FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

Interplay between hippocampal TACR3 and systemic testosterone in regulating anxiety-associated synaptic plasticity.

Tachykinin receptor 3 (TACR3) is a member of the tachykinin receptor family and falls within the rhodopsin subfamily. As a G protein-coupled receptor, it responds to neurokinin B (NKB), its high-affinity ligand. Dysfunctional TACR3 has been associated with pubertal failure and anxiety, yet the mechanisms underlying this remain unclear. Hence, we have investigated the relationship between TACR3 expression, anxiety, sex hormones, and synaptic plasticity in a rat model, which indicated that severe anxiety is linked to dampened TACR3 expression in the ventral hippocampus. TACR3 expression in female rats fluctuates during the estrous cycle, reflecting sensitivity to sex hormones. Indeed, in males, sexual development is associated with a substantial increase in hippocampal TACR3 expression, coinciding with elevated serum testosterone and a significant reduction in anxiety. TACR3 is predominantly expressed in the cell membrane, including the presynaptic compartment, and its modulation significantly influences synaptic activity. Inhibition of TACR3 activity provokes hyperactivation of CaMKII and enhanced AMPA receptor phosphorylation, associated with an increase in spine density. Using a multielectrode array, stronger cross-correlation of firing was evident among neurons following TACR3 inhibition, indicating enhanced connectivity. Deficient TACR3 activity in rats led to lower serum testosterone levels, as well as increased spine density and impaired long-term potentiation (LTP) in the dentate gyrus. Remarkably, aberrant expression of functional TACR3 in spines results in spine shrinkage and pruning, while expression of defective TACR3 increases spine density, size, and the magnitude of cross-correlation. The firing pattern in response to LTP induction was inadequate in neurons expressing defective TACR3, which could be rectified by treatment with testosterone. In conclusion, our study provides valuable insights into the intricate interplay between TACR3, sex hormones, anxiety, and synaptic plasticity. These findings highlight potential targets for therapeutic interventions to alleviate anxiety in individuals with TACR3 dysfunction and the implications of TACR3 in anxiety-related neural changes provide an avenue for future research in the field.

Distinct gut microbiota signatures associated with progression of atherosclerosis in people living with HIV.

BACKGROUND: The relationship of microbiota composition dynamics and the progression of subclinical atherosclerosis in people with HIV (PWH) remains unknown. METHODS: 96-week, prospective, longitudinal study in virologically-suppressed PWH. Carotid intima-media thickness (cIMT) measurements and stool samples were obtained at baseline, 48-week and 96-week visits. cIMT progression was defined as an increase >10% and/or detection of new carotid plaque. To profile the gut microbiome, amplification and sequencing of 16S ribosomal-RNA (V3-V4 variable regions) were carried out following the Illumina protocol. Sequencing was performed with MiSeq platform. RESULTS: 191, 190 and 167 patients had available fecal samples for microbiome analysis at the baseline, 48- and 96-week visits, respectively. 87 (43%) participants showed atherosclerosis progression, and 54 (26.7%) presented new carotid plaque. No significant differences were observed in adjusted α-diversity indices between groups defined by cIMT progression. Beta-diversity determined through principal coordinate analysis distances showed that the groups exhibited distinct microbial profiles (PERMANOVA p-value = 0.03). Longitudinal analysis with ANCOM-BC2 adjusted for traditional cardiovascular risk factors, MSM and nadir CD4 count revealed that cIMT progression was consistently associated with Agathobacter and Ruminococcus_2, while non-progression was consistently associated with Prevotella_7. CONCLUSION: Progression of atherosclerosis in PWH might be associated with distinctive signatures in the gut microbiota.

Virological History Predicts Non-sustained Viral Suppression with Long-Acting Cabotegravir and Rilpivirine Therapy, independent of Pharmacokinetic Parameters.

