Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (ß = 12.85; P < 0.001) that was independent of amyloid deposits (ß = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (ß = 3.64; P = 0.03) and argyrophilic grain disease (ß = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.

Role of Posterior Medial Thalamus in the Modulation of Striatal Circuitry and Choice Behavior.

The posterior medial (POm) thalamus is heavily interconnected with sensory and motor circuitry and is likely involved in behavioral modulation and sensorimotor integration. POm provides axonal projections to the dorsal striatum, a hotspot of sensorimotor processing, yet the role of POm-striatal projections has remained undetermined. Using optogenetics with slice electrophysiology, we found that POm provides robust synaptic input to direct and indirect pathway striatal spiny projection neurons (D1- and D2-SPNs, respectively) and parvalbumin-expressing fast spiking interneurons (PVs). During the performance of a whisker-based tactile discrimination task, POm-striatal projections displayed learning-related activation correlating with anticipatory, but not reward-related, pupil dilation. Inhibition of POm-striatal axons across learning caused slower reaction times and an increase in the number of training sessions for expert performance. Our data indicate that POm-striatal inputs provide a behaviorally relevant arousal-related signal, which may prime striatal circuitry for efficient integration of subsequent choice-related inputs.

Respiratory drive heterogeneity associated with systemic inflammation and vascular permeability in acute respiratory distress syndrome.

BACKGROUND: In acute respiratory distress syndrome (ARDS), respiratory drive often differs among patients with similar clinical characteristics. Readily observable factors like acid-base state, oxygenation, mechanics, and sedation depth do not fully explain drive heterogeneity. This study evaluated the relationship of systemic inflammation and vascular permeability markers with respiratory drive and clinical outcomes in ARDS. METHODS: ARDS patients enrolled in the multicenter EPVent-2 trial with requisite data and plasma biomarkers were included. Neuromuscular blockade recipients were excluded. Respiratory drive was measured as PES0.1, the change in esophageal pressure during the first 0.1 s of inspiratory effort. Plasma angiopoietin-2, interleukin-6, and interleukin-8 were measured concomitantly, and 60-day clinical outcomes evaluated. RESULTS: 54.8% of 124 included patients had detectable respiratory drive (PES0.1 range of 0-5.1 cm H2O). Angiopoietin-2 and interleukin-8, but not interleukin-6, were associated with respiratory drive independently of acid-base, oxygenation, respiratory mechanics, and sedation depth. Sedation depth was not significantly associated with PES0.1 in an unadjusted model, or after adjusting for mechanics and chemoreceptor input. However, upon adding angiopoietin-2, interleukin-6, or interleukin-8 to models, lighter sedation was significantly associated with higher PES0.1. Risk of death was less with moderate drive (PES0.1 of 0.5-2.9 cm H2O) compared to either lower drive (hazard ratio 1.58, 95% CI 0.82-3.05) or higher drive (2.63, 95% CI 1.21-5.70) (p = 0.049). CONCLUSIONS: Among patients with ARDS, systemic inflammatory and vascular permeability markers were independently associated with higher respiratory drive. The heterogeneous response of respiratory drive to varying sedation depth may be explained in part by differences in inflammation and vascular permeability.

A Zero-Gap Gas Phase Photoelectrolyzer for CO2 Reduction with Porous Carbon Supported Photocathodes.

A modified Metal-Organic Framework UiO-66-NH2-based photocathode in a zero-gap gas phase photoelectrolyzer was applied for CO2 reduction. Four types of porous carbon fiber layers with different wettability were employed to tailor the local environment of the cathodic surface reactions, optimizing activity and selectivity towards formate, methanol, and ethanol. Results are explained by mass transport through the different type and arrangement of carbon fiber support layers in the photocathodes and the resulting local environment at the UiO-66-NH2 catalyst. The highest energy-to-fuel conversion efficiency of 1.06% towards hydrocarbons was achieved with the most hydrophobic carbon fiber (H23C2). The results are a step further in understanding how the design and composition of the electrodes in photoelectrochemical electrolyzers can impact the CO2 reduction efficiency and selectivity.

