The influence of social media and video-on-demand platforms on the appeal and consumption of tobacco and emerging tobacco products: A cross-sectional study.

INTRODUCTION: Digital platforms serve as an avenue for the tobacco industry to promote both conventional tobacco and emerging products, with a notable focus on capturing the attention of young people through sophisticated marketing campaigns. This research aims to analyze the prevalence of different advertising strategies on digital platforms and to assess the impact of exposure to these strategies on the probability of use initiation and increased consumption of conventional tobacco and new tobacco products among young Spaniards. METHODS: An online survey was conducted on a representative sample of 1730 young Spaniards aged 16-21 years in November 2022 using a comprehensive approach, considering all possible relevant factors and perspectives regarding the issue of the study. A descriptive analysis and two adjusted logistic regression models were employed to explore the association of exposure to digital platforms with the likelihood of conventional tobacco and new tobacco product use among this population. RESULTS: Among the participants, 83.2% reported witnessing individuals smoking, 61.6% observed identifiable logos or explicit advertisements, and 77.6% encountered indirect product placement on social media. Notably, exposure to conventional tobacco product placement (AOR=1.71; 95% CI: 1.27-2.30) emerged as the variable most significantly associated with an increased probability of tobacco use. Furthermore, exposure to advertising related to new tobacco products (AOR=2.47; 95% CI: 1.90-3.21) was linked to a heightened likelihood of subsequent use. Similarly, the direct promotion of these novel products is also associated with a higher probability of conventional tobacco use (AOR=1.58; 95% CI: 1.21-2.07). CONCLUSIONS: A reciprocal impact was identified, with the promotion of vaping being associated with an elevated probability of engaging in conventional tobacco smoking. Urgent attention is warranted for formulating public policies to mitigate the adverse effects of such insidious indirect advertising practices on digital platforms.

Comparison between the use of subdural and subgaleal drainage in treatment of chronic subdural hematoma.

BACKGROUND AND OBJECTIVES: Chronic subdural hematoma (CSDH) is one of the most common pathologies in our daily practice. The standard treatment is the evacuation making a burr-hole and placement of a subdural drainage, which has shown to decrease its recurrence. However, this procedure can entail risks such as parenchymal damage, infection, or the onset of seizures, prompting the consideration of subgaleal drainage as an alternative. Our objective is to compare the use of subdural and subgaleal drainage in a cohort of patients undergoing intervention for CSDH, as well as to analyze the differences in complication rates and recurrence between the two groups. METHODOLOGY: A retrospective analytical observational study was conducted, analyzing 152 patients diagnosed with CSDH who underwent intervention at our center from January 2020 to April 2022. Patients in whom drainage was not placed were excluded. In all patients, a burr-hole was performed and the type of drainage was chosen by the neurosurgeon. RESULTS: Out of the 152 patients, subdural drainage was placed in 80 cases (52.63%), while subgaleal drainage was used in 72 cases (47.37%). There were no significant differences in the recurrence rate (30% in the subdural drainage group vs. 20.83% in the subgaleal drainage group; P = .134) or in the complication rate (7.5% in the subdural drainage group vs. 5.5% in the subgaleal drainage group; P = .749). CONCLUSIONS: Subgaleal drainage shows similar clinical outcomes with a recurrence and complication rate comparable to subdural drainage, suggesting it as a safe and effective alternative to subdural drainage in the treatment of CSDH.

Removal of metals and emergent contaminants from liquid digestates in constructed wetlands for agricultural reuse.

