WLB-87848, a Selective σ1 Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.

The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of ß-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aß peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.

Lack of association between COVID-19 vaccines and miscarriage onset using a case-crossover design.

Pregnant women might have an increased risk of SARS-COV-2 infection. Although evidence towards the efficacy and safety of COVID-19 is growing still there is room for improvement on the knowledge towards pregnancy adverse events, such as miscarriage. We explored the association of COVID-19 vaccine with the risk of miscarriages using the Real-World. We identified a cohort of vaccinated pregnancies using the BIFAP database which contains systematically recorded data on care patients in Spain (N = 4054). We then restricted it to those women who had a miscarriage using a validated algorithm (N = 607). Among them, we performed a case-crossover design to evaluate the effect of intermittent exposures on the risk of miscarriage. Adjusted Odds Ratio with their confidence intervals were calculated using two analytical approaches: conditional logistic regression and Generalized Linear Mixed-Effects Models. A total of 225 (37.1%) were aged 35-39 years. The most common comorbidities were asthma, migraine, gastritis, and hypothyroidism. A total of 14.7% received only one dose of COVID-19 and 85.3% two doses, respectively. A total of 36.8% of women with one dose and 27.6% with two doses received the vaccine 7 days prior to the miscarriage. Corresponding adjusted estimates for the risk of miscarriage using the conditional logistic regression where as follows: 1.65 (95% CI 0.85-3.23) when using as the sum of 3 control moments among women with one dose, 1.02 (95% CI 0.72-1.46) among women with two doses and 1.03 (95% CI 0.72, 1.46) using the whole study population. Very similar results were obtained when conducting the Generalized Linear Mixed-Effects Models. There was no overall increased risk of miscarriage onset associated with COVID-19 vaccine although contradictory results were found according to the number of doses. Further studies are required with larger sample sizes to assess this association.

COVID-19 Distribution in Pregnancy, Drug Use Patterns and COVID-19 Medication during the Pandemic in Spain: Data from Real-World Electronic Health Records.

Although pregnant women were considered a risk population for COVID-19, little is known of their drug use during the pandemic. We aimed to investigate COVID-19 distribution, drug use patterns and COVID-19 medication. We conducted a retrospective cohort of validated pregnancies aged 15-49 years, from January 2020 to December 2022, using the BIFAP database. An identified cohort of pregnant women with COVID-19 was matched by age, gestational age, length of pregnancy and outcome to a cohort free of COVID-19 (8413 vs. 24,975). We performed a descriptive analysis on COVID-19 cases, estimated the drug use patterns and assessed COVID-19-specific drugs within the week prior/after diagnosis, stratified by pandemic wave and gestational week. The results showed that 72% of pregnant women with COVID-19 received at least one prescription vs. 66.6% of those free of COVID-19, with analgesics, antibiotics and thyroid hormones being the most prescribed drugs in both groups. In the COVID-19 group, they were antithrombotics (40 prescriptions per 100 women), analgesic/NSAIDs (19.64/6.29) and antibiotics (6.95). COVID-19 cases gradually increased, peaking at the fifth and second waves. Prescription rates were similar when compared to pre-pandemic studies. The use of drugs compatible with COVID-19 treatments was in line with recommendations.

The Risk of SARS-CoV-2 Infection in Pregnant Women: An Observational Cohort Study Using the BIFAP Database.