Analysis of Spatial Offensive Performance in Handball: Differences between Men's and Women's Senior World Championships.

The aim of this study was to carry out a descriptive analysis of the main performance variables of national teams that competed in the Men's (Germany-Denmark 2019) and Women's (Germany 2017) senior handball World Cups, and to compare the spatial offensive performance indices of laterality and depth according to the gender of players, considering for this purpose the total number of throws made according to the finishing area. A documentary study was carried out based on the total number of throws made in 192 male and 154 female games of 48 national teams belonging to 33 countries, which participated in previous World Cups. The data were collected from the International Handball Federation (IHF) statistics. The results showed that the areas from which the highest number of shots were taken in both World Cups were the central and shallow areas of the field. Several gender differences were observed. More specifically, male teams made much more attempts from the left side area than female teams (data), who finished from the right side (data). The depth index reflected that, although the dominant execution by gender was from deep offensive zones, men's teams finished more often from the 1st offensive line, while female teams finished from the 2nd offensive line. This information will be useful for coaches in designing training tasks and for players in improving decision making.

Cell-Type Specific Connectivity of Whisker-Related Sensory and Motor Cortical Input to Dorsal Striatum.

The anterior dorsolateral striatum (DLS) is heavily innervated by convergent excitatory projections from the primary motor (M1) and sensory cortex (S1) and considered an important site of sensorimotor integration. M1 and S1 corticostriatal synapses have functional differences in their connection strength with striatal spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in the DLS and, as a result, exert distinct influences on sensory-guided behaviors. In the present study, we tested whether M1 and S1 inputs exhibit differences in the subcellular anatomical distribution of striatal neurons. We injected adeno-associated viral vectors encoding spaghetti monster fluorescent proteins (sm.FPs) into M1 and S1 in male and female mice and used confocal microscopy to generate 3D reconstructions of corticostriatal inputs to single identified SPNs and FSIs obtained through ex vivo patch clamp electrophysiology. We found that M1 and S1 dually innervate SPNs and FSIs; however, there is a consistent bias towards the M1 input in SPNs that is not found in FSIs. In addition, M1 and S1 inputs were distributed similarly across the proximal, medial, and distal regions of SPN and FSI dendrites. Notably, closely localized M1 and S1 clusters of inputs were more prevalent in SPNs than FSIs, suggesting that cortical inputs are integrated through cell-type specific mechanisms. Our results suggest that the stronger functional connectivity from M1 to SPNs compared to S1, as previously observed, is due to a higher quantity of synaptic inputs. Our results have implications for how sensorimotor integration is performed in the striatum through cell-specific differences in corticostriatal connections.

Clinical study with sandblasted dental implants: a 17-year retrospective follow up.

Sandblasting is a standard procedure used for treating dental implant (DI) surfaces to enhance the osseointegration with known clinical success. This clinical study aimed to evaluate the long-term clinical outcomes of DIs with external hexagon connections and a surface sandblasted with calcium phosphate. Two hundred and seventy-five Mg-osseous™ (Mozo-Grau™) screw DIs were placed in 86 patients using a two-stage surgical technique and conventional loading protocol (at three months). Dental implants and prosthetic clinical findings were evaluated during a 17-year follow up. Four DIs were lost during the healing period, and 108 prostheses were placed over the 271 DIs left: 58 unitary implant-supported prosthesis (ISP), 31 partially ISP, 14 full-arch ISP, and five overdentures. Fourteen DIs were lost during the follow-up period. Clinical results indicated a DI survival rate of 93.50%. A total of 11.80% of DIs showed peri-implantitis as the primary biological complication. The mean (SD) marginal bone loss was 1.78 (0.40) mm, ranging from 0.90 to 2.80 mm. The most frequent complication was mechanical prosthodontic complications (24.40%). Sandblasted surface DIs inserted in both maxillary and mandibular areas produce favourable long-term (17-year follow up) outcomes and stable tissue conditions when a delayed loading protocol is followed.