BACKGROUND: This study aimed to investigate factors contributing to non-sustained viral suppression, including intermittent viremia and persistent low-level viremia, during cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) injectable therapy, with a focus on pharmacokinetics (PK). METHODS: A prospective cohort study was conducted on people with HIV (PWH) transitioning from stable oral antiretroviral therapy (ART) to bimonthly CAB+RPV LA. Standardized follow-up included close monitoring through blood sampling for plasma HIV-1 viral load (VL) and multiple plasma drug concentrations measurements to analyze the connection between PK parameters and virologic outcomes. RESULTS: Among 173 patients with a median (IQR) follow-up of 11.1(7.1-13.2) months and 789 pre-dose measurements, 38.7% experienced VL≥20 copies/mL, and 16.2% had levels ≥50 copies/mL. Intermittent viremia occurred in 34.7% of patients, and persistent low-level viremia in 4%. Virological failure developed in two cases. Predictors of non-sustained viral suppression included VL at HIV diagnosis [AHR: 1.49 per log10 VL, 95% CI: 1.04-2.12, P =.027], detectable viremia on oral ART [AHR: 2.45, 95% CI: 1.29-4.65, P =.006], and the level of viral suppression at transition [AHR: 0.38, 95% CI: 0.19-0.75, P =.004]. We found a significant association between low trough concentrations of CAB and RPV and episodes of detectable viremia exceeding 50 copies/mL. However, none of the assessed PK covariates predicted non-sustained viral suppression in multivariable models. CONCLUSION: Non-sustained viral suppression in PWH transitioning from stable oral ART to CAB+RPV LA was linked to pre-existing factors before transition. Higher VL pre-ART and incomplete suppression on oral therapy increased the risk, independent of PK parameters.

Early Detection of Cancer and Precancerous Lesions in Persons with HIV through a Comprehensive Cancer Screening Protocol.

BACKGROUND: Non-AIDS defining malignancies present a growing challenge for persons with HIV (PWH), yet tailored interventions for timely cancer diagnosis are lacking. The Spanish IMPAC-Neo protocol was designed to compare two comprehensive cancer screening strategies integrated into routine HIV care. This study reports baseline data on the prevalence and types of precancerous lesions and early-stage cancer among participants at enrolment. Acceptability of the procedure was additionally assessed. METHODS: Cross-sectional analysis of a comprehensive screening protocol to detect precancer and cancer. The readiness of healthcare providers to implement the protocol was evaluated using a validated 4-item survey. RESULTS: Among the 1430 enrolled PWH, 1172 underwent 3181 screening tests, with positive findings in 29.4% of cases, leading to further investigation in 20.7%. Adherence to the protocol was 84%, with HIV providers expressing high acceptability (97.1%), appropriateness (91.4%), and feasibility (77.1%). A total of 145 lesions were identified in 109 participants, including 60 precancerous lesions in 35 patients (3.0%), 9 early-stage cancers in 9 patients (0.8%), and 76 low-risk lesions in 65 subjects (5.5%). Adverse events related to screening occurred in 0.8% of participants, all mild. The overall prevalence of cancer precursors or early-stage cancer was 3.8% (95% CI, 2.74%-5.01%), with highest rates observed in individuals screened for anal and colorectal cancers. CONCLUSIONS: The baseline comprehensive cancer screening protocol of the IMPAC-Neo study successfully identified a significant proportion of PWH with precancerous lesions and early-stage cancer. High adherence rates and positive feedback from providers suggest effective implementation potential in real-world healthcare settings.

No accelerated progression of subclinical atherosclerosis with integrase strand transfer inhibitors compared to non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: The role of integrase strand transfer inhibitors (INSTI) in the cardiovascular risk of people with HIV is controversial. OBJECTIVES: To assess the association of INSTI to subclinical atherosclerosis progression measured with the carotid intima-media thickness (cIMT). METHODS: Prospective study in virologically suppressed people with HIV receiving INSTI- or NNRTI-based regimens. cIMT was measured at baseline, 48 and 96 weeks. cIMT progression was analysed both as a continuous and categorical variable, defined as cIMT increase ≥ 10% and/or new carotid plaque. Adjustments through Cox proportional hazard regression and linear mixed models, and propensity score matching were conducted. RESULTS: 190 participants were recruited and 173 completed the 96 week follow-up. 107 (56.3%) were receiving an INSTI-containing, 128 (67.4%) a NNRTI-containing and 45 (23.7%) a NNRTI plus an INSTI-containing regimen. The overall median (IQR) 2-year change of cIMT was 0.029 (-0.041 to 0.124) mm; 87 (45.8%) participants experienced a cIMT increase ≥ 10%, of whom 54 (28.4%) developed a new carotid plaque. Adjusted Cox regression showed no differences between INSTI and NNRTI groups in the categorical 2-year progression of cIMT, both including or excluding participants receiving INSTI + NNRTI. Similar results were observed for the continuous cIMT increase through adjusted linear mixed models. Propensity score matching showed no significant differences in the 2 year cIMT change between treatment groups [0.049 mm (-0.031-0.103) in the INSTI group versus 0.047 mm (-0.023-0.115) in the NNRTI group; P = 0.647]. cIMT progression was associated with traditional cardiovascular risk factors. CONCLUSIONS: INSTI-based regimens are not associated with increased progression of subclinical atherosclerosis when compared to NNRTI.