Given the increasing pressure on water bodies, it is imperative to explore sustainable methodologies for wastewater treatment and reuse. The simultaneous presence of multiples contaminants in complex wastewater, such as the liquid effluents from biogas plants, can compromise biological treatment effectiveness for reclaiming water. Vertical subsurface flow constructed wetlands were established as low-cost decentralized wastewater treatment technologies to treat the liquid fraction of digestate from municipal organic waste with metals, antibiotics, and antibiotic resistance genes, to allow its reuse in irrigation. Twelve lab-scale planted constructed wetlands were assembled with gravel, light expanded clay aggregate and sand, testing four different treating conditions (liquid digestate spiked with oxytetracycline, sulfadiazine, or ofloxacin, at 100 µg/ L, or without dosing) during 3 months. Physicochemical parameters (pH, chemical oxygen demand (COD), nutrients, metals, and antibiotics), the microbial communities dynamics (through 16S high-throughput sequencing) and antibiotic resistance genes removal (qPCR) were monitored in influents and effluents. Systems removed 85.8%-96.9% of organic matter (as COD), over 98.1% of ammonium and phosphate ions, and 69.3%-99.4% of nitrate and nitrite ions, with no significant differences between the presence or absence of antibiotics. Removal of Fe, Mn, Zn, Cu, Pb and Cr exceeded 82% in all treatment cycles. The treatment also removed oxytetracycline, sulfadiazine and ofloxacin over 99%, and decreased intl1, tetA, tetW, sul1 and qnrS gene copies. Nonetheless, after 3 months of ofloxacin dosing, qnrS gene started being detected. Removal processes relied on high HRT (14 days) and various mechanisms including sorption, biodegradation, and precipitation. Microbial community diversity in liquid digestate changed significantly after treatment in constructed wetlands with a decrease in the initial Firmicutes dominance, but with no clear effect of antibiotics on the microbial community structure. Removals above 85% and 94% were observed for Streptococcus and Clostridium, respectively. Results suggest that vertical subsurface flow constructed wetlands were a suitable technology for treating the liquid digestate to reuse it in irrigation agricultural systems, contributing to the circular bioeconomy concept. However, a more profound understanding of effective wastewater treatment strategies is needed to avoid antibiotic resistance genes dissemination.

End-of-life care needs in cancer patients: a qualitative study of patient and family experiences.

BACKGROUND: Cancer is a disease that transcends what is purely medical, profoundly affecting the day-to-day life of both patients and family members. Previous research has shown that the consequences of cancer are greatly aggravated in patients at the end of life, at a time when they must also grapple with numerous unmet needs. The main objective of this study was to obtain more in-depth insight into these needs, primarily in patients with end-stage cancer nearing death. METHODS: Semi-structured interviews were conducted in Spain with cancer patients at the end of life (n = 3) and their family members (n = 12). The findings from the interviews were analyzed using qualitative thematic analysis and a grounded theory approach. RESULTS: Four major themes emerged from the interviews that explored the needs and concerns of patients with cancer at the end of life: (1) physical well-being (2) emotional well-being (3) social well-being and (4), needs relating to information and autonomous decision-making. The interviews also shed light on the specific needs of family members during this period, namely the difficulties of managing increased caregiver burden and maintaining a healthy work-life balance. CONCLUSIONS: A lack of support, information and transparency during a period of immense vulnerability makes the end-of-life experience even more difficult for patients with cancer. Our findings highlight the importance of developing a more in-depth understanding of the needs of this population, so that informed efforts can be made to improve palliative healthcare and implement more comprehensive care and support at the end of life.

Impact on the time elapsed since SARS-CoV-2 infection, vaccination history, and number of doses, on protection against reinfection.