Complete chloroplast genome of the marine red alga Rhodochorton tenue (Rhodochortonaceae, Rhodophyta) from San Juan Island, Washington.

We present the complete chloroplast genome sequence of Rhodochorton tenue from San Juan Island, Washington. The chloroplast genome of R. tenue is 192,037 bp in length, contains 244 genes, and is similar in content to Acrochaetium secundatum. Rhodochorton tenue is genetically distinct from Rhodochorton purpureum from the North Atlantic Ocean.

A paradigm for ethanol consumption in head-fixed mice during prefrontal cortical two-photon calcium imaging.

The prefrontal cortex (PFC) is a hub for cognitive behaviors and is a key target for neuroadaptations in alcohol use disorders. Recent advances in genetically encoded sensors and functional microscopy allow multimodal in vivo PFC activity recordings at subcellular and cellular scales. While these methods could enable a deeper understanding of the relationship between alcohol and PFC function/dysfunction, they typically require animals to be head-fixed. Here, we present a method in mice for binge-like ethanol consumption during head-fixation. Male and female mice were first acclimated to ethanol by providing home cage access to 20% ethanol (v/v) for 4 or 8 days. After home cage drinking, mice consumed ethanol from a lick spout during head-fixation. We used two-photon calcium imaging during the head-fixed drinking paradigm to record from a large population of PFC neurons (>1000) to explore how acute ethanol affects their activity. Drinking exerted temporally heterogeneous effects on PFC activity at single neuron and population levels. Intoxication modulated the tonic activity of some neurons while others showed phasic responses around ethanol receipt. Population level activity did not show tonic or phasic modulation but tracked ethanol consumption over the minute-timescale. Network level interactions assessed through between-neuron pairwise correlations were largely resilient to intoxication at the population level while neurons with increased tonic activity showed higher synchrony by the end of the drinking period. By establishing a method for binge-like drinking in head-fixed mice, we lay the groundwork for leveraging advanced microscopy technologies to study alcohol-induced neuroadaptations in PFC and other brain circuits. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".

La promoción de la lectura y su relación con las vocaciones y entornos profesionales / Reading promotion and its association with professional vocations and care settings

Introducción: la promoción de hábitos de vida saludables es una práctica habitual entre los pediatras. Dentro de estos se encuentra la promoción de la lectura, que entraña numerosos beneficios para la infancia: estimula la actividad cerebral y su reserva cognitiva, aumenta la concentración y el desarrollo del lenguaje y permite trabajar las emociones. El objetivo de este estudio es conocer la realidad de la práctica de la promoción de la lectura desde las consultas de Pediatría, así como su relación con la vocación pediátrica (clínica, preventiva y social) y los entornos profesionales (residencia, hospital y Atención Primaria). Material y métodos: estudio transversal, descriptivo de ámbito nacional, mediante encuesta en línea a residentes de Pediatría, pediatras hospitalarios/as y de Atención Primaria llevado a cabo en marzo de 2022. Resultados: participaron 326 pediatras, un 16,8% hospitalarios/as, un 69,8% de Atención Primaria y 13,4% residentes de Pediatría. El 18,8% seleccionaron la vocación preventiva, el 60,8%, la clínica y el 20,5%, la social. Junto con una descripción detallada del tipo de actividades de promoción de la lectura que se realizan en nuestro país, los resultados mostraron, en primer lugar, que la vocación médica se relacionó con su mayor o menor realización (χ2(2) = 13,11, p <0,001), siendo los pediatras con vocación social los que informaron llevarlas a cabo en un mayor porcentaje. En segundo lugar, también el ámbito de trabajo apareció como un condicionante para la realización de estas actividades (χ2(2) = 19,0, p <0,001), que se llevan a cabo más frecuentemente en las consultas de Atención Primaria. Conclusiones: las actividades de promoción de la lectura son realizadas mayormente por los profesionales de Atención Primaria, en el marco de otras actividades de promoción de la salud, vinculadas principalmente con su mayor vocación por la Pediatría social. (AU)