Selinexor, daratumumab, bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the phase II, nonrandomized, multicenter GEM-SELIBORDARA study.

The treatment landscape for multiple myeloma has significantly evolved in the last decade. Notwithstanding, a large proportion of patients continue to relapse and novel combinations continue to be needed. In this phase II study, selinexor, a first-in-class inhibitor of exportin-1 was evaluated in combination with standard daratumumab-bortezomib-dexamethasone (DVd), for the treatment of relapsed and refractory multiple myeloma (RRMM). The aim of the trial was to assess the efficacy and safety of the combination of selinexor with DVd (S-DVd). A total of 57 patients were enrolled in the two parts of the study. Part 1 enrolled a heavily pretreated population with at least three prior lines (PL) of therapy and part 2 enrolled an early relapse population with at least one PL of therapy. The primary endpoint was complete response (CR) rate in part 2 and overall response rate (ORR) in part 1. In the latter, 24 patients were treated with a median of three PL. Overall response rate (ORR) was 50% with two CR. Median progression- free survival (PFS) was 7 months. In part 2, 33 patients were enrolled, with a median of one PL. ORR was 82% and CR or better was 33%. Median PFS was 24 months. In lenalidomide-refractory patients, a median PFS of 22.1 months was observed. Thrombocytopenia was the most common hematological adverse event (69%; grade 3-4: 34%) and nausea, the most frequent non-hematological adverse event (38%; grade 3-4: 6%). Sixty-two percent of the patients required dose modifications. In summary, although the primary endpoint of the study was not met, the combination of S-DVd showed encouraging clinical efficacy with a generally manageable safety profile representing a potential option for the treatment of RRMM patients.

Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high risk smoldering multiple myeloma included in the GEM-CESAR trial.

The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in high-risk smoldering myeloma (HRsMM). We have therefore investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by NGF identified cases with a significantly shorter median PFS (mPFS; MS: not reached vs 1,4 years, p=0.001; NGF: not reached vs 2 years, p=0.0002) but reaching CR+sCR did not discriminate patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with a mPFS not yet reached vs 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can thus conclude that 1) the standard response categories of the IMWG do not seem to be useful for treatment monitoring in HRsMM patients, 2) MS could be used as a non-invasive, clinical valuable tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference) and 3) similarly to NGF, sequential results of MS are able identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT02415413).

In vitro platform to model the function of ionocytes in the human airway epithelium.

BACKGROUND: Pulmonary ionocytes have been identified in the airway epithelium as a small population of ion transporting cells expressing high levels of CFTR (cystic fibrosis transmembrane conductance regulator), the gene mutated in cystic fibrosis. By providing an infinite source of airway epithelial cells (AECs), the use of human induced pluripotent stem cells (hiPSCs) could overcome some challenges of studying ionocytes. However, the production of AEC epithelia containing ionocytes from hiPSCs has proven difficult. Here, we present a platform to produce hiPSC-derived AECs (hiPSC-AECs) including ionocytes and investigate their role in the airway epithelium. METHODS: hiPSCs were differentiated into lung progenitors, which were expanded as 3D organoids and matured by air-liquid interface culture as polarised hiPSC-AEC epithelia. Using CRISPR/Cas9 technology, we generated a hiPSCs knockout (KO) for FOXI1, a transcription factor that is essential for ionocyte specification. Differences between FOXI1 KO hiPSC-AECs and their wild-type (WT) isogenic controls were investigated by assessing gene and protein expression, epithelial composition, cilia coverage and motility, pH and transepithelial barrier properties. RESULTS: Mature hiPSC-AEC epithelia contained basal cells, secretory cells, ciliated cells with motile cilia, pulmonary neuroendocrine cells (PNECs) and ionocytes. There was no difference between FOXI1 WT and KO hiPSCs in terms of their capacity to differentiate into airway progenitors. However, FOXI1 KO led to mature hiPSC-AEC epithelia without ionocytes with reduced capacity to produce ciliated cells. CONCLUSION: Our results suggest that ionocytes could have role beyond transepithelial ion transport by regulating epithelial properties and homeostasis in the airway epithelium.

Epidemiology of infectious diseases in migrant populations from endemic or high-endemic countries: A multicentric primary care-based study in Spain.