BACKGROUND: It has been suggested that women experiencing during pregnancy several physiological and immunological changes that might increase the risk of any infection including the SARS-CoV-2. OBJECTIVE: We aimed to quantify the risk of SARS-CoV-2 infection during pregnancy compared with women with no pregnancies. METHODS: We used data from the BIFAP database and a published algorithm to identify all pregnancies during 2020. Pregnancies were matched (1:4) by age region, and length of pregnancy with a cohort of women of childbearing age. All women with SARS-CoV-2 infection before entering the study were discarded. We estimated incidence rates of SARS-CoV-2 with 95% confidence intervals (CIs) expressed by 1000 person-months as well as Kaplan-Meier figures overall and also stratified according to pregnancy period: during pregnancy, at puerperium (from end of pregnancy up to 42 days) and after pregnancy. (from 43 days after pregnancy up to end pf study period (i.e., June 2021). We conducted a Cox regression to assess risk factors for SARS-COV infection. The incidence rate of SARS-CoV-2 infection expressed by 1000 person-months were. RESULTS: There was a total of 103,185 pregnancies and 412,740 matched women at childbearing, with a mean age of 32.3 years. The corresponding incidence rates of SARS-CoV-2 infection according to cohorts were: 2.44 cases per 1000 person-months (confidence interval (CI) 95%: 2.40-2.50) and 4.29 (95% CI: 4.15-4.43) for comparison cohort. The incidence rate ratio (IRR) of SARS-CoV-2 was 1.76 (95% CI: 1.69-1.83). When analyzing according to pregnancy period, the IRRs were 1.30 (95% CI: 11.20-1.41) during the puerperium and 1.19 (95% CI: 41.15-1.23) after pregnancy. In addition to pregnancy itself, other important risk factors were obesity (1.33 (95% CI: 1.23-1.44)) and diabetes (1.23 (95% CI: 11.00-1.50). CONCLUSION: Pregnant women are at increased risk of SARS-CoV-2 infection compared with women of childbearing age not pregnant. Nevertheless, there is a trend towards reverting during puerperium and after pregnancy.

Use of hydrochlorothiazide and risk of skin cancer in a large nested case-control study in Spain.

PURPOSE: Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population. METHODS: Two parallel nested case-control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP. Cancer cases were matched to 10 controls by age and gender through risk-set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). RESULTS: In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26-1.34) in SIDIAP and 1.20 (1.12-1.30) in BIFAP, with a lower risk for BCC (1.11 [1.02-1.21]) than for SCC (1.71 [1.45-2.02]). A dose-response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09-1.43) in SIDIAP and 0.85 (0.64-1.13) in BIFAP. CONCLUSIONS: In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose-response pattern.

Digital competence in higher education research: A systematic literature review.

In the information and knowledge society, where technology develops rapidly and penetrates deeply into our lives, the discussion about digital competence has become a hot topic today. After the emergence of the Coronavirus (Covid-19) and with its huge impact on the education industry, the concern about digital competence has reached a new height. This systematic literature review uses Web of science and Scopus as databases to store and analyze the existing research on digital competence in higher education settings. The purpose of this review is to provide the scholar community with a current overview of digital competence research from 2015 to 2021 in the context of higher education regarding the definition of digital competence, dimensions used to evaluate digital competence, research purposes, methodologies, and results and limitations. Major findings include that the majority of publications cited both research and EU policy in describing the definition of digital competence. The review indicates that most university students and teachers have a basic level of digital competence. Besides, the institutions of higher education are encouraged to focus on the development students and teachers' digital competence, create relevant learning strategies and use appropriate tools to improve the quality of education.

Burnout and posttraumatic stress in paediatric critical care personnel: Prediction from resilience and coping styles.

INTRODUCTION: Our aims were (1) to explore the prevalence of burnout syndrome (BOS) and posttraumatic stress disorder (PTSD) in a sample of Spanish staff working in the paediatric intensive care unit (PICU) and compare these rates with a sample of general paediatric staff and (2) to explore how resilience, coping strategies, and professional and demographic variables influence BOS and PTSD. MATERIALS AND METHODS: This is a multicentre, cross-sectional study. Data were collected in the PICU and in other paediatric wards of nine hospitals. Participants consisted of 298 PICU staff members (57 physicians, 177 nurses, and 64 nursing assistants) and 189 professionals working in non-critical paediatric units (53 physicians, 104 nurses, and 32 nursing assistants). They completed the Brief Resilience Scale, the Coping Strategies Questionnaire for healthcare providers, the Maslach Burnout Inventory, and the Trauma Screening Questionnaire. RESULTS: Fifty-six percent of PICU working staff reported burnout in at least one dimension (36.20% scored over the cut-off for emotional exhaustion, 27.20% for depersonalisation, and 20.10% for low personal accomplishment), and 20.1% reported PTSD. There were no differences in burnout and PTSD scores between PICU and non-PICU staff members, either among physicians, nurses, or nursing assistants. Higher burnout and PTSD rates emerged after the death of a child and/or conflicts with patients/families or colleagues. Around 30% of the variance in BOS and PTSD is predicted by a frequent usage of the emotion-focused coping style and an infrequent usage of the problem-focused coping style. DISCUSSION AND CONCLUSIONS: Interventions to prevent and treat distress among paediatric staff members are needed and should be focused on: (i) promoting active emotional processing of traumatic events and encouraging positive thinking; (ii) developing a sense of detached concern; (iii) improving the ability to solve interpersonal conflicts, and (iv) providing adequate training in end-of-life care.