Introduction: healthy lifestyle promotion is a common practice among paediatricians. Reading promotion is included in that practice. It has numerous benefits for children: it stimulates brain activity and cognitive reserve, improves concentration and language development and helps develop emotional skills.The aim of our study was to assess the implementation of reading promotion activities in real-world paediatric care practice, as well as its association with the underlying vocation for paediatrics (clinical, preventive or social) and the care setting (residency programme, hospital and primary care). Material and methods: cross-sectional, descriptive study of national scope through an online survey of paediatrics residents and hospital-based and primary care paediatricians carried out in March 2022. Results: 326 paediatricians participated, of who 16.8% worked in hospitals, 69.8% in primary care and were 13.4% paediatrics residents. Of this total, 18.8% reported a vocation for preventive care, 60.8% for clinical work and 20.5% for social paediatrics. In addition to carrying a detailed descriptive analysis of the type of reading promotion activities carried out in Spain, we found, firstly, that the vocation for medical practice was associated to the frequency of reading promotion (χ2(2)=13.11; p<0.001), with a higher proportion of paediatricians with a social vocation reporting performance of these activities. Secondly, the care setting also seemed to be a determining factor for the performance of these activities (χ2(2)=19.0; p<0.001), which were conducted more frequently in the primary care setting. Conclusion: activities to promote reading are carried out mainly by primary care professionals within the framework of other health promotion work, and their performance was mainly associated with the greater proportion of primary care professionals with a vocation for social paediatrics. (AU)

Immediate Loading of Implants with Fixed Rehabilitations in Geriatric Edentulous Patients; Biological Complications.

BACKGROUND: This study aimed to report the outcomes of the immediate loading of implants with fixed rehabilitations in edentulous geriatric patients. METHODS: Edentulous geriatric patients were diagnosed with an oral examination, radiographic evaluation, and intermaxillary relations and treated with fixed rehabilitation over several implants. After immediate surgery, the implants were immediately loaded with a fully fixed prosthesis. RESULTS: Twenty-four patients (20 females and 4 males) were treated using a total 210 implants. All patients (100%) had a previous history of periodontitis. Eleven patients (45.8%) were smokers. Eleven patients (45.8%) suffered from chronic medical diseases (i.e., diabetes, cardiovascular diseases). The study's clinical follow-up period extended for three years, during which thirty-three fixed prostheses were installed over the implants in 24 patients. The average marginal bone loss measured was 1.33 ± 0.17 mm. The success rate of the implants and prosthodontics being placed in this study yielded 98.5% and 97%, respectively. One patient (4.2%) showed some kind of technical complications. Eleven patients (45.8%) showed mucositis, and 25 implants (11.9%) in 10 patients (41.7%) were associated with peri-implantitis. CONCLUSIONS: This study shows that the treatment of edentulous geriatric patients by immediate loading of implants with fixed rehabilitations is a clinically successful protocol but with a high prevalence of peri-implant diseases.

A murine model of BSCL2-associated Celia's encephalopathy.

Celia's encephalopathy or progressive encephalopathy with/without lipodystrophy is a neurodegenerative disease with a fatal prognosis in childhood. It is generally caused by the c.985C > T variant in the BSCL2 gene, leading to the skipping of exon 7 and resulting in an aberrant seipin protein (Celia-seipin). To precisely define the temporal evolution and the mechanisms involved in neurodegeneration, lipodystrophy and fatty liver in Celia's encephalopathy, our group has generated the first global knock-in murine model for the aberrant human transcript of BSCL2 (Bscl2Celia/Celia) using a strategy based on the Cre/loxP recombination system. In order to carry out a characterization at the neurological, adipose tissue and hepatic level, behavioral studies, brain PET, metabolic, histological and molecular studies were performed. Around 12% of homozygous and 5.4% of heterozygous knock-in mice showed severe neurological symptoms early in life, and their life expectancy was dramatically reduced. Severe generalized lipodystrophy and mild hepatic steatosis were present in these affected animals, while serum triglycerides and glucose metabolism were normal, with no insulin resistance. Furthermore, the study revealed a reduction in brain glucose uptake, along with patchy loss of Purkinje cells and the presence of intranuclear inclusions in cerebellar cortex cells. Homozygous, non-severely-affected knock-in mice showed a decrease in locomotor activity and greater anxiety compared with their wild type littermates. Bscl2Celia/Celia is the first murine model of Celia's encephalopathy which partially recapitulates the phenotype and severe neurodegenerative picture suffered by these patients. This model will provide a helpful tool to investigate both the progressive encephalopathy with/without lipodystrophy and congenital generalized lipodystrophy.

Effectiveness of Therapeutic Education in Patients with Cancer Pain: Systematic Review and Meta-Analysis.

(1) Objective: To review the existing evidence on pain education in patients with pain derived from an oncological process. (2) Methods: A systematic review was conducted using the databases Pubmed, Web of Science, PEDro, and Scopus. The selected studies had to incorporate instruction about the neurophysiology of pain into their educational program. The target population was cancer patients who had suffered pain for at least one month. The methodological quality of the articles collected was assessed using the PEDro scale. (3) Results: Some 698 studies were initially identified, of which 12 were included in this review. Four different models of pain education programs were found in the studies' interventions. Pain intensity, pain experience, quality of life, pain tolerance, and catastrophism were the variables that appeared most frequently. (4) Conclusions: This review demonstrates that pain education in patients with cancer pain may produce effects such as decreased pain intensity and catastrophism. Knowledge about pain also seems to increase. However, no benefit was reported for patients' overall quality of life. Therefore, more research is needed to clarify the effects of these interventions on the oncology population.

A paradigm for ethanol consumption in head-fixed mice during prefrontal cortical two-photon calcium imaging.

The prefrontal cortex (PFC) is a hub for higher-level cognitive behaviors and is a key target for neuroadaptations in alcohol use disorders. Preclinical models of ethanol consumption are instrumental for understanding how acute and repeated drinking affects PFC structure and function. Recent advances in genetically encoded sensors of neuronal activity and neuromodulator release combined with functional microscopy (multiphoton and one-photon widefield imaging) allow multimodal in-vivo PFC recordings at subcellular and cellular scales. While these methods could enable a deeper understanding of the relationship between alcohol and PFC function/dysfunction, they require animals to be head-fixed. Here, we present a method in mice for binge-like ethanol consumption during head-fixation. Male and female mice were first acclimated to ethanol by providing home cage access to 20% ethanol (v/v) for 4 or 8 days. After home cage drinking, mice consumed ethanol from a lick spout during head-fixation. We used two-photon calcium imaging during the head-fixed drinking paradigm to record from a large population of PFC neurons (>1000) to explore how acute ethanol affects their activity. Drinking modulated activity rates in a subset of neurons on slow (minutes) and fast (seconds) time scales but the majority of neurons were unaffected. Moreover, ethanol intake did not significantly affect network level interactions in the PFC as assessed through inter-neuronal pairwise correlations. By establishing a method for binge-like drinking in head-fixed mice, we lay the groundwork for leveraging advanced microscopy technologies to study alcohol-induced neuroadaptations in PFC and other brain circuits.

Impact of thoracic endovascular aortic repair following blunt traumatic thoracic aortic injury on blood pressure.