SARS-CoV-2 reinfections have been frequent, even among those vaccinated. The aim of this study is to know if hybrid immunity (infection + vaccination) is affected by the moment of vaccination and number of doses received. We conducted a retrospective study in 746 patients with a history of COVID-19 reinfection and recovered the dates of infection and reinfection and vaccination status (date and number of doses). To assess differences in the time to reinfection(tRI) between unvaccinated, vaccinated before 6 months, and later; and comparing one, two or three doses (incomplete, complete and booster regime) we performed the log-rank test of the cumulative incidence calculated as 1 minus the Kaplan-Meier estimator. Also, an adjusted Cox-regression was performed to evaluate the risk of reinfection in all groups. The tRI was significantly higher in those vaccinated vs. non-vaccinated (p < 0.001). However, an early incomplete regime protects similar time than not receiving a vaccine. Vaccination before 6 months after infection showed a lower tRI compared to those vaccinated later with the same regime (adj-p < 0.001). Actually, early vaccination with complete and booster regimes provided lower length of protection compared to vaccinating later with incomplete and complete regime, respectively. Vaccination with complete and booster regimes significantly increases the tRI (adj-p < 0.001). Vaccination increases the time it takes for a person to become reinfected with SARS-CoV-2. Increasing the time from infection to vaccination increases the time in which a person could be reinfected and reduces the risk of reinfection, especially in complete and booster regimes. Those results emphasize the role of vaccines and boosters during the pandemic and can guide strategies on future vaccination policy.

A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells.

Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.

Efficacy of physical exercise on sleep quality in patients with chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: To revise and critically summarize the available scientific evidence regarding the effect of exercise on sleep quality in patients with chronic kidney disease (CKD). METHODS: A systematic review of randomized controlled trials (RCTs) and comparative studies was conducted, searching MEDLINE/PubMed, SPORTDiscus, and Scopus using keywords "Exercise", "Physical Activity", "Chronic Kidney Disease," and "Sleep". The methodological quality of included studies was assessed using the PEDRo and MINORS scales. RESULTS: A total of 8 RCTs and 3 comparative studies were included, showing a low (n = 1), fair (n = 7), and good (n = 3) methodological quality. Most of the studies included patients undergoing hemodialysis (HD) (n = 8). Self-reported sleep quality (n = 9), sleepiness (n = 2), and objective sleep status (n = 2) were the main outcomes analyzed. The most frequent exercise interventions included aerobic training (n = 7), resistance training (n = 2), or a combination of both (n = 4). Generally, exercise induced positive effects on the reported outcomes. Data synthesis indicated that participants who exercised obtained significant improvements on their self-reported sleep quality in comparison with those included in the control groups, with a mean difference in the Pittsburgh Sleep Quality Index of - 5.27 points (95% CI - 7.76, - 2.77; p < 0.001). CONCLUSION: Preliminary scientific evidence indicates that patients with CKD, especially those undergoing HD, report improvements in self-reported sleep quality after taking part in aerobic exercise programs, while combined training interventions yielded diverse findings. The effects of exercise on sleepiness and objective sleep status were backed by few studies with mixed results.

Susceptibility Evaluation to Fire Blight and Genome-Wide Associations within a Collection of Asturian Apple Accessions.

Fire blight, caused by Erwinia amylovora, is one of the most devastating apple diseases. The selection of cultivars of low susceptibility and the study of the genetic mechanisms of the disease play important roles in fire blight management. The susceptibility level to fire blight was evaluated in 102 accessions originating from Asturias, a cider-producing region located in the north of Spain with a wide apple germplasm. Evaluations took place under quarantine conditions using artificial inoculations of grafted plants. The results revealed wide variation in susceptibility responses and low-susceptible cultivars were identified. In addition, 91 cultivars were genotyped using the Affymetrix Axiom® Apple 480 K SNP array to conduct genome-wide association studies (GWAS). A statistically significant signal was detected on chromosome 10 using the multi-locus mixed model (MLMM). Two genes were identified as major putative candidate genes: a TIR-NBS-LRR class disease protein and a protein containing a development and cell death (DCD) domain. The outcomes of this study provide a promising source of information, particularly in the context of cider apples, and set a starting point for future genetic and breeding approaches.

[Cetoacidosis diabética al diagnóstico de diabetes mellitus tipo 1 en Asturias entre 2011 y 2020: influencia de la duración de los síntomas en la prevalencia de cetoacidosis y en la pérdida de peso.] / Diabetic ketoacidosis at diagnosis of type 1 diabetes in Asturias (Spain) between 2011 and 2020: influence of symptom duration on prevalence of ketoacidosis and weight loss.

