was developed. Integrating the main aspects involved in diabetic foot disease could help to detect more accurately the risk or severity of these patients. DiaFootQ is a well-structured, valid, and reliable tool whose use should be promoted in clinical and research settings.

Influence of BMI, Cigarette Smoking and Cryopreservation on Tyrosine Phosphorylation during Sperm Capacitation.

Capacitation involves tyrosine phosphorylation (TP) as a key marker. Lifestyle-related factors, such as obesity and smoking, are recognized for their adverse effects on semen quality and male fertility, yet the underlying mechanisms, including their potential impact on TP, remain unclear. Moreover, the effect of sperm cryopreservation on TP at the human sperm population level is unexplored. Flow cytometry analysis of global TP was performed on pre-capacitated, post-capacitated and 1- and 3-hours' incubated fresh and frozen-thawed samples from sperm donors (n = 40). Neither being overweight nor smoking (or both) significantly affected the percentage of sperm showing TP. However, elevated BMI and smoking intensity correlated with heightened basal TP levels (r = 0.226, p = 0.003) and heightened increase in TP after 3 h of incubation (r = 0.185, p = 0.017), respectively. Cryopreservation resulted in increased global TP levels after capacitation but not immediately after thawing. Nonetheless, most donors' thawed samples showed increased TP levels before and after capacitation as well as after incubation. Additionally, phosphorylation patterns in fresh and frozen-thawed samples were similar, indicating consistent sample response to capacitation stimuli despite differences in TP levels. Overall, this study sheds light on the potential impacts of lifestyle factors and cryopreservation on the dynamics of global TP levels during capacitation.

Glioma and Peptidergic Systems: Oncogenic and Anticancer Peptides.

Glioma cells overexpress different peptide receptors that are useful for research, diagnosis, management, and treatment of the disease. Oncogenic peptides favor the proliferation, migration, and invasion of glioma cells, as well as angiogenesis, whereas anticancer peptides exert antiproliferative, antimigration, and anti-angiogenic effects against gliomas. Other peptides exert a dual effect on gliomas, that is, both proliferative and antiproliferative actions. Peptidergic systems are therapeutic targets, as peptide receptor antagonists/peptides or peptide receptor agonists can be administered to treat gliomas. Other anticancer strategies exerting beneficial effects against gliomas are discussed herein, and future research lines to be developed for gliomas are also suggested. Despite the large amount of data supporting the involvement of peptides in glioma progression, no anticancer drugs targeting peptidergic systems are currently available in clinical practice to treat gliomas.

Effects of anther-stigma position on cross-pollination efficiency in a hermaphroditic plant.

PREMISE: Evolution of cross-pollination efficiency depends on the genetic variation of flower traits, the pollen vector, and flower trait matching between pollen donors and recipients. Trait matching has been almost unexplored among nonheterostylous species, and we examined whether the match of anther length in pollen donors and stigma length in pollen recipients influences the efficiency of cross-pollination. To explore potential constraints for evolutionary response, we also quantified genetic variation and covariation among sepal length, petal length and width, stamen length, style length, and herkogamy. METHODS: We created 58 experimental arrays of Turnera velutina that varied in the extent of mismatch in the position of anthers and stigmas between single-flowered plants. Genetic variation and correlations among flower traits were estimated under greenhouse conditions. RESULTS: Style length, but not herkogamy, influenced the efficiency of cross-pollination. Plants with stamen length that matched the style length of other plants were more efficient pollen donors, whereas those with the style protruding above the stamens of other plants were more efficient pollen recipients. Significant broad-sense heritability (0.22 > hB 2 < 0.42) and moderate genetic correlations (0.33 > r < 0.85) among floral traits were detected. CONCLUSIONS: Our results demonstrated that anther-stigma mismatch between flowers contributed to variation in the efficiency of cross-pollination. The genetic correlations between stamen length and other floral traits suggests that any change in cross-pollination efficiency would be driven by changes in style rather than in stamen length.

The ephemeral microbiota: Ecological context and environmental variability drive the body surface microbiota composition of Magellanic penguins across subantarctic breeding colonies.