OBJECTIVES: We aimed to evaluate the epidemiology of seven infections (Chagas disease, strongyloidiasis, schistosomiasis, human immunodeficiency virus, hepatitis B and C virus, and active tuberculosis) in migrant populations attended at primary care facilities in Catalonia, Spain. METHODS: This is a cross sectional study conducted from March to December 2018 at eight primary care centres in Catalonia, Spain where health professionals were recommended to systematically screen multiple infections in migrants considering the endemicity of the pathogens in their country of birth. Routine health data were retrospectively extracted from electronic health records of the primary care centres. The proportion of cases among individuals tested for each infection was estimated with its 95% confident interval (CI). Mixed-effects logistics regression models were conducted to assess any possible association between the exposure variables and the primary outcome. RESULTS: Out of the 15,780 migrants that attended primary care centres, 2410 individuals were tested for at least one infection. Of the 508 (21.1%) migrants diagnosed with at least one condition, a higher proportion originated from Sub-Saharan Africa (207, 40.7%), followed by South-East Europe (117, 23.0%) and Latin-America (88, 17.3%; p value <0.001). The proportion of migrants diagnosed with Chagas disease was 5/122 (4.1%, 95%CI 0.5-7.7), for strongyloidiasis 56/409 (13.7%, 95%CI 10.3-17.0) and for schistosomiasis 2/101 (2.0%, 95%CI 0.0-4.7) with very few cases tested. The estimated proportion for human immunodeficiency virus was 67/1176 (5.7%, 95%CI 4.4-7.0); 377/1478 (25.5%, 95%CI 23.3-27.7) for hepatitis B virus, with 108/1478 (7.3%, 95%CI 6.0-8.6) of them presenting an active infection, while 31/1433 (2.2%, 95%CI 1.4-2.9) were diagnosed with hepatitis C virus. One case of active tuberculosis was diagnosed after testing 172 migrant patients (0.6%, 95%CI 0.0-1.7). CONCLUSIONS: We estimated a high proportion of the studied infections in migrants from endemic areas. Country-specific estimations of the burden of infections in migrants are fundamental for the implementation of preventive interventions.

Flow starvation during square-flow assisted ventilation detected by supervised deep learning techniques.

BACKGROUND: Flow starvation is a type of patient-ventilator asynchrony that occurs when gas delivery does not fully meet the patients' ventilatory demand due to an insufficient airflow and/or a high inspiratory effort, and it is usually identified by visual inspection of airway pressure waveform. Clinical diagnosis is cumbersome and prone to underdiagnosis, being an opportunity for artificial intelligence. Our objective is to develop a supervised artificial intelligence algorithm for identifying airway pressure deformation during square-flow assisted ventilation and patient-triggered breaths. METHODS: Multicenter, observational study. Adult critically ill patients under mechanical ventilation > 24 h on square-flow assisted ventilation were included. As the reference, 5 intensive care experts classified airway pressure deformation severity. Convolutional neural network and recurrent neural network models were trained and evaluated using accuracy, precision, recall and F1 score. In a subgroup of patients with esophageal pressure measurement (ΔPes), we analyzed the association between the intensity of the inspiratory effort and the airway pressure deformation. RESULTS: 6428 breaths from 28 patients were analyzed, 42% were classified as having normal-mild, 23% moderate, and 34% severe airway pressure deformation. The accuracy of recurrent neural network algorithm and convolutional neural network were 87.9% [87.6-88.3], and 86.8% [86.6-87.4], respectively. Double triggering appeared in 8.8% of breaths, always in the presence of severe airway pressure deformation. The subgroup analysis demonstrated that 74.4% of breaths classified as severe airway pressure deformation had a ΔPes > 10 cmH2O and 37.2% a ΔPes > 15 cmH2O. CONCLUSIONS: Recurrent neural network model appears excellent to identify airway pressure deformation due to flow starvation. It could be used as a real-time, 24-h bedside monitoring tool to minimize unrecognized periods of inappropriate patient-ventilator interaction.

Oocyte collection and outcome following oncologic treatment: a retrospective multicentre study.

