Direct retino-iridal projections and intrinsic iris contraction mediate the pupillary light reflex in early vertebrates.

The pupillary light reflex (PLR) adapts the amount of light reaching the retina, protecting it and improving image formation. Two PLR mechanisms have been described in vertebrates. First, the pretectum receives retinal inputs and projects to the Edinger-Westphal nucleus (EWN), which targets the ciliary ganglion through the oculomotor nerve (nIII). Postganglionic fibers enter the eye-globe, traveling to the iris sphincter muscle. Additionally, some vertebrates exhibit an iris-intrinsic PLR mechanism mediated by sphincter muscle cells that express melanopsin inducing muscle contraction. Given the high degree of conservation of the lamprey visual system, we investigated the mechanisms underlying the PLR to shed light onto their evolutionary origins. Recently, a PLR mediated by melanopsin was demonstrated in lampreys, suggested to be brain mediated. Remarkably, we found that PLR is instead mediated by direct retino-iridal cholinergic projections. This retina-mediated PLR acts synergistically with an iris-intrinsic mechanism that, as in other vertebrates, is mediated by melanopsin and has contribution of gap junctions between muscle fibers. In contrast, we show that lampreys lack the brain-mediated PLR. Our results suggest that two eye-intrinsic PLR mechanisms were present in early vertebrate evolution, whereas the brain-mediated PLR has a more recent origin.

Does the coexistence of pain and depressive symptoms accelerate cognitive decline?

OBJECTIVES: Investigate whether the coexistence of pain and depressive symptoms is a risk factor for cognitive decline in individuals aged 50 or older. METHOD: Longitudinal trajectory study involving 4,718 participants from the English Longitudinal Study of Ageing (ELSA). Joint pain was self-reported, and intensity was classified as mild, moderate/intense. Depressive symptoms were investigated using the Centre for Epidemiologic Studies Depression Scale (CES-D-8 ≥ 4). The sample was divided into six groups: no pain and no depression (NP/NDe), mild pain and no depression (MP/NDe), moderate/intense pain and no depression (M-IP/NDe), no pain and depression (NP/De), mild pain and depression (MP/De), and moderate/intense pain and depression (M-IP/De). The outcome of interest was performance in memory, executive function, and global cognition. Generalised linear mixed models were used to analyse performance in the cognitive domains and global cognition score as a function of pain and depressive symptoms during 12 years of follow-up. RESULTS: Over time, individuals with M-IP/De had a greater memory decline (-0.038 SD/year, 95%CI: -0.068 to -0.007) and the global cognition score (-0.033 SD/year, 95%CI: -0.063 to -0.002) than those with NP/NDe. CONCLUSION: The coexistence of moderate/intense pain and depressive symptoms is a risk factor for the decline of global cognition and memory.

Dynapenia and sarcopenia identify walking speed decline in women but not in men.

OBJECTIVE: To determine the best indicator of mobility decline between dynapenia, low skeletal muscle mass index (SMMI), and sarcopenia defined by the EWGSOP2 using different cutoff points for grip strength. METHODS: A longitudinal study was conducted with a follow-up of eight years, involving 2,680 individuals aged 60 and older who participated in the ELSA study with a walking speed greater than 0.8 m/s at baseline. Dynapenia was defined using different cutoff points for grip strength. SMMI was defined by the 20th percentile of the entire ELSA sample distribution and sarcopenia was defined based on the EWGSOP2, using different cutoff points for grip strength. Mobility was analysed using the walking speed test. RESULTS: Over time, the greatest decline in walking speed occurred in dynapenic women with grip strength < 17 kg (-0.005 m/s per year; 95 % CI: -0.01 to -0.001) and < 20 kg (-0.007 m/s per year; 95 % CI: -0.01 to -0.001). With regards to sarcopenia, the greatest walking speed decline occurred in women with probable sarcopenia when defined by grip strength < 17 kg [(-0.006 m/s per year; 95 % CI: -0.01 to -0.001) or grip strength < 20 kg (-0.007 m/s per year; 95 % CI: -0.01 to -0.001)]. Dynapenia in men as well as low SMMI and sarcopenia in men and women did not enable identifying the risk of mobility decline. CONCLUSION: Dynapenia and probable sarcopenia defined by grip strength < 17 kg and < 20 kg enabled identifying walking speed decline over time only in women.

Biomarkers in pulmonary infections: a clinical approach.

Severe acute respiratory infections, such as community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia, constitute frequent and lethal pulmonary infections in the intensive care unit (ICU). Despite optimal management with early appropriate empiric antimicrobial therapy and adequate supportive care, mortality remains high, in part attributable to the aging, growing number of comorbidities, and rising rates of multidrug resistance pathogens. Biomarkers have the potential to offer additional information that may further improve the management and outcome of pulmonary infections. Available pathogen-specific biomarkers, for example, Streptococcus pneumoniae urinary antigen test and galactomannan, can be helpful in the microbiologic diagnosis of pulmonary infection in ICU patients, improving the timing and appropriateness of empiric antimicrobial therapy since these tests have a short turnaround time in comparison to classic microbiology. On the other hand, host-response biomarkers, for example, C-reactive protein and procalcitonin, used in conjunction with the clinical data, may be useful in the diagnosis and prediction of pulmonary infections, monitoring the response to treatment, and guiding duration of antimicrobial therapy. The assessment of serial measurements overtime, kinetics of biomarkers, is more informative than a single value. The appropriate utilization of accurate pathogen-specific and host-response biomarkers may benefit clinical decision-making at the bedside and optimize antimicrobial stewardship.

Could poor glycaemic control be a predictor of walking speed decline in older adults? Evidence from the English Longitudinal Study of Ageing.

AIM: Although diabetes is a risk factor for walking speed decline in older adults, it remains unclear how glycaemic control [assessed by glycated haemoglobin (HbA1c)] might affect the long-term trajectories of walking speed. We investigated whether the glycaemic control status accelerates the walking speed decline and whether this decline differs depending on previous mobility conditions. MATERIALS AND METHODS: In total, 3202 individuals aged ≥60 years from the English Longitudinal Study of Ageing (ELSA) were classified at baseline and after 4 and 8 years of follow-up according to glycaemic control status as 'without diabetes' (no self-reported diabetes and HbA1c <6.5%), 'good glycaemic control' (self-reported diabetes and HbA1c ≥6.5% and <7.0%) and 'poor glycaemic control' (PGC) (self-reported diabetes and HbA1c ≥7.0%). The generalized linear mixed models verified the walking speed trajectories in m/s. A second analysis was performed, including only participants without slowness at baseline (>0.8 m/s). RESULTS: Compared with the status 'without diabetes', the annual walking speed decline was -0.015 m/s for PGC and -0.011 m/s for good glycaemic control, totalling -0.160 and -0.130 m/s, respectively, over 8 years. Among those without slowness at baseline, only PGC had a significant walking speed decline, corresponding to -0.014 m/s per year and -0.222 m/s over 8 years. CONCLUSIONS: Poor glycaemic control is a discriminator of walking speed decline in older adults, regardless of previous mobility conditions. It may serve as an early screening tool for those at risk of decreased functional performance later in life.

Environmental DNA reveals temporal variation in mesophotic reefs of the Humboldt upwelling ecosystems of central Chile: Toward a baseline for biodiversity monitoring of unexplored marine habitats.

Temperate mesophotic reef ecosystems (TMREs) are among the least known marine habitats. Information on their diversity and ecology is geographically and temporally scarce, especially in highly productive large upwelling ecosystems. Lack of information remains an obstacle to understanding the importance of TMREs as habitats, biodiversity reservoirs and their connections with better-studied shallow reefs. Here, we use environmental DNA (eDNA) from water samples to characterize the community composition of TMREs on the central Chilean coast, generating the first baseline for monitoring the biodiversity of these habitats. We analyzed samples from two depths (30 and 60 m) over four seasons (spring, summer, autumn, and winter) and at two locations approximately 16 km apart. We used a panel of three metabarcodes, two that target all eukaryotes (18S rRNA and mitochondrial COI) and one specifically targeting fishes (16S rRNA). All panels combined encompassed eDNA assigned to 42 phyla, 90 classes, 237 orders, and 402 families. The highest family richness was found for the phyla Arthropoda, Bacillariophyta, and Chordata. Overall, family richness was similar between depths but decreased during summer, a pattern consistent at both locations. Our results indicate that the structure (composition) of the mesophotic communities varied predominantly with seasons. We analyzed further the better-resolved fish assemblage and compared eDNA with other visual methods at the same locations and depths. We recovered eDNA from 19 genera of fish, six of these have also been observed on towed underwater videos, while 13 were unique to eDNA. We discuss the potential drivers of seasonal differences in community composition and richness. Our results suggest that eDNA can provide valuable insights for monitoring TMRE communities but highlight the necessity of completing reference DNA databases available for this region.

Efficacy and Experience of Bacteriophages in Biofilm-Related Infections.

Bacterial infection has always accompanied human beings, causing suffering and death while also contributing to the advancement of medical science. However, the treatment of infections has become more complex in recent times. The increasing resistance of bacterial strains to antibiotics has diminished the effectiveness of the therapeutic arsenal, making it less likely to find the appropriate empiric antibiotic option. Additionally, the development and persistence of bacterial biofilms have become more prevalent, attributed to the greater use of invasive devices that facilitate biofilm formation and the enhanced survival of chronic infection models where biofilm plays a crucial role. Bacteria within biofilms are less susceptible to antibiotics due to physical, chemical, and genetic factors. Bacteriophages, as biological weapons, can overcome both antimicrobial resistance and biofilm protection. In this review, we will analyze the scientific progress achieved in vitro to justify their clinical application. In the absence of scientific evidence, we will compile publications of clinical cases where phages have been used to treat infections related to biofilm. The scientific basis obtained in vitro and the success rate and safety observed in clinical practice should motivate the medical community to conduct clinical trials establishing a protocol for the proper use of bacteriophages.

Cardiac Toxicity in the Treatment of Light Chain Amyloidosis: Systematic Review of Clinical Studies.

BACKGROUND: Light chain amyloidosis (AL) is a progressive and a fatal disease that primarily affects cardiac tissue. Although the current approach to anti-amyloidosis treatments has managed to reduce amyloidosis morbimortality, the dynamics of cardiac adverse events are unknown. OBJECTIVE: to provide evidence about reported cardiac toxicity during treatment of AL amyloidosis through a systematic review of the literature. METHODS: A search was performed for registered clinical trials on ClinicalTrials.gov filtered for AL amyloidosis up to December 31, 2022. Studies were filtered by those that reported intervention in patients with AL amyloidosis and that had reported adverse events. The type of study, the intervention performed, and the frequency of reported cardiac adverse events were discriminated from each trial. RESULTS: 25 clinical trials were analyzed, representing a population of 1,542 patients, among whom 576 (38.95%) adverse events were reported, 326 being serious (SAE) and 242 nonserious (nSAE). The most frequent SAEs were cardiac failure, atrial fibrillation, and cardiac arrest, while the most frequent nSAEs were palpitations, atrial fibrillation, and sinus tachycardia. CONCLUSION: cardiac toxicity during treatment for amyloidosis seems common, and it is important to evaluate the relationship of therapies with its occurrence.

De novo heterozygous missense variants in CELSR1 as cause of fetal pleural effusions and progressive fetal hydrops.

Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops.

Folate regulation of planar cell polarity pathway and F-actin through folate receptor alpha.

Folate deficiency contribute to neural tube defects (NTDs) which could be rescued by folate supplementation. However, the underlying mechanisms are still not fully understood. Besides, there is considerable controversy concerning the forms of folate used for supplementation. To address this controversy, we prepared culture medium with different forms of folate, folic acid (FA), and 5-methyltetrahydrofolate (5mTHF), at concentrations of 5 µM, 500 nM, 50 nM, and folate free, respectively. Mouse embryonic fibroblasts (MEFs) were treated with different folates continuously for three passages, and cell proliferation and F-actin were monitored. We determined that compared to 5mTHF, FA showed stronger effects on promoting cell proliferation and F-actin formation. We also found that FOLR1 protein level was positively regulated by folate concentration and the non-canonical Wnt/planar cell polarity (PCP) pathway signaling was significantly enriched among different folate conditions in RNA-sequencing analyses. We demonstrated for the first time that FOLR1 could promote the transcription of Vangl2, one of PCP core genes. The transcription of Vangl2 was down-regulated under folate-deficient condition, which resulted in a decrease in PCP activity and F-actin formation. In summary, we identified a distinct advantage of FA in cell proliferation and F-actin formation over 5mTHF, as well as demonstrating that FOLR1 could promote transcription of Vangl2 and provide a new mechanism by which folate deficiency can contribute to the etiology of NTDs.

PATHway: Intervention optimization of a prevention program for adolescents at-risk for depression in the primary care setting.

With as many as 13% of adolescents diagnosed with depressive disorders each year, prevention of depressive disorders has become a key priority for the National Institute of Mental Health (NIMH). Currently, we have no widely available interventions to prevent these disorders. To address this need, we developed a multi-health system collaboration to develop and evaluate the primary care based technology "behavioral vaccine," Competent Adulthood Transition with Cognitive-Behavioral Humanistic and Interpersonal Therapy (CATCH-IT). The full CATCH-IT program demonstrated evidence of efficacy in prevention of depressive episodes in clinical trials. However, CATCH-IT became larger and more complex across trials, creating issues with adherence and scalability. We will use a multiphase optimization strategy approach to optimize CATCH-IT. The theoretically grounded components of CATCH-IT include: behavioral activation, cognitive-behavioral therapy, interpersonal psychotherapy, and parent program. We will use a 4-factor (2x2x2x2) fully crossed factorial design with N = 16 cells (25 per cell, after allowing 15% dropout) to evaluate the contribution of each component. Eligible at-risk youth will be high school students 13 through 18 years old, with subsyndromal symptoms of depression. The study design will enable us to eliminate non-contributing components while preserving efficacy and to optimize CATCH-IT by strengthening tolerability and scalability by reducing resource use. By reducing resource use, we anticipate satisfaction and acceptability will also increase, preparing the way for an implementation trial.

Ten Issues to Update in Nosocomial or Hospital-Acquired Pneumonia: An Expert Review.

Nosocomial pneumonia, or hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) are important health problems worldwide, with both being associated with substantial morbidity and mortality. HAP is currently the main cause of death from nosocomial infection in critically ill patients. Although guidelines for the approach to this infection model are widely implemented in international health systems and clinical teams, information continually emerges that generates debate or requires updating in its management. This scientific manuscript, written by a multidisciplinary team of specialists, reviews the most important issues in the approach to this important infectious respiratory syndrome, and it updates various topics, such as a renewed etiological perspective for updating the use of new molecular platforms or imaging techniques, including the microbiological diagnostic stewardship in different clinical settings and using appropriate rapid techniques on invasive respiratory specimens. It also reviews both Intensive Care Unit admission criteria and those of clinical stability to discharge, as well as those of therapeutic failure and rescue treatment options. An update on antibiotic therapy in the context of bacterial multiresistance, in aerosol inhaled treatment options, oxygen therapy, or ventilatory support, is presented. It also analyzes the out-of-hospital management of nosocomial pneumonia requiring complete antibiotic therapy externally on an outpatient basis, as well as the main factors for readmission and an approach to management in the emergency department. Finally, the main strategies for prevention and prophylactic measures, many of them still controversial, on fragile and vulnerable hosts are reviewed.

Evaluation of the Kinetics of Pancreatic Stone Protein as a Predictor of Ventilator-Associated Pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a severe condition. Early and adequate antibiotic treatment is the most important strategy for improving prognosis. Pancreatic Stone Protein (PSP) has been described as a biomarker that increases values 3-4 days before the clinical diagnosis of nosocomial sepsis in different clinical settings. We hypothesized that serial measures of PSP and its kinetics allow for an early diagnosis of VAP. METHODS: The BioVAP study was a prospective observational study designed to evaluate the role of biomarker dynamics in the diagnosis of VAP. To determine the association between repeatedly measured PSP and the risk of VAP, we used joint models for longitudinal and time-to-event data. RESULTS: Of 209 patients, 43 (20.6%) patients developed VAP, with a median time of 4 days. Multivariate joint models with PSP, CRP, and PCT did not show an association between biomarkers and VAP for the daily absolute value, with a hazard ratio (HR) for PSP of 1.01 (95% credible interval: 0.97 to 1.05), for CRP of 1.00 (0.83 to 1.22), and for PCT of 0.95 (0.82 to 1.08). The daily change of biomarkers provided similar results, with an HR for PSP of 1.15 (0.94 to 1.41), for CRP of 0.76 (0.35 to 1.58), and for PCT of 0.77 (0.40 to 1.45). CONCLUSION: Neither absolute PSP values nor PSP kinetics alone nor in combination with other biomarkers were useful in improving the prediction diagnosis accuracy in patients with VAP. CLINICAL TRIAL REGISTRATION: Registered retrospectively on August 3rd, 2012. NCT02078999.

Transcriptomics reveals shared immunosuppressive landscapes in ventilator-associated lower respiratory tract infections (VA-LRTI) patients.

BACKGROUND: Ventilator-associated pneumonia (VAP) represents a transitory status of immunoparalysis, and we hypothesized that ventilator-associated tracheobronchitis (VAT) could share also some degree of immune response to a respiratory infection. RESEARCH DESIGN AND METHODS: A prospective observational study in five medical ICUs to evaluate immunological alterations of patients with VA-LRTI. Immunological gene expression profiles in the blood using whole transcriptome microarrays in the first 24 hours following diagnosis. The area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of mRNA levels to differentiate VA-LRTI and lack of infection. A principal component analysis (PCA) was employed for analyzing the impact of each genetic expression footprint variable in explaining the variance of the cohort. RESULTS: There was overlapping between the three classes of patients encompassing gene expression levels of 8 genes (i.e. HLA, IL2RA, CD40LG, ICOS, CCR7, CD1C, CD3E). HLA-DRA was equally low among VAT and VAP patients characterizing immune depression, and significantly lower than the control group. CONCLUSIONS: Our findings suggest that VAP and VAT are not so different regarding gene expression levels suggesting a degree of immunosuppression. Our results indicate a state of immunoparalysis in respiratory infections in critically ill patients.

Impact of the COVID-19 pandemic on demand for emergency department care for older patients: the EDEN-7 COVID cohort study. / Estudio EDEN-7: impacto de la pandemia COVID-19 sobre la demanda asistencial de personas mayores en los servicios de urgencias españoles.

OBJECTIVES: To analyze the impact of the COVID-19 pandemic on Spanish emergency department (ED) care for patients aged 65 years or older during the first wave vs. a pre-pandemic period. MATERIAL AND METHODS: Retrospective cross-sectional study of a COVID-19 portion of the EDEN project (Emergency Department and Elder Needs). The EDEN-COVID cohort included all patients aged 65 years or more who were treated in 52 EDs on 7 consecutive days early in the pandemic. We analyzed care variables, discharge diagnoses, use of diagnostic and therapeutic resources, use of observation units, need for hospitalization, rehospitalization, and mortality. These data were compared with data for an EDEN cohort in the same age group recruited during a similar period the year before the pandemic. RESULTS: The 52 participating hospital EDs attended 33 711 emergencies during the pandemic vs. 96 173 emergencies in the pre-COVID period, representing a 61.7% reduction during the pandemic. Patients aged 65 years or older accounted for 28.8% of the caseload during the COVID-19 period and 26.4% of the earlier cohort (P .001). The COVID-19 caseload included more men (51.0%). Comorbidity and polypharmacy were more prevalent in the pandemic cohort than in the earlier one (comorbidity, 92.6% vs. 91.6%; polypharmacy, 65.2% vs. 63.6%). More esturesources (analgesics, antibiotics, heparins, bronchodilators, and corticosteroids) were applied in the pandemic period, and common diagnoses were made less often. Observation wards were used more often (for 37.8% vs. 26.2% in the earlier period), and hospital admissions were more frequent (in 56.0% vs. 25.3% before the pandemic). Mortality was higher during the pandemic than in the earlier cohort either in ED (1.8% vs 0.5%) and during hospitalization (11.5 vs 2.9%). CONCLUSION: The proportion of patients aged 65 years or older decreased in the participating Spanish EDs. However, more resources were required and the pattern of diagnoses changed. Observation ward stays were longer, and admissions and mortality increased over the numbers seen in the reference period.

OBJETIVO: Analizar el impacto de la pandemia COVID-19 sobre la asistencia a las personas mayores ($ 65 años) en los servicios de urgencias hospitalarios (SUH) españoles durante la primera oleada pandémica, comparándola con un periodo previo. METODO: Estudio transversal retrospectivo de la cohorte EDEN-COVID (Emergency Department and Elder Needs during COVID), que incluyó a todos los pacientes $ 65 años atendidos en 52 SUH españoles durante 7 días consecutivos de un periodo pandémico. Se analizaron variables asistenciales, diagnósticos de alta, consumo de recursos diagnósticos y terapéuticos, utilización de las unidades de observación, necesidad de ingreso, rehospitalización y mortalidad. Estos datos se compararon con la cohorte EDEN (Emergency Department and Elder Needs), que reclutó a pacientes del mismogrupo de edad durante un periodo similar del año anterior. RESULTADOS: Durante el periodo COVID-19 se atendieron 33.711 episodios en los 52 SUH participantes, frente a 96.173 del periodo pre-COVID, lo que supone una disminución de la demanda de 61,7%. La proporción de asistencias a pacientes de 65 o más años fue de 28,8% en el periodo COVID-19 y 26,4% en el periodo previo (p 0,001). Durante el periodo COVID hubo mayor proporción de hombres (51,0% vs 44,9%), mayor comorbilidad (92,6% vs 91,6%) y polifarmacia (65,2% vs 63,6%), mayor uso de recursos, de analgésicos, antibióticos, heparinas, broncodilatadores y corticoides, menor proporción de los diagnósticos más habituales, mayor utilización de las unidades de observación (37,8% vs 26,2%) y un incremento de la proporción de ingresos (56,0% vs 25,3%), y de mortalidad en urgencias (1,8% vs 0,5%) y durante la hospitalización (11,5% vs 2,9%). CONCLUSIONES: La primera ola de la pandemia COVID-19 ha provocado una disminución global de las asistencias a personas mayores ($ 65 años) en los SUH españoles analizados, mayor consumo de recursos, un mapa diferente de procesos diagnósticos asistidos y un aumento proporcional de estancias en observación, de ingresos y de mortalidad, respecto al periodo de referencia.

Grafting of Crown Ether and Cryptand Macrocycles on Large Pore Stellate Mesoporous Silica for Sodium Cation Extraction.

Regulation of the sodium cations level in the case of renal failure diseases is a very challenging task for clinicians, and new pollutant extractors based on nanomaterials are emerging as potential treatments. In this work, we report different strategies for the chemical functionalization of biocompatible large pore mesoporous silica, denoted stellate mesoporous silica (STMS), with chelating ligands able to selectively capture sodium. We address efficient methods to covalently graft highly chelating macrocycles onto STMS NPs such as crown ethers (CE) and cryptands (C221) through complementary carbodiimidation reactions. Regarding sodium capture in water, C221 cryptand-grafted STMS showed better capture efficiency than CE-STMS due to higher sodium atom chelation in the cryptand cage (Na+ coverage of 15.5% vs. 3.7%). The sodium selectivity was hence tested with C221 cryptand-grafted STMS in a multi-element aqueous solution (metallic cations with the same concentration) and in a solution mimicking peritoneal dialysis solution. Results obtained indicate that C221 cryptand-grafted STMS are relevant nanomaterials to extract sodium cations in such media and allow us to regulate their levels.