OBJECTIVE: Diabetic ketoacidosis (DKA) is a serious complication that usually occurs at diagnosis of type 1 diabetes mellitus (T1D). However, the prevalence of DKA at diagnosis of T1D is heterogeneous in different regions of the world. The aim of this study was to determine the prevalence of DKA at diagnosis of T1D in Asturias. METHODS: This study included all patients under nineteen years of age diagnosed with T1D in Asturias between 2011 and 2020. Retrospective review of medical records was performed to analyse DKA and other characteristics at diagnosis. A log binary regression model was constructed to obtain an estimate of the prevalence ratio of DKA to diagnosis in the years studied. RESULTS: A total of 267 people were diagnosed with a mean age of 9.85±4.46 years. The prevalence of DKA at diagnosis during this period was 38.63%. There was an increasing trend, with a prevalence ratio over the years studied of 1.015 (95%CI: 0.96-1.07; p=0.61). Duration of symptoms before diagnosis was 4.57±7.64 weeks. Weight loss was 7.56±7.26%, being more than 10% of previous weight in almost half of the patients who loosed weight. There was a positive relationship between symptoms duration and prevalence of DKA and between time to diagnosis and weight loss. CONCLUSIONS: Asturias has a high prevalence of DKA at diagnosis of T1D, slightly higher than observed in other studies at national level and higher than in other similar countries, with a tendency to increase. Delayed diagnosis is a key factor in the prevalence of DKA and weight loss. Thus, health actions are needed for the early detection of T1D to avoid DKA at diagnosis.

OBJETIVO: La cetoacidosis diabética (CAD) es una complicación grave que puede producirse al diagnóstico de la diabetes mellitus tipo 1 (DM1). La prevalencia de CAD al diagnóstico de DM1 es desigual en las distintas regiones del mundo. El objetivo de este estudio fue conocer la prevalencia de CAD al diagnóstico de DM1 en Asturias. METODOS: Se incluyeron los pacientes menores de diecinueve años diagnosticados de DM1 en Asturias entre 2011 y 2020. Mediante revisión de historia clínica se analizó la prevalencia de CAD así como otras características al diagnóstico. Se construyó un modelo de regresión log binaria para obtener una estimación de la razón de prevalencia de CAD al diagnóstico en los años estudiados. RESULTADOS: Se diagnosticaron 267 personas con edad media de 9,85±4,46 años. La prevalencia de CAD al diagnóstico fue del 38,63%. Se apreció una tendencia al aumento, con una razón de prevalencia en los años estudiados de 1,015 (IC95%:0,96-1,07; p=0,61). La duración de los síntomas hasta el diagnóstico fue de 4,57±7,64 semanas. La pérdida de peso fue de 7,56±7,26%, siendo superior al 10% en casi la mitad de los pacientes que perdieron peso. Se apreció relación entre la duración de los síntomas y la prevalencia de CAD, y entre el tiempo de evolución y la pérdida de peso. CONCLUSIONES: Asturias presenta una alta prevalencia de CAD al diagnóstico de DM1, levemente superior a otros estudios a nivel nacional y superior a otros países de nuestro entorno, con tendencia al aumento. El retraso diagnóstico es clave en la prevalencia de CAD y en la pérdida de peso. Son necesarias actuaciones sanitarias para la detección precoz de la DM1.

Adaptation, reliability and validity of health-related quality of life questionnaires: Disabkids chronic and specific diabetes disease in children and adolescents with diabetes mellitus type 1.

INTRODUCTION: It is recommended to periodically evaluate the health-related quality of life (HRQoL) in children and adolescents with type 1 diabetes mellitus (DM1). Despite this, no specific paediatric HRQoL instrument for DM1 has been validated in Spanish. OBJECTIVES: Multicentre, prospective descriptive study in children and adolescents with DM1 with the aim of carrying out cross-cultural adaptation to Spanish and evaluating the reliability and validity of the DISABKIDS chronic disease and diabetes-specific HRQoL questionnaires, using reverse translation. MATERIAL AND METHODS: Sociodemographic variables were compiled together with the most recent capillary glycated haemoglobin (HbA1c) value and HRQoL questionnaires were handed out to 200 Spanish children and adolescents with DM1 aged between 8 and 18 years of age under evaluation in 12 different hospitals. RESULTS: The mean score on the HRQoL questionnaire (patient version) for chronic disease was 80.32 (13.66), being significantly lower (P = .04) in patients with a shorter duration of the disease (≤5 years): 78.34 (13.70) vs. 82.60 (13.36). The mean score of the DM1-specific modules was: 60.81 (16.23) for disease impact and 65.59 (26.19) for treatment impact. The mean HbA1c value was 7.08 (0.79), with no differences (P > .05) noted in the mean score of the HRQoL instruments in patients with HbA1c ≤7% vs. HbA1c >7%. The Cronbach α value varied between 0.72 and 0.90. CONCLUSIONS: The Spanish versions of the DISABKIDS HRQoL instruments meet the proposed objectives of semantic equivalence and internal consistency, making it possible to periodically assess HRQoL in these patients. The good average glycaemic control presented by the patients may explain why no difference was found in the HRQoL instruments based on the HbA1c value.

Protocol to measure centrosome cohesion deficits mediated by pathogenic LRRK2 in cultured cells using confocal microscopy.

The present protocol allows for quantification of inter-centrosome distances in G2 phase cells by confocal fluorescence microscopy to determine centrosome cohesion deficits. We describe transfection and immunofluorescence approaches followed by image acquisition and analysis of inter-centrosome distances. This protocol is for adherent A549 cells transiently overexpressing pathogenic LRRK2 and for immortalized murine embryonic fibroblasts endogenously expressing LRRK2 but is amenable to any other cultured cell type as well. For complete details on the use and execution of this protocol, please refer to Fdez et al.1 and Lara Ordóñez et al.2.

Use of wood and cork in biofilters for the simultaneous removal of nitrates and pesticides from groundwater.

About 13% and 7% of monitored groundwater stations in Europe exceed the permitted levels of nitrates (50 mg NO3- L-1) or pesticides (0.1 µg L-1), respectively. Although slow sand filtration can remove nitrates via denitrification when oxygen is limited, it requires an organic carbon source. The present study evaluates the performance of the use of wood pellets and granulated cork as carbon sources in bench-scale biofilters operated under water-saturated and water-unsaturated conditions for more than 400 days. The biofilters were monitored for nitrate (200 mg L-1) and pesticide (mecoprop, diuron, atrazine, and bromacil, each at a concentration of 5 µg L-1) attenuation, as well as for the formation of nitrite and pesticide transformation products. Microbiological characterization of each biofilter was also performed. The water-saturated wood biofilter achieved the best nitrate removal (>99%), while the cork biofilters lost all denitrification power over time (from 38% to no removal). The unsaturated biofilter columns were not effective for removing nitrates (20-30% removal). As for pesticides, all the biofilters achieved high removal rates of mecoprop and diuron (>99% and >75%, respectively). Atrazine removal was better in the wood-pellet biofilters than the cork ones (68-96% vs. 31-38%). Bromacil was only removed in the water-unsaturated cork biofilter (67%). However, a bromacil transformation product was formed there. The water-saturated wood biofilter contained the highest number of denitrifying microorganisms, with Methyloversatilis as the characteristic genus. Microbial composition could explain the high removal of pesticides and nitrates achieved in the wood-pellet biofilter. Overall, the results indicate that wood-pellet biofilters operated under water-saturated conditions are a good solution for treating groundwater contaminated with nitrates and pesticides.

Longitudinal Monitoring of Microstructural Alterations in Cerebral Ischemia with in Vivo Diffusion-weighted MR Spectroscopy.