PURPOSE: This study assesses fertility treatment outcomes in female patients who had undergone successful oocyte retrieval following cancer therapy. METHODS: Between January 2020 and December 2022, we collected fertility treatment data from six participating centres in Spain and Germany. All patients associated with this data had undergone successful oocyte retrieval following cancer treatment. RESULTS: Women had most frequently been diagnosed with a haematological (41.9%), breast (22.6%) or gynaecological malignancy (12.9%); two thirds (67.7%) had previously received a chemotherapy, half a radiotherapy (53.3%) and 45.2% had undergone surgery. On average, 7 years (range 0-28) had passed between cancer treatment and first ovarian stimulation cycle. Forty-nine ovarian stimulation cycles had been conducted on these 31 women between 2004 and 2021 (mean age at first oocyte collection following treatment: 34.8 ± 5.7 years). On average, 7 oocytes were collected per cycle (range 0-26) and 11 were collected per patient (range 0-51). Out of the 190 oocytes collected for immediate use of artificial reproductive technique, 139 were fertilised at a rate of 73%. Live birth rate per fresh transfer was 45% (9/20); no births were reported following cryotransfer (0/10). Mean values of anti-Mullerian hormone (AMH) before stimulation declined with time since treatment; however, oocytes were successfully collected from four women with an AMH of <0.5 ng/ml, although no pregnancies were reported. Ten pregnancies were documented; 3 ended in miscarriage. Two twin and 5 single pregnancies resulted in nine live births. On average, children were carried to term. CONCLUSION: In this small cohort, oocytes were successfully collected after chemotherapy and radiotherapy, despite-in individual cases-low AMH values. Further studies are needed to enrich the database and ultimately provide appropriate counselling to female cancer patients regarding expectations and ART outcome following cancer therapy.

Calling for allied efforts to strengthen digital health literacy in Sweden: perspectives of policy makers.

BACKGROUND: A more digitalised world comes with the promise to improve people's lives. Therefore, it is essential that policymakers also align digital interventions with initiatives to empower citizens and strengthen their digital health literacy. The aim of this study was to explore the views of Swedish policymakers regarding the potential and barriers of a European strategy to strengthen digital health literacy. METHOD: Representatives from Swedish governmental agencies and regions were purposively approached by email to ask them to participate in online workshops to discuss the potential and barriers of developing a European strategy to strengthen digital health literacy. RESULTS: The results highlight the need for a national strategy to strengthen digital health literacy. The findings point to critical areas for improvement, ethical and social considerations, and the importance of inclusive and accessible health information online. Participants identified vulnerable groups requiring targeted support to enhance their digital health literacy, particularly those at risk of digital exclusion. Participants emphasised the importance of considering various combinations of conditions or problems that people may have, urging policymakers to adopt a nuanced approach to enhance digital literacy. CONCLUSIONS: There is a critical need for policymakers to strengthen digital health literacy in the population to ensure health equity in relation to digitalisation opportunities. Policymakers advocate for a dedicated national strategy, supporting policymakers to prioritize digital health literacy. Tailoring information, enhancing digital support for prevention, and considering ethical implications are reported as important aspects to improve digital health literacy.

Characterization of postintensive care syndrome in a prospective cohort of survivors of COVID-19 critical illness: a 12-month follow-up study.

PURPOSE: Studies integrating an exhaustive longitudinal long-term follow-up of postintensive care syndrome (PICS) in critically ill COVID-19 survivors are scarce. We aimed to 1) describe PICS-related sequelae over a 12-month period after intensive care unit (ICU) discharge, 2) identify relevant demographic and clinical factors related to PICS, and 3) explore how PICS-related sequelae may influence health-related quality of life (HRQoL) in critically ill COVID-19 survivors. METHODS: We conducted a prospective cohort study in adult critically ill survivors of SARS-CoV-2 infection that did or did not need invasive mechanical ventilation (IMV) during the COVID-19 pandemic in Spain (March 2020 to January 2021). We performed a telemedicine follow-up of PICS-related sequelae (physical/functional, cognitive, and mental health) and HRQoL with five data collection points. We retrospectively collected demographic and clinical data. We used multivariable mixed-effects models for data analysis. RESULTS: We included 142 study participants in the final analysis, with a median [interquartile range] age of 61 [53-68] yr; 35% were female and 59% needed IMV. Fatigue/dyspnea, pain, impaired muscle function, psychiatric symptomatology and reduced physical HRQoL were prominent sequelae early after ICU discharge. Over the 12-month follow-up, functionality and fatigue/dyspnea improved progressively, while pain remained stable. We observed slight fluctuations in anxiety symptoms and perception of cognitive deficit, whereas posttraumatic stress disorder (PTSD) and depressive symptoms improved, with a mild rebound at the end of the follow-up. Female sex, younger age, and the need for IMV were risk factors for PICS, while having higher cognitive reserve was a potential protective factor. Physical HRQoL scores showed a general improvement over time, whereas mental HRQoL remained stable. Shorter ICU stay, better functionality, and lower scores for fatigue/dyspnea and pain were associated with better physical HRQoL, while lower scores for anxiety, depression, and PTSD were associated with better mental HRQoL. CONCLUSIONS: Postintensive care syndrome was common in COVID-19 critical illness survivors and persisted in a significant proportion of patients one year after ICU discharge, impacting HRQoL. The presence of risk factors for PICS may identify patients who are more likely to develop the condition and who would benefit from more specific and closer follow-up after ICU admission. STUDY REGISTRATION: ClinicalTrials.gov ( NCT04422444 ); first submitted 9 June 2020.