BACKGROUND: Blunt traumatic thoracic aortic injuries (BTAIs) are associated with a high mortality rate. Thoracic endovascular aortic repair (TEVAR) is the most frequently used surgical strategy in patients with BTAI, as it offers good short- and middle-term results. Previous studies have reported an abnormally high prevalence of hypertension (HT) in these patients. This work aimed to describe the long-term prevalence of HT and provide a comprehensive evaluation of the biomechanical, clinical, and functional factors involved in HT development. METHODS: Twenty-six patients treated with TEVAR following BTAI with no history of HT at the time of trauma were enrolled. They were matched with 37 healthy volunteers based on age, sex, and body surface area and underwent a comprehensive follow-up study, including cardiovascular magnetic resonance, 24-hour ambulatory blood pressure monitoring, and assessment of carotid-femoral pulse wave velocity (cfPWV, a measure of aortic stiffness) and flow-mediated vasodilation. RESULTS: The mean patient age was 43.5 ± 12.9 years, and the majority were male (23 of 26; 88.5%). At a mean of 120.2 ± 69.7 months after intervention, 17 patients (65%) presented with HT, 14 (54%) had abnormal nighttime blood pressure dipping, and 6 (23%) high cfPWV. New-onset HT was related to a more proximal TEVAR landing zone and greater distal oversizing. Abnormal nighttime blood pressure was related to high cfPWV, which in turn was associated with TEVAR length and premature arterial aging. CONCLUSIONS: HT frequently occurs otherwise healthy subjects undergoing TEVAR implantation after BTAI. TEVAR stiffness and length, the proximal landing zone, and distal oversizing are potentially modifiable surgical characteristics related to abnormal blood pressure.

Early Loading of Two Implants Supporting Mandibular Overdentures in Geriatric Edentulous Patients: A 12-Year Follow-Up Study.

Background: This study aims to show the clinical outcomes of implants supporting mandibular overdentures in edentulous patients. Methods: Mandibular edentulous patients were diagnosed with an oral examination, panoramic radiograph, and diagnostic casts for intermaxillary relations and treated with overdentures over two implants. After two-stage surgery, implants were early loaded with an overdenture at 6 weeks. Results: Fifty-four patients (28 females and 24 males) were treated with 108 implants. Thirty-two patients (59.2%) had a previous history of periodontitis. Twenty-three patients (46%) were smokers. Forty patients (74.1%) suffered from systemic diseases (i.e., diabetes, cardiovascular diseases). The clinical follow-up of the study was 147.8 ± 10.4 months. The clinical outcomes showed a global success of 94.5% of implants. Fifty-four overdentures were placed in the patients over the implants. The mean marginal bone loss was 1.12 ± 0.34 mm. Nineteen patients (35.2%) showed some kind of mechanical prosthodontic complication. Sixteen implants (14.8%) were associated with peri-implantitis. Conclusions: Based on the clinical results obtained, we can determine that the treatment of elderly edentulous patients with mandibular overdentures through the early loading of two placed implants is a successful implant protocol.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Relevant Aspects of Titanium Topography for Osteoblastic Adhesion and Inhibition of Bacterial Colonization.

The influence of the surface topography of dental implants has been studied to optimize titanium surfaces in order to improve osseointegration. Different techniques can be used to obtain rough titanium, however, their effect on wettability, surface energy, as well as bacterial and cell adhesion and differentiation has not been studied deeply. Two-hundred disks made of grade 4 titanium were subjected to different treatments: machined titanium (MACH), acid-attacked titanium (AE), titanium sprayed with abrasive alumina particles under pressure (GBLAST), and titanium that has been treated with GBLAST and then subjected to AE (GBLAST + AE). The roughness of the different treatments was determined by confocal microscopy, and the wettability was determined by the sessile drop technique; then, the surface energy of each treatment was calculated. Osteoblast-like cells (SaOs-2) were cultured, and alkaline phosphatase was determined using a colorimetric test. Likewise, bacterial strains S. gordonii, S. oralis, A. viscosus, and E. faecalis were cultured, and proliferation on the different surfaces was determined. It could be observed that the roughness of the GBLAST and GBLAS + AE was higher, at 1.99 and 2.13 µm of Ra, with respect to the AE and MACH samples, which were 0.35 and 0.20 µm, respectively. The abrasive treated surfaces showed lower hydrophilicity but lower surface energy. Significant differences could be seen at 21 days between SaOS-2 osteoblastic cell adhesion for the blasted ones and higher osteocalcin levels. However, no significant differences in terms of bacterial proliferation were observed between the four surfaces studied, demonstrating the insensitivity of bacteria to topography. These results may help in the search for the best topographies for osteoblast behavior and for the inhibition of bacterial colonization.