Environmental microbes routinely colonize wildlife body surface microbiota. However, animals experience dynamic environmental shifts throughout their daily routine. Yet, the effect of ecological shifts in wildlife body surface microbiota has been poorly explored. Here, we sequenced the hypervariable region V3-V4 of the 16S rRNA gene to characterize the body surface microbiota of wild Magellanic penguins (Spheniscus magellanicus) under two ecological contexts: (1) Penguins walking along the coast and (2) Penguins sheltered underground in their nest, across three subantarctic breeding colonies in the Magellan Strait, Chile. Despite ecological contexts, our results revealed that Moraxellaceae bacteria were the most predominant and abundant taxa associated with penguin body surfaces. Nevertheless, we detected colony-specific core bacteria associated with penguin bodies. The most abundant were: Deinococcus in the Contramaestre colony, Fusobacterium in the Tuckers 1 colony, and Clostridium sensu stricto 1 in the Tuckers 2 colony. Our results give a new perspective on the niche environmental hypothesis for wild seabirds. First, the ecological characteristics of each colony were associated with the microbial communities from the nest soil and the body surface of penguins inside the nests. For example, in the colonies with heterogenous vegetation cover (i.e. the Tuckers Islets), there was a similar microbial composition between the nest soil and the body surface of penguins. In contrast, on the more arid colony (Contramaestre), we detected differences in the microbial communities between the nest soil and the body surface of penguins.

Colchicine in acute heart failure: Rationale and design of a randomized double-blind placebo-controlled trial (COLICA).

AIMS: Heart failure (HF) elicits a pro-inflammatory state, which is associated with impaired clinical outcomes, but no anti-inflammatory therapies have demonstrated a clinical benefit yet. Inflammatory pathways related with the interleukin-1 axis are overactivated during episodes of acute HF. Colchicine, an anti-inflammatory drug with proven benefits in acute pericarditis and ischaemic heart disease, may target this inflammatory response. This study aims to assess the efficacy of colchicine in acute HF patients. METHODS: COLICA is a multicentre, randomized, double-blind, placebo-controlled trial enrolling 278 patients across 12 sites. Patients presenting with acute HF, clinical evidence of congestion requiring ≥40 mg of intravenous furosemide and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >900 pg/ml, are eligible for participation. Patients are enrolled irrespective of left ventricular ejection fraction, HF type (new-onset or not) and setting (hospital or outpatient clinic). Patients are randomized 1:1 within the first 24 h of presentation to either placebo or colchicine, with an initial loading dose of 2 mg followed by 0.5 mg every 12 h for 8 weeks (reduced dose if <70 kg, >75 years old, or glomerular filtration rate <50 ml/min/1.73 m2). The primary efficacy endpoint is the time-averaged proportional change in NT-proBNP concentrations from baseline to week 8. Key secondary and exploratory outcomes include symptoms, diuretic use, worsening HF episodes, related biomarkers of cardiac stress and inflammation, total and cardiovascular readmissions, mortality and safety events. CONCLUSION: COLICA will be the first randomized trial testing the efficacy and safety of colchicine for acute HF.

Hybrid Micro-/Nanoprotein Platform Provides Endocrine-like and Extracellular Matrix-like Cell Delivery of Growth Factors.

Protein materials are versatile tools in diverse biomedical fields. Among them, artificial secretory granules (SGs), mimicking those from the endocrine system, act as mechanically stable reservoirs for the sustained release of proteins as oligomeric functional nanoparticles. Only validated in oncology, the physicochemical properties of SGs, along with their combined drug-releasing and scaffolding abilities, make them suitable as smart topographies in regenerative medicine for the prolonged delivery of growth factors (GFs). Thus, considering the need for novel, safe, and cost-effective materials to present GFs, in this study, we aimed to biofabricate a protein platform combining both endocrine-like and extracellular matrix fibronectin-derived (ECM-FN) systems. This approach is based on the sustained delivery of a nanostructured histidine-tagged version of human fibroblast growth factor 2. The GF is presented onto polymeric surfaces, interacting with FN to spontaneously generate nanonetworks that absorb and present the GF in the solid state, to modulate mesenchymal stromal cell (MSC) behavior. The results show that SGs-based topographies trigger high rates of MSCs proliferation while preventing differentiation. While this could be useful in cell therapy manufacture demanding large numbers of unspecialized MSCs, it fully validates the hybrid platform as a convenient setup for the design of biologically active hybrid surfaces and in tissue engineering for the controlled manipulation of mammalian cell growth.

Outcomes of patients with heart failure followed in units accredited by the SEC-Excelente-IC quality program according to the type of unit.

INTRODUCTION AND OBJECTIVES: The development of specific heart failure (HF) units has improved the management of patients with this disease due to improved organization and resource management. The Spanish Society of Cardiology (SEC) has defined 3 types of HF units (community, specialized, and advanced) based on their complexity and service portfolio. Our aim was to compare the characteristics, treatment, and outcomes of patients with HF according to the type of unit. METHODS: We analyzed data from the SEC-Excelente-IC quality accreditation program registry, with 1716 patients consecutively included in two 1-month cutoffs (March and October) from 2019 to 2021 by 45 SEC-accredited HF units. We compared the characteristics, treatment and 1-year outcomes between the 3 types of units. RESULTS: Of the 1716 patients, 13.2% were treated in community units, 65.9% in specialized units, and 20.9% in advanced units. The rates of mortality (27.5 vs 15.5/100 patients-year; P<.001), admissions for HF (39.7 vs 29.2/100 patients-year; P=.019), total decompensations (56.1 vs 40.5/100 patients-year; P=.003), and combined death/admission for HF (45.2 vs 31.4/100 patients-year; P=.005) were higher in community units than in specialized/advanced units. Follow-up in a community unit was an independent predictor of higher mortality and admissions at 1 year. CONCLUSIONS: Compared with follow-up by more specialized units, follow-up in a community unit was associated with a higher decompensation rate and increased 1-year mortality.