RéSUMé: OBJECTIF: Les études intégrant un suivi longitudinal exhaustif à long terme des syndromes post-soins intensifs (SPSI) chez les survivant·es gravement malades de la COVID-19 sont rares. Notre objectif était 1) de décrire les séquelles liées au SPSI sur une période de 12 mois après la sortie de l'unité de soins intensifs (USI), 2) d'identifier les facteurs démographiques et cliniques pertinents liés au SPSI, et 3) d'explorer comment les séquelles liées au SPSI peuvent influencer la qualité de vie liée à la santé (QVLS) chez les survivant·es gravement malades de la COVID-19. MéTHODE: Nous avons mené une étude de cohorte prospective chez des adultes gravement malades survivant·es d'une infection par le SRAS-CoV-2 qui ont eu ou non besoin d'une ventilation mécanique invasive (VMI) pendant la pandémie de COVID-19 en Espagne (mars 2020 à janvier 2021). Nous avons effectué un suivi par télémédecine des séquelles liées au SPSI (santé physique/fonctionnelle, cognitive et mentale) et à la QVLS avec cinq points de collecte de données. Nous avons rétrospectivement colligé des données démographiques et cliniques. Des modèles multivariés à effets mixtes ont été utilisés pour l'analyse des données. RéSULTATS: Nous avons inclus 142 participant·es à l'étude dans l'analyse finale, avec un âge médian [intervalle interquartile] de 61 [53-68] ans; 35 % étaient des femmes et 59 % avaient besoin de VMI. La fatigue/dyspnée, la douleur, l'altération de la fonction musculaire, la symptomatologie psychiatrique et la réduction de la QVLS physique étaient des séquelles importantes peu après la sortie de l'USI. Au cours du suivi de 12 mois, la fonctionnalité et la fatigue/dyspnée se sont améliorées progressivement, tandis que la douleur est restée stable. Nous avons observé de légères fluctuations des symptômes d'anxiété et de perception du déficit cognitif, tandis que le trouble de stress post-traumatique (ESPT) et les symptômes dépressifs se sont améliorés, avec un léger rebond à la fin du suivi. Le sexe féminin, un jeune âge et le besoin de VMI étaient des facteurs de risque de SPSI, tandis qu'une réserve cognitive plus élevée était un facteur potentiel de protection. Les scores physiques de la QVLS ont montré une amélioration générale au fil du temps, tandis que la QVLS mentale est restée stable. Un séjour plus court aux soins intensifs, une meilleure fonctionnalité et des scores plus faibles pour la fatigue/dyspnée et la douleur étaient associés à une meilleure QVLS physique, tandis que des scores plus faibles pour l'anxiété, la dépression et le ESPT étaient associés à une meilleure QVLS mentale. CONCLUSION: Le syndrome post-soins intensifs était fréquent chez les survivant·es d'une maladie grave de la COVID-19 et a persisté chez une proportion importante de patient·es un an après leur sortie de l'unité de soins intensifs, ce qui a eu un impact sur la QVLS. La présence de facteurs de risque de SPSI peut identifier les patient·es qui sont plus susceptibles de développer la maladie et qui bénéficieraient d'un suivi plus spécifique et plus étroit après leur admission aux soins intensifs. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov ( NCT04422444 ); première soumission le 9 juin 2020.

An emerging epidemic of allergic contact dermatitis due to phytonadione epoxide (oxidised vitamin K1).

BACKGROUND: Reports of allergic contact dermatitis (ACD) to phytonadione epoxide (PE) in cosmetics suggest that PE is as powerful a sensitiser as its parent compound phytonadione. OBJECTIVE: To evaluate a case series of ACD to PE in Spain. METHODS: We reviewed the records of 20 patients with ACD to cosmetics containing PE diagnosed across Spain between January 2019 and June 2023. RESULTS: All 20 patients developed patch test (PT) or repeated open application test (ROAT) reactions to cosmetics containing PE. All involved women with eyelid eczema. PT or ROAT with PE preparations were positive in 17/20 (85%). PE at 1%, 5%, 10% and 20% in pet. was patch-tested in 8/17, 14/17, 11/17 and 8/17 patients; being positive in 6/8 (75%), 13/14 (92.85%), 11/11 (100%) and 8/8 (100%), respectively. CONCLUSION: Regulators should, not only ban the specific dangerous cosmetic ingredients, but also consider to ban or keep under close surveillance those closely related products or derivatives that might potentially cause similar harmful effects. PTs with PE are suggested to be performed at a 5% concentration in pet. Higher concentrations (10% pet.) should be tested whenever PTs with 5% pet. PE are negative.

Locus coeruleus integrity and neuropsychiatric symptoms in a cohort of early- and late-onset Alzheimer's disease.

INTRODUCTION: Early-onset Alzheimer's disease (EOAD) shows a higher burden of neuropsychiatric symptoms than late-onset Alzheimer's disease (LOAD). We aim to determine the differences in the severity of neuropsychiatric symptoms and locus coeruleus (LC) integrity between EOAD and LOAD accounting for disease stage. METHODS: One hundred four subjects with AD diagnosis and 32 healthy controls were included. Participants underwent magnetic resonance imaging (MRI) to measure LC integrity, measures of noradrenaline levels in cerebrospinal fluid (CSF) and Neuropsychiatric Inventory (NPI). We analyzed LC-noradrenaline measurements and clinical and Alzheimer's disease (AD) biomarker associations. RESULTS: EOAD showed higher NPI scores, lower LC integrity, and similar levels of CSF noradrenaline compared to LOAD. Notably, EOAD exhibited lower LC integrity independently of disease stage. LC integrity negatively correlated with neuropsychiatric symptoms. Noradrenaline levels were increased in AD correlating with AD biomarkers. DISCUSSION: Decreased LC integrity negatively contributes to neuropsychiatric symptoms. The higher LC degeneration in EOAD compared to LOAD could explain the more severe neuropsychiatric symptoms in EOAD. HIGHLIGHTS: LC degeneration is greater in early-onset AD (EOAD) compared to late-onset AD. Tau-derived LC degeneration drives a higher severity of neuropsychiatric symptoms. EOAD harbors a more profound selective vulnerability of the LC system. LC degeneration is associated with an increase of cerebrospinal fluid noradrenaline levels in AD.

Differentially Expressed Genes Involved in Primary Resistance to Immunotherapy in Patients with Advanced-Stage Pulmonary Cancer.

In the last few years, nivolumab has become the standard of care for advanced-stage lung cancer patients. Unfortunately, up to 60% of patients do not respond to this treatment. In our study, we identified variations in gene expression related to primary resistance to immunotherapy. Bronchoscopy biopsies were obtained from advanced non-small cell lung cancer (NSCLC) patients previously characterized as responders or non-responders after nivolumab treatment. Ten tumor biopsies (from three responders and seven non-responders) were analyzed by the differential expression of 760 genes using the NanoString nCounter platform. These genes are known to be involved in the response to anti-PD1/PD-L1 therapy. All the patients were treated with nivolumab. Examining the dysregulated expression of 24 genes made it possible to predict the response to nivolumab treatment. Supervised analysis of the gene expression profile (GEP) revealed that responder patients had significantly higher levels of expression of CXCL11, NT5E, KLRK1, CD3G, GZMA, IDO1, LCK, CXCL9, GNLY, ITGAL, HLA-DRB1, CXCR6, IFNG, CD8A, ITK, B2M, HLA-B, and HLA-A than did non-responder patients. In contrast, PNOC, CD19, TP73, ARG1, FCRL2, and PTGER1 genes had significantly lower expression levels than non-responder patients. These findings were validated as predictive biomarkers in an independent series of 201 patients treated with nivolumab (22 hepatocellular carcinomas, 14 non-squamous cell lung carcinomas, 5 head and neck squamous cell carcinomas, 1 ureter/renal pelvis carcinoma, 120 melanomas, 4 bladder carcinomas, 31 renal cell carcinomas, and 4 squamous cell lung carcinomas). ROC curve analysis showed that the expression levels of ITK, NT5E, ITGAL, and CD8A were the best predictors of response to nivolumab. Further, 13/24 genes showed an adverse impact on overall survival (OS) in an independent, large series of patients with NSCLC (2166 cases). In summary, we found a strong association between the global GEP of advanced NSCLC and the response to nivolumab. The classification of NSCLC patients based on GEP enabled us to identify those patients who genuinely benefited from treatment with immune checkpoint inhibitors (ICIs). We also demonstrated that abnormal expression of most of the markers comprising the genomic signature has an adverse influence on OS, making them significant markers for therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these biomarkers.