Background The time course of cellular damage after acute ischemic stroke (IS) is currently not well known, and specific noninvasive markers of microstructural alterations linked to inflammation are lacking, which hinders the monitoring of anti-inflammatory treatment. Purpose To evaluate the temporal pattern of neuronal and glial microstructural changes after stroke using in vivo single-voxel diffusion-weighted MR spectroscopy. Materials and Methods In this prospective longitudinal study, participants with IS and healthy volunteers (HVs) underwent MRI at 3.0 T. In participants with IS, apparent diffusion coefficients (ADCs) and concentrations of total N-acetyl-aspartate (tNAA), total creatine (tCr), and total choline (tCho) were measured in volumes of interest (VOIs), including the lesion VOI (VOIles) and the contralateral VOI (VOIcl) at 2 weeks, 1 month, and 3 months after IS. HVs were examined once, with VOIs located in the same brain regions as participants with IS. Within- and between-group differences and longitudinal changes were examined using linear mixed-effects models. Results Twenty participants with IS (mean age, 61 years ± 13 [SD]; 12 women) and 20 HVs (mean age, 59 years ± 13; 12 women) were evaluated. No differences in ADCs or concentrations were observed in VOIcl between HVs and participants with IS. In participants with IS, the ADC of tCr was higher in VOIles than in VOIcl at 1 month (+14.4%, P = .004) and 3 months after IS (+19.0%, P < .001), while the ADC of tCho was higher only at 1 month (+16.7%, P = .001). No difference in the ADC of tNAA was observed between the two VOIs at any time point. tNAA and tCr concentrations were lower in VOIles than in VOIcl and were stable over time (approximately -50% and -30%, respectively; P < .001). Conclusion High diffusivity of choline-containing compounds and total creatine (tCr) in the ischemic lesion 1 month after ischemic stroke (IS) indicates glial morphologic changes, suggesting that active inflammation is still ongoing at this time point. High tCr diffusivity up to 3 months after IS likely reflects the presence of astrogliosis at the chronic stage of cerebral ischemia. Clinical trial registration no. NCT02833961 © RSNA, 2022 Online supplemental material is available for this article.

Fermentation of D-xylose to Ethanol by Saccharomyces cerevisiae CAT-1 Recombinant Strains.

Ethanol production by the D-xylose fermentation of lignocellulosic biomass would augment environmental sustainability by increasing the yield of biofuel obtained per cultivated area. A set of recombinant strains derived from the industrial strain Saccharomyces cerevisiae CAT-1 was developed for this purpose. First, two recombinant strains were obtained by the chromosomal insertion of genes involved in the assimilation and transport of D-xylose (Gal2-N376F). Strain CAT-1-XRT was developed with heterologous genes for D-xylose metabolism from the oxo-reductive pathway of Scheffersomyces stipitis (XYL1-K270R, XYL2); and strain CAT-1-XIT, with D-xylose isomerase (xylA gene, XI) from Streptomyces coelicolor. Moreover, both recombinant strains contained extra copies of homologous genes for xylulose kinase (XK) and transaldolase (TAL1). Furthermore, plasmid (pRS42K::XI) was constructed with xylA from Piromyces sp. transferred to CAT-1, CAT-1-XRT, and CAT-1-XIT, followed by an evolution protocol. After 10 subcultures, CAT-1-XIT (pRS42K::XI) consumed 74% of D-xylose, producing 12.6 g/L ethanol (0.31 g ethanol/g D-xylose). The results of this study show that CAT-1-XIT (pRS42K::XI) is a promising recombinant strain for the efficient utilization of D-xylose to produce ethanol from lignocellulosic materials.

Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB.

Increased brain iron content has been consistently reported in sporadic Parkinson's disease (PD) patients, and an increase in cytosolic free iron is known to cause oxidative stress and cell death. However, whether iron also accumulates in susceptible brain areas in humans or in mouse models of familial PD remains unknown. In addition, whilst the lysosome functions as a critical intracellular iron storage organelle, little is known about the mechanisms underlying lysosomal iron release and how this process is influenced by lysosome biogenesis and/or lysosomal exocytosis. Here, we report an increase in brain iron content also in PD patients due to the common G2019S-LRRK2 mutation as compared to healthy age-matched controls, whilst differences in iron content are not observed in G2019S-LRRK2 knockin as compared to control mice. Chemically triggering iron overload in cultured cells causes cytotoxicity via the endolysosomal release of iron which is mediated by TRPML1. TFEB expression reverts the iron overload-associated cytotoxicity by causing lysosomal exocytosis, which is dependent on a TRPML1-mediated increase in cytosolic calcium levels. Therefore, approaches aimed at increasing TFEB levels, or pharmacological TRPML1 activation in conjunction with iron chelation may prove beneficial against cell death associated with iron overload conditions such as those associated with PD.

Effect of EARLY administration of DEXamethasone in patients with COVID-19 pneumonia without acute hypoxemic respiratory failure and risk of development of acute respiratory distress syndrome (EARLY-DEX COVID-19): study protocol for a randomized controlled trial.

BACKGROUND: Corticosteroids are one of the few drugs that have shown a reduction in mortality in coronavirus disease 2019 (COVID-19). In the RECOVERY trial, the use of dexamethasone reduced 28-day mortality compared to standard care in hospitalized patients with suspected or confirmed COVID-19 requiring supplemental oxygen or invasive mechanical ventilation. Evidence has shown that 30% of COVID-19 patients with mild symptoms at presentation will progress to acute respiratory distress syndrome (ARDS), particularly patients in whom laboratory inflammatory biomarkers associated with COVID-19 disease progression are detected. We postulated that dexamethasone treatment in hospitalized patients with COVID-19 pneumonia without additional oxygen requirements and at risk of progressing to severe disease might lead to a decrease in the development of ARDS and thereby reduce death. METHODS/DESIGN: This is a multicenter, randomized, controlled, parallel, open-label trial testing dexamethasone in 252 adult patients with COVID-19 pneumonia who do not require supplementary oxygen on admission but are at risk factors for the development of ARDS. Risk for the development of ARDS is defined as levels of lactate dehydrogenase > 245 U/L, C-reactive protein > 100 mg/L, and lymphocyte count of < 0.80 × 109/L. Eligible patients will be randomly assigned to receive either dexamethasone or standard of care. Patients in the dexamethasone group will receive a dose of 6 mg once daily during 7 days. The primary outcome is a composite of the development of moderate or more severe ARDS and all-cause mortality during the 30-day period following enrolment. DISCUSSION: If our hypothesis is correct, the results of this study will provide additional insights into the management and progression of this specific subpopulation of patients with COVID-19 pneumonia without additional oxygen requirements and at risk of progressing to severe disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04836780. Registered on 8 April 2021 as EARLY-DEX COVID-19.

The LRRK2 signaling network converges on a centriolar phospho-Rab10/RILPL1 complex to cause deficits in centrosome cohesion and cell polarization.

The Parkinson's-disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases including Rab8 and Rab10, which enhances their binding to RILPL1 and RILPL2. The nascent interaction between phospho-Rab10 and RILPL1 blocks ciliogenesis in vitro and in the intact brain, and interferes with the cohesion of duplicated centrosomes in dividing cells. We show here that regulators of the LRRK2 signaling pathway including vps35 and PPM1H converge upon causing centrosomal deficits. The cohesion alterations do not require the presence of other LRRK2 kinase substrates including Rab12, Rab35 and Rab43 or the presence of RILPL2. Rather, they depend on the RILPL1-mediated centrosomal accumulation of phosphorylated Rab10. RILPL1 localizes to the subdistal appendage of the mother centriole, followed by recruitment of the LRRK2-phosphorylated Rab proteins to cause the centrosomal defects. The centrosomal alterations impair cell polarization as monitored by scratch wound assays which is reverted by LRRK2 kinase inhibition. These data reveal a common molecular pathway by which enhanced LRRK2 kinase activity impacts upon centrosome-related events to alter the normal biology of a cell.