Consensus Report and Recommendations on the Management of Late-stage Internal Derangement of the Temporomandibular Joint.

Introduction: This report investigates late-stage internal derangement (ID) of the temporomandibular joint (TMJ) with the aim of establishing a more effective and personalized treatment protocol to improve patients' quality of life (QoL). Material and methods: A consensus was reached among maxillofacial surgeons specializing in LSID, based on a literature research and collective expert experience following the Delphi method. Consensus was considered to be achieved when a response received at least 80% of votes. Results: Four expert groups were established, respectively, focusing on diagnosis, minimally invasive surgery (MIS), open surgery and joint replacement. A comprehensive approach to late-stage ID of the TMJ requires a consensus report. This underscores the need for a personalized treatment plan, considering the variability in clinical presentations and progression of this pathology. Our recommendations aim to optimize clinical outcomes and enhance patient QoL.

Exploring Binocular Visual Attention by Presenting Rapid Dichoptic and Dioptic Series.

This study addresses an issue in attentional distribution in a binocular visual system using RSVP tasks under Attentional Blink (AB) experimental protocols. In Experiment 1, we employed dichoptic RSVP to verify whether, under interocular competition, attention may be captured by a monocular channel. Experiment 2 was a control experiment, where a monoptic RSVP assessed by both or only one eye determines whether Experiment 1 monocular condition results were due to an allocation of attention to one eye. Experiment 3 was also a control experiment designed to determine whether Experiment 1 results were due to the effect of interocular competition or to a diminished visual contrast. Results from Experiment 1 revealed that dichoptic presentations caused a delay in the type stage of the Wyble's eSTST model, postponing the subsequent tokenization process. The delay in monocular conditions may be further explained by a visual attenuation, due to fusion of target and an empty frame. Experiment 2 evidenced the attentional allocation to monocular channels when forced by eye occlusion. Experiment 3 disclosed that monocular performance in Experiment 1 differs significantly from conditions with interocular competition. While both experiments revealed similar performance in monocular conditions, rivalry conditions exhibit lower detection rates, suggesting that competing stimuli was not responsible for Experiment 1 results. These findings highlight the differences between dichoptic and monoptic presentations of stimuli, particularly on the AB effect, which appears attenuated or absent in dichoptic settings. Furthermore, results suggest that monoptic presentation and binocular fusion stages were a necessary condition for the attentional allocation.

Modulation of neuronal dynamics by sustained and activity-dependent continuous-wave near-infrared laser stimulation.

Significance: Near-infrared laser illumination is a non-invasive alternative/complement to classical stimulation methods in neuroscience but the mechanisms underlying its action on neuronal dynamics remain unclear. Most studies deal with high-frequency pulsed protocols and stationary characterizations disregarding the dynamic modulatory effect of sustained and activity-dependent stimulation. The understanding of such modulation and its widespread dissemination can help to develop specific interventions for research applications and treatments for neural disorders. Aim: We quantified the effect of continuous-wave near-infrared (CW-NIR) laser illumination on single neuron dynamics using sustained stimulation and an open-source activity-dependent protocol to identify the biophysical mechanisms underlying this modulation and its time course. Approach: We characterized the effect by simultaneously performing long intracellular recordings of membrane potential while delivering sustained and closed-loop CW-NIR laser stimulation. We used waveform metrics and conductance-based models to assess the role of specific biophysical candidates on the modulation. Results: We show that CW-NIR sustained illumination asymmetrically accelerates action potential dynamics and the spiking rate on single neurons, while closed-loop stimulation unveils its action at different phases of the neuron dynamics. Our model study points out the action of CW-NIR on specific ionic-channels and the key role of temperature on channel properties to explain the modulatory effect. Conclusions: Both sustained and activity-dependent CW-NIR stimulation effectively modulate neuronal dynamics by a combination of biophysical mechanisms. Our open-source protocols can help to disseminate this non-invasive optical stimulation in novel research and clinical applications.

Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs.

BACKGROUND AND PURPOSE: This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. EXPERIMENTAL APPROACH: Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks. KEY RESULTS: Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects. CONCLUSIONS AND IMPLICATIONS: First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication.