SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex.

The Sirtuin family of NAD+-dependent enzymes plays an important role in maintaining genome stability upon stress. Several mammalian Sirtuins have been linked directly or indirectly to the regulation of DNA damage during replication through Homologous recombination (HR). The role of one of them, SIRT1, is intriguing as it seems to have a general regulatory role in the DNA damage response (DDR) that has not yet been addressed. SIRT1-deficient cells show impaired DDR reflected in a decrease in repair capacity, increased genome instability and decreased levels of γH2AX. Here we unveil a close functional antagonism between SIRT1 and the PP4 phosphatase multiprotein complex in the regulation of the DDR. Upon DNA damage, SIRT1 interacts specifically with the catalytical subunit PP4c and promotes its inhibition by deacetylating the WH1 domain of the regulatory subunits PP4R3α/ß. This in turn regulates γH2AX and RPA2 phosphorylation, two key events in the signaling of DNA damage and repair by HR. We propose a mechanism whereby during stress, SIRT1 signaling ensures a global control of DNA damage signaling through PP4.

Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation.

Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium in cluster structures that protrude into the embryonic aortic lumen. Although much is known about the molecular characteristics of the developing hematopoietic cells, we lack a complete understanding of their origin and the three-dimensional organization of the niche. Here, we use advanced live imaging techniques of organotypic slice cultures, clonal analysis, and mathematical modeling to show the two-step process of intra-aortic hematopoietic cluster (IACH) formation. First, a hemogenic progenitor buds up from the endothelium and undergoes division forming the monoclonal core of the IAHC. Next, surrounding hemogenic cells are recruited into the IAHC, increasing their size and heterogeneity. We identified the Notch ligand Dll4 as a negative regulator of the recruitment phase of IAHC. Blocking of Dll4 promotes the entrance of new hemogenic Gfi1+ cells into the IAHC and increases the number of cells that acquire HSC activity. Mathematical modeling based on our data provides estimation of the cluster lifetime and the average recruitment time of hemogenic cells to the cluster under physiologic and Dll4-inhibited conditions.

Sleep and Circadian Health of Critical Survivors: A 12-Month Follow-Up Study.

OBJECTIVES: To investigate the sleep and circadian health of critical survivors 12 months after hospital discharge and to evaluate a possible effect of the severity of the disease within this context. DESIGN: Observational, prospective study. SETTING: Single-center study. PATIENTS: Two hundred sixty patients admitted to the ICU due to severe acute respiratory syndrome coronavirus 2 infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort was composed of 260 patients (69.2% males), with a median (quartile 1-quartile 3) age of 61.5 years (52.0-67.0 yr). The median length of ICU stay was 11.0 days (6.00-21.8 d), where 56.2% of the patients required invasive mechanical ventilation (IMV). The Pittsburgh Sleep Quality Index (PSQI) revealed that 43.1% of the cohort presented poor sleep quality 12 months after hospital discharge. Actigraphy data indicated an influence of the disease severity on the fragmentation of the circadian rest-activity rhythm at the 3- and 6-month follow-ups, which was no longer significant in the long term. Still, the length of the ICU stay and the duration of IMV predicted a higher fragmentation of the rhythm at the 12-month follow-up with effect sizes (95% CI) of 0.248 (0.078-0.418) and 0.182 (0.005-0.359), respectively. Relevant associations between the PSQI and the Hospital Anxiety and Depression Scale (rho = 0.55, anxiety; rho = 0.5, depression) as well as between the fragmentation of the rhythm and the diffusing lung capacity for carbon monoxide (rho = -0.35) were observed at this time point. CONCLUSIONS: Our findings reveal a great prevalence of critical survivors presenting poor sleep quality 12 months after hospital discharge. Actigraphy data indicated the persistence of circadian alterations and a possible impact of the disease severity on the fragmentation of the circadian rest-activity rhythm, which was attenuated at the 12-month follow-up. This altogether highlights the relevance of considering the sleep and circadian health of critical survivors in the long term.

Shared decision-making for patients with vaccine-related concerns of blood transfusion: A single institution experience.

BACKGROUND: Some patients express concerns regarding receipt of allogeneic blood transfusions from donors potentially vaccinated against SARS-CoV-2 (COVID-19). However, limited information exists about patients' expression of these concerns or how to address them during the blood transfusion consent process. In this study, we describe our experience of working collaboratively with patients with vaccine-related transfusion concerns prior to elective surgery, summarizing treatment decisions and clinical outcomes. STUDY DESIGN AND METHODS: This observational descriptive study includes patients seen in our Bloodless Medicine and Surgery clinic between June 2022 and June 2024 for vaccine-related transfusion concerns prior to elective surgery. A shared decision-making framework was employed to foster conversation, share information, provide reassurance, reconcile conflict, and match preferences with available care options. Patient characteristics, treatment decisions, and surgical outcomes were reviewed and summarized. RESULTS: Thirty-five patients were included, with median (1st, 3rd quartile) age of 61 (53, 69) years. Cardiac surgery was the most common type of surgery (29%). Twelve patients (34%) were anemic preoperatively, and all received preoperative treatment. After discussion with a Bloodless Medicine specialist, 24 (68.6%) decided to consent to the use of all blood products, 5 (14.3%) accepted only red blood cells, and 6 (17.1%) declined all blood products. Among 28 patients undergoing surgery, only 4 (14%) received allogeneic transfusion perioperatively. CONCLUSION: Many patients concerned about the vaccination status of blood donors may ultimately consent to allogeneic blood products after shared decision-making with a Bloodless Medicine specialist, highlighting the importance of patient empowerment and collaborative care.

KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination.

BACKGROUND: KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. METHODS: Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. RESULTS: Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. CONCLUSIONS: We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

The relationship between female orgasmic disorder, attention-deficit/hyperactivity disorder, and depression in Dominican women.

BACKGROUND: Female orgasmic disorder is listed in the DSM-5 and is defined as the persistent or recurrent inability to have an orgasm. Many depressed women may experience sexual dysfunction, including female orgasmic disorder. AIM: The study sought to analyze the relationship between depressive disorders and attention-deficit/hyperactivity disorder (ADHD) and their influence on the development of female orgasmic disorder. METHODS: A total of 221 Dominican women participated in this case-control study. The case group consisted of 107 women diagnosed with female orgasmic disorder, while the control group consisted of 114 women without any sexual dysfunction. OUTCOMES: The diagnosis of ADHD was obtained from the participants' medical records, previously conducted using the DSM-5-TR criteria. The Beck Depression Inventory II was used to assess the severity of depressive symptoms in both groups. RESULTS: There was a significant relationship between female orgasmic disorder and ADHD and depression. The results of multiple logistic regression indicated that the highest risk of female orgasmic disorder was observed in women with ADHD (odds ratio [OR], 4.91; 95% confidence interval [CI], 2.46-9.20; P < .001), women with severe depression (OR, 2.50; 95% CI, 1.08-6.96; P = .04), and women who had sexual intercourse that focused on penetration (OR, 2.02; 95% CI, 1.03-3.98; P = .04). CLINICAL IMPLICATIONS: These findings may have important implications for the prevention and treatment of sexual disorders in women. STRENGTHS AND LIMITATIONS: This design selected all diagnosed cases of female orgasmic disorder and did not select a specific subgroup. However, some limitations must be considered. This study was conducted in a single clinic, although it should be noted that it is the main clinic for the treatment of sexual dysfunction in the country. A further limitation could be that this type of study design does not allow for statements about causality to be made. CONCLUSION: There is an increased risk of female orgasmic disorder in women with ADHD, with severe depression, and who engage in penetrative sex.

Eating disorder debut cases during COVID-19 lockdown in adults. Exploring differences in treatment outcome contrasting with pre-pandemic onset cases.

OBJECTIVE: Despite an increase in eating disorder (ED) cases during the COVID-19 pandemic, there are limited longitudinal studies exploring treatment outcomes. The aims of the present study were: (1) to compare the clinical features of patients with EDs whose onset was during the COVID-19 lockdown (pandemic cohort) against patients with EDs whose onset was prior to the pandemic (pre-pandemic cohort) and, (2) to compare therapy responses between the cohorts. METHOD: The sample consisted of 115 adult women with an ED. N = 37 new ED cases (pandemic cohort) were diagnosed and included in the study during the pandemic (May 2020-May 2021); these patients did not have any previous history of an ED. We also included N = 78 ED cases (pre-pandemic cohort) diagnosed prior to the COVID-19 pandemic breakout (prior to March 2020). All ED subtypes were considered in both groups and several clinical variables were assessed. RESULTS: At baseline, pandemic cohort reported lower levels of impulsivity and higher emotional regulation capacities than the pre-pandemic cohort; however, no differences were found in aspects of general psychopathology and ED related severity. Following treatment, the pandemic cohort showed higher rates of good outcome and lower rates of dropouts than the pre-pandemic cohort. CONCLUSIONS: Although both cohorts showed similar ED-related symptoms and general psychopathology scores, treatment outcomes were more favourable in the pandemic cohort.

Effect of motivational interviewing on preventive strategies for children receiving full-mouth dental rehabilitation under general anesthesia: A randomized controlled trial.

BACKGROUND: Motivational interviewing (MI) is an approach to increase parental compliance to follow up and recall of their children. It has proven to be successful in motivating parents to adopt and maintain preventive child oral health behaviors. AIM: To assess the effectiveness of motivational interviewing on prevention strategies for parents of children who have received full-mouth dental rehabilitation under general anesthesia (GA). DESIGN: This is a parallel-arm randomized controlled trial. Parents in the treatment arm were randomized and received a combination of motivational interviewing, individualized goal setting, visual aids, and verbal education post-GA. Those in the control arm received the same information by verbal and written education. Both groups were evaluated at 2-week follow-up and 3-month recall. Differences in attendance, oral health knowledge, readiness to change, and parental self-efficacy (PSE) were compared between groups and at return visits. RESULTS: Of 74 parents of children randomly allocated in this study, 22 (61%) and 13 (38%) from the intervention group, and 21 (55%) and 16 (46%) from the control group attended the 2-week, and 3-month follow-up, respectively. The average PSE for participants in the intervention group was significantly higher than that of the control group at the follow-up visit (p = .0050). CONCLUSION: Readiness to change dietary habits and average PSE for parents in the intervention group were significantly higher than that of the control group after receiving the modified preventive strategy.

Exploring the presence of bovine leukemia virus among breast cancer tumors in a rural state.

PURPOSE: The bovine leukemia virus (BLV) is a deltaretrovirus that causes malignant lymphoma and lymphosarcomas in cattle globally and has high prevalence among large scale U.S. dairy herds. Associations between presence of BLV DNA in human mammary tissue and human breast cancer incidence have been reported. We sought to estimate the prevalence of BLV DNA in breast cancer tissue samples in a rural state with an active dairy industry. METHODS: We purified genomic DNA from 56 fresh-frozen breast cancer tissue samples (51 tumor samples, 5 samples representing adjacent normal breast tissue) banked between 2016 and 2019. Using nested PCR assays, multiple BLV tax sequence primers and primers for the long terminal repeat (LTR) were used to detect BLV DNA in tissue samples and known positive control samples, including the permanently infected fetal lamb kidney cell line (FLK-BLV) and blood from BLV positive cattle. RESULTS: The median age of patients from which samples were obtained at the time of treatment was 60 (40-93) and all were female. Ninety percent of patients had invasive ductal carcinoma. The majority were poorly differentiated (60%). On PCR assay, none of the tumor samples tested positive for BLV DNA, despite having consistent signals in positive controls. CONCLUSION: We did not find BLV DNA in fresh-frozen breast cancer tumors from patients presenting to a hospital in Vermont. Our findings suggest a low prevalence of BLV in our patient population and a need to reevaluate the association between BLV and human breast cancer.

A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study.

BACKGROUND: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. METHODS: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. RESULTS: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. CONCLUSIONS: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.

Reversible Pressure-Magnetic Modulation in a Tetrathiafulvalene-Based Dyad Piezochromic Dysprosium Single-Molecule Magnet.

The extreme sensitivity of trivalent lanthanide ions to crystal field variations led to the emergence of single-molecule magnetic switching under various stimuli. The use of pressure as an external stimulus instead of classic light irradiation, oxidation or any chemical reactions allows a fine tuning of the magnetic modulation. Here the well-known pure isotopically enriched [162 Dy(tta)3 (L)]⋅C6 H14 (162 Dy) Single-Molecule Magnet (SMM) (tta- =2-2-thenoyltrifluoroacetonate and L=4,5-bis(propylthio)-tetrathiafulvalene-2-(2-pyridyl)benzimidazole-methyl-2-pyridine) was experimentally investigated by single-crystal diffraction and squid magnetometry under high applied pressures. Both reversible piezochromic properties and pressure modulation of the slow magnetic relaxation behavior were demonstrated and supported by ab initio calculations. The magnetic study of the diluted sample [162 Dy0.05 Y0.95 (tta)3 (L)]⋅C6 H14 (162 Dy@Y) indicated that variations in the electronic structure have mainly intermolecular origin with weak intramolecular contribution. Quantitative magnetic interpretation concludes to a deterioration of the Orbach process for the benefit of both Raman and QTM mechanisms under applied pressure.

Controlling block copolymer one-dimensional self-assembly in polymeric matrices.

The synthesis of one-dimensional (1D) nanostructures in polymeric matrices has become the focus of much research, as the presence of these highly anisotropic domains determines the transport behaviour and mechanical properties of the resulting nanostructured polymers. In this work, 1D PEO nanocrystals were synthesized in situ from polystyrene-b-polyethylene oxide (PS-b-PEO) self-assembly in a polystyrene matrix. For this, three different block copolymers (BCP) were employed: L-BCP (PS = 32 000 Da and PEO = 11 000 Da), M-BCP, (PS = 59 000 Da and PEO = 31 000 Da), and H-BCP, (PS = 102 000 Da and PEO = 34 000 Da). The formation of 1D nanocrystals starts with the reaction-induced microphase separation of BCP during styrene photopolymerization at room temperature. Then, as matrix polymerizes, the primary crystalline micelles aggregate via epitaxial crystallization by end-to-end coupling. The morphology of the resulting nanocrystals was highly dependent on the BCP employed. While L-BCP self-assembles into 1D ribbon-like nanocrystals, M-BCP macro-phase separates and, H-BCP self-assembles into short disk-like nanocrystals. This dissimilar behavior was mainly associated to the length of the stabilizing corona block. In the case of H-BCP, it was found that 1D self-assembly occurred when the conditions for core thickening were given, that is, when a non-reactive period was introduced in the cure cycle. During such a period, core thickening clears the lateral surface of the nanocrystals, allowing end-to-end coupling. The driving force for crystallization was also modified. An increase in undercooling resulted in an elevated nucleation rate and accelerated crystal growth. This led to a narrower size distribution of shorter 1D nanocrystals. This knowledge will enable the synthesis of customized 1D nanocrystals in a thermoplastic matrix, through the precise selection of the BCP formulation and curing conditions.

Spanish version of the ICIQ-Bowel questionnaire among colorectal cancer patients: construct and criterion validity : Comprehensive assessment of bowel function.

PURPOSE: Bowel complaints are very common among patients with colorectal cancer. However, the most used questionnaires for colorectal cancer survivors do not comprehensively comprise bowel symptoms. This study aimed to examine construct and criterion validity, as well as internal consistency, of the Chilean Version of the International Consultation on Incontinence Questionnaire Bowel Module (ICIQ-B) among people with colorectal cancer. METHODS: Cross-sectional, validation study performed with 106 colorectal cancer patients from Hospital del Salvador, Chile. Bowel function was assessed with the ICIQ-B. Construct validity was assessed with confirmatory factor analysis and hypothesis testing. Specific items of a quality-of-life questionnaire (EORTC QLQ-CR29) were used to correlate with similar ICIQ-B items for criterion validity. For internal consistency, Cronbach's alpha was computed. RESULTS: For construct validity, the confirmatory factor analysis showed that the three factors model did not fit our data. Meanwhile, hypothesis testing favored the construct validity of the instrument, considering that rectal cancer patients showed worse bowel pattern (p = 0.001), bowel control (p = 0.001) and quality of life (p < 0.001) scores compared to colon cancer patients. In addition, those patients assessed before surgery also presented worse scores bowel control (p = 0.023) and quality of life (p = 0.009) compared to post-surgical patients. Regarding criterion validity, the ICIQ-B items showed a significant correlation with similar QLQ-CR29 items. The internal reliability of the instrument was good (Cronbach's α = 0.909). CONCLUSION: Considering that this questionnaire appraises bowel function in more depth, it is recommended for use in clinical practice and research with colorectal cancer patients.

Consequences of the Covid-19 pandemic on complex multimorbid elderly: Follow-up of a community-based cohort. SAMAC3 Study.

BACKGROUND: The restrictions imposed during the management of the pandemic led to lack of care of other health problems. PURPOSE: To assess changes in the health status of complex multimorbidity elderly, functional and cognitive capacities, perception of the social surroundings, care provided by the nurses, including nursing diagnosis and interventions, use of health services, adverse events, and use of devices and technical help during the first 6 months of the Covid-19 pandemic. DESIGN: A 1-year longitudinal cohort study was conducted. METHODS: Ninety-seven complex multimorbid elderly attended in primary care were evaluated every 3 months in a health area of the Spanish National Health System (SNHS). The research was called "SAMAC3 study". RESULTS: Significant negative changes were observed in the functional and cognitive capacity of the elderly, and in several nursing diagnoses. A decrease was observed in the frequency of visit to the nurses, hospital admittance, length of hospital stays, and falls. CONCLUSIONS: The functional and cognitive capacities of the cohort became worse. However, a significant decrease in the frequency of use of health services was observed. The nurses detected significant changes in activity-exercise, cognitive-perception, and roles-relationships, but their interventions were mostly centered on resolving clinical matters that required immediate attention. CLINICAL RELEVANCE: The present study allowed us to observe that a situation of social and health stress has worsened the health indicators of multimorbid elderly, and the clinical care of community nurses was insufficient to providing care for the deterioration of the physical and cognitive domains.

Sleep and Circadian Health of Critical COVID-19 Survivors 3 Months After Hospital Discharge.

OBJECTIVES: To evaluate the sleep and circadian rest-activity pattern of critical COVID-19 survivors 3 months after hospital discharge. DESIGN: Observational, prospective study. SETTING: Single-center study. PATIENTS: One hundred seventy-two consecutive COVID-19 survivors admitted to the ICU with acute respiratory distress syndrome. INTERVENTIONS: Seven days of actigraphy for sleep and circadian rest-activity pattern assessment; validated questionnaires; respiratory tests at the 3-month follow-up. MEASUREMENTS AND MAIN RESULTS: The cohort included 172 patients, mostly males (67.4%) with a median (25th-75th percentile) age of 61.0 years (52.8-67.0 yr). The median number of days at the ICU was 11.0 (6.00-24.0), and 51.7% of the patients received invasive mechanical ventilation (IMV). According to the Pittsburgh Sleep Quality Index (PSQI), 60.5% presented poor sleep quality 3 months after hospital discharge, which was further confirmed by actigraphy. Female sex was associated with an increased score in the PSQI (p < 0.05) and IMV during ICU stay was able to predict a higher fragmentation of the rest-activity rhythm at the 3-month follow-up (p < 0.001). Furthermore, compromised mental health measured by the Hospital Anxiety and Depression Scale was associated with poor sleep quality (p < 0.001). CONCLUSIONS: Our findings highlight the importance of considering sleep and circadian health after hospital discharge. Within this context, IMV during the ICU stay could aid in predicting an increased fragmentation of the rest-activity rhythm at the 3-month follow-up. Furthermore, compromised mental health could be a marker for sleep disruption at the post-COVID period.

IκBα deficiency imposes a fetal phenotype to intestinal stem cells.

The intestinal epithelium is a paradigm of adult tissue in constant regeneration that is supported by intestinal stem cells (ISCs). The mechanisms regulating ISC homeostasis after injury are poorly understood. We previously demonstrated that IκBα, the main regulator of NF-κB, exerts alternative nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. Here, we show that nuclear IκBα is present in the ISC compartment. Mice deficient for IκBα show altered intestinal cell differentiation with persistence of a fetal-like ISC phenotype, associated with aberrant PRC2 activity at specific loci. Moreover, IκBα-deficient intestinal cells produce morphologically aberrant organoids carrying a PRC2-dependent fetal-like transcriptional signature. DSS treatment, which induces acute damage in the colonic epithelium of mice, results in a temporary loss of nuclear P-IκBα and its subsequent accumulation in early CD44-positive regenerating areas. Importantly, IκBα-deficient mice show higher resistance to damage, likely due to the persistent fetal-like ISC phenotype. These results highlight intestinal IκBα as a chromatin sensor of inflammation in the ISC compartment.

Impact of time to intubation on mortality and pulmonary sequelae in critically ill patients with COVID-19: a prospective cohort study.

QUESTION: We evaluated whether the time between first respiratory support and intubation of patients receiving invasive mechanical ventilation (IMV) due to COVID-19 was associated with mortality or pulmonary sequelae. MATERIALS AND METHODS: Prospective cohort of critical COVID-19 patients on IMV. Patients were classified as early intubation if they were intubated within the first 48 h from the first respiratory support or delayed intubation if they were intubated later. Surviving patients were evaluated after hospital discharge. RESULTS: We included 205 patients (140 with early IMV and 65 with delayed IMV). The median [p25;p75] age was 63 [56.0; 70.0] years, and 74.1% were male. The survival analysis showed a significant increase in the risk of mortality in the delayed group with an adjusted hazard ratio (HR) of 2.45 (95% CI 1.29-4.65). The continuous predictor time to IMV showed a nonlinear association with the risk of in-hospital mortality. A multivariate mortality model showed that delay of IMV was a factor associated with mortality (HR of 2.40; 95% CI 1.42-4.1). During follow-up, patients in the delayed group showed a worse DLCO (mean difference of - 10.77 (95% CI - 18.40 to - 3.15), with a greater number of affected lobes (+ 1.51 [95% CI 0.89-2.13]) and a greater TSS (+ 4.35 [95% CI 2.41-6.27]) in the chest CT scan. CONCLUSIONS: Among critically ill patients with COVID-19 who required IMV, the delay in intubation from the first respiratory support was associated with an increase in hospital mortality and worse pulmonary sequelae during follow-up.

Where does purging disorder lie on the symptomatologic and personality continuum when compared to other eating disorder subtypes? Implications for the DSM.

OBJECTIVES: To assess the clinical significance and distinctiveness of purging disorder (PD) from other eating disorder (ED) diagnoses. METHOD: Participants included 3127 women consecutively admitted to an ED treatment centre (246 PD, 465 anorexia nervosa restrictive [AN-R], 327 AN-binge purging [AN-BP], 1436 bulimia nervosa [BN], 360 binge eating disorder [BED], 177 atypical AN and 116 unspecified feeding or eating disorder [UFED]) who were diagnosed according to DSM-5 criteria. Additionally, 822 control participants were recruited from the community. All participants completed measures assessing ED symptoms (EDI-2), general psychopathology (SCL-90-R) and personality (TCI-R). RESULTS: Patients with PD, when compared to controls, scored significantly higher on the EDI-2 and SCL-90-R, and most TCI-R dimensions. Most of the significant differences between PD and the other ED diagnoses emerged between PD and AN-R, followed by Atypical-AN, UFED, AN-BP and BED, with patients with PD typically reporting higher scores on the EDI-2 and SCL-90-R subscales. Significant differences between PD and BN were also present, but to a lesser extent. The findings for personality varied amongst the different ED diagnoses. CONCLUSIONS: PD is a clinically significant disorder, which seems to be more similar to BN than it is to AN and the other ED subtypes.

Food addiction in anorexia nervosa: Implications for the understanding of crossover diagnosis.

OBJECTIVE: Food addiction (FA) construct was introduced to reflect abnormal eating patterns that resemble behavioural ones found in substance use disorders. FA has been barely explored in anorexia nervosa (AN). This study evaluated FA occurrence and associated factors in a sample of patients with AN, distinguishing between restrictive and binge-purging subtypes and focussing on the influence of FA in the crossover diagnosis between them. METHOD: A sample of 116 patients with AN admitted for treatment seeking at an Bellvitge Hospital Eating Disorders Unit were included (72 restrictive [AN-R]; 44 binge-purge AN [AN-BP]), and eating-related, personality and psychopathological variables were assessed. Most participants were women (92.2%), mean age 27.1 years old (SD = 10.5). RESULTS: FA was more prevalent in patients with AN-BP compared to the AN-R group (75.0% and 54.2%, respectively). The patients with AN-R FA+, presented more similar ED symptomatology, general psychopathology and personality traits, with the AN-BP patients, than with the AN-R FA-. CONCLUSIONS: Patients with AN-R FA+, exhibit more similarities with the AN-BP subgroup than with the AN-R FA-. Thus, it is possible to hypothesise that the presence of FA might be an indicator of the possible crossover from AN-R to AN-BP.

Solvato Modulation of the Magnetic Memory in Isotopically Enriched Erbium Polyoxometalate.

Single-Molecule Magnet (SMM) property is by essence molecular, while commonly measured in solid crystalline state. Solvent crystallization molecules are usually neglected in the analysis and interpretation of solid-state properties. The solvation/desolvation process in the polyoxometalate(POM)-based Na9 [Er(W5 O18 )2 ] ⋅ 35 H2 O SMM demonstrates that the dehydrated form relaxes more than 1000 times faster than the initial state, while the rehydration process allows the quasi complete recovering of the initial magnetic behaviour. This dehydration process is monitored by thermogravimetric analysis (TGA) and temperature-dependent X-ray powder diffraction, and rationalized by periodic quantum chemical calculations evidencing the tremendous role of the labile water molecules in the stability of the edifice. Ab-initio calculations highlight that sodium ions localization in the structure drive the magnetic responses. Isotopic enrichment with nuclear spin free (166 Er, I=0) ErIII ions shows that the relaxation dynamics in the quantum regime depends on the nuclear spin.