T-Cell Immunity Against Severe Acute Respiratory Syndrome Coronavirus 2 Measured by an Interferon-γ Release Assay Is Strongly Associated With Patient Outcomes in Vaccinated Persons Hospitalized With Delta or Omicron Variants.

BACKGROUND: We measured T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vaccinated patients hospitalized for coronavirus disease 2019 (COVID-19) and explored their potential value to predict outcomes. METHODS: This was a prospective, longitudinal study including vaccinated patients hospitalized with Delta and Omicron SARS-CoV-2 variants. TrimericS-IgG antibodies and SARS-CoV-2 T-cell response were measured using a specific quantitative interferon-γ release assay (IGRA). Primary outcome was all-cause 28-day mortality or need for intensive care unit (ICU) admission. Cox models were used to assess associations with outcomes. RESULTS: Of 181 individuals, 158 (87.3%) had detectable SARS-CoV-2 antibodies, 92 (50.8%) showed SARS-CoV-2-specific T-cell responses, and 87 (48.1%) had both responses. Patients who died within 28 days or were admitted to ICU were less likely to have both unspecific and specific T-cell responses in IGRA. In adjusted analyses (adjusted hazard ratio [95% confidence interval]), for the entire cohort, having both T-cell and antibody responses at admission (0.16 [.05-.58]) and Omicron variant (0.38 [.17-.87]) reduced the hazard of 28-day mortality or ICU admission, whereas higher Charlson comorbidity index score (1.27 [1.07-1.51]) and lower oxygen saturation to fraction of inspired oxygen ratio (2.36 [1.51-3.67]) increased the risk. CONCLUSIONS: Preexisting immunity against SARS-CoV-2 is strongly associated with patient outcomes in vaccinated individuals requiring hospital admission for COVID-19. Persons showing both T-cell and antibody responses have the lowest risk of severe outcomes.

Human Immunodeficiency Virus Type 1 RNA Levels in Rectal and Seminal Compartments After Switching to Long-Acting Cabotegravir Plus Rilpivirine: A Longitudinal Study.

Human immunodeficiency virus type 1 RNA levels were longitudinally evaluated in 211 rectal and 152 seminal samples from 12 virologically suppressed participants switching to monthly long-acting cabotegravir plus rilpivirine or continuing with daily dolutegravir-abacavir-lamivudine. Maintenance of viral suppression in rectal and seminal compartments was comparable, and blips occurred with similar frequency with both treatment regimens. CLINICAL TRIALS REGISTRATION: NCT02938520.

Structural Analysis and Intrinsic Enzyme Mimicking Activities of Ligand-Free PtAg Nanoalloys.

Nanozymes are nanomaterials with biocatalytic properties under physiological conditions and are one class of artificial enzymes to overcome the high cost and low stability of natural enzymes. However, surface ligands on nanomaterials will decrease the catalytic activity of the nanozymes by blocking the active sites. To address this limitation, ligand-free PtAg nanoclusters (NCs) are synthesized and applied as nanozymes for various enzyme-mimicking reactions. By taking advantage of the mutual interaction of zeolitic imidazolate frameworks (ZIF-8) and Pt precursors, a good dispersion of PtAg bimetal NCs with a diameter of 1.78 ± 0.1 nm is achieved with ZIF-8 as a template. The incorporation of PtAgNCs in the voids of ZIF-8 is confirmed with structural analysis using the atomic pair-distribution function and powder X-ray diffraction. Importantly, the PtAgNCs present good catalytic activity for various enzyme-mimicking reactions, including peroxidase-/catalase- and oxidase-like reactions. Further, this work compares the catalytic activity between PtAg NCs and PtAg nanoparticles with different compositions and finds that these two nanozymes present a converse dependency of Ag-loading on their activity. This study contributes to the field of nanozymes and presents a potential option to prepare ligand-free bimetal biocatalysts with sizes in the nanocluster regime.