An Exploratory Study of Sevoflurane as an Alternative for Difficult Sedation in Critically Ill Children.

OBJECTIVES: To analyze the effectiveness of inhaled sevoflurane in critically ill children with challenging sedation. DESIGN: Prospective case series. SETTING: Two PICUs of university hospitals in Spain. INTERVENTIONS: Prospective observational study and exploratory investigation conducted in two PICUs in Madrid, Spain, over a 6-year period. Children treated with inhaled sevoflurane due to difficult sedation were included. Sevoflurane was administered via the anesthetic conserving device (AnaConDa) connected to a Servo-I ventilator (Maquet, Solna, Sweden). A morphine infusion was added to sevoflurane for analgesia. Demographic and clinical data, oral and IV sedatives, Sedation and Analgesic Clinical scores, and Bispectral Index Score monitoring were registered. MEASUREMENTS AND MAIN RESULTS: Twenty-three patients with a median age of 6 months old were included. Fifty percentage of the patients had critical heart diseases. Sedative and analgesic drugs used before starting sevoflurane were mainly midazolam (63%) and fentanyl (53%). Six patients (32%) also received muscle relaxants. Sevoflurane was administered for a median of 5 days (interquartile range, 5.5-8.5 d). Median end-tidal sevoflurane concentration was 0.8% (interquartile range, 0.7-0.85%), achieved with an infusion rate of 7.5 mL/hr (5.7-8.6 mL/hr). After 48 hours of treatment, some sedative drugs could be removed in 18 patients (78%). Median Bispectral Index Score value prior to sevoflurane administration was 61 (interquartile range, 49-62), falling to 42 (interquartile range, 41-47; p < 0.05) after 6 hours of treatment. Six patients (26%) presented withdrawal syndrome after sevoflurane suspension, and all of them had received sevoflurane at least for 6 days. The main side effect was moderate hypotension in seven patients (30%). CONCLUSIONS: Inhaled sevoflurane appeared to be an effective sedative agent in critically ill children and can be useful in those patients on mechanical ventilation difficult to sedate with conventional drugs. It can be administered easily in the PICU with conventional ventilators using the AnaConDa system. Withdrawal syndrome may occur with prolonged treatment.

Sevoflurane Therapy for Severe Refractory Bronchospasm in Children.

OBJECTIVES: To describe the effect of inhaled sevoflurane in the treatment of severe refractory bronchospasm in children. DESIGN: Retrospective case series. SETTING: Two PICUs of tertiary general university hospitals in Spain. PATIENTS: Ten patients ranging from 5 months to 14 years old with severe bronchospasm and acute respiratory failure requiring tracheal intubation and mechanical ventilation and treated with sevoflurane from 2008 to 2015. INTERVENTION: Inhaled sevoflurane therapy was initiated after failure of conventional medical management and mechanical ventilation. In two patients, sevoflurane was administered through a Servo 900C ventilator (Maquet, Bridgewater, NJ) equipped with a vaporizer and in the other eight patients via the Anesthetic Conserving Device (AnaConDa; Sedana medical, Uppsala, Sweden) with a critical care ventilator. MEASUREMENTS AND MAIN RESULTS: Inhaled sevoflurane resulted in statistically significant decreases of PaCO2 of 34.2 torr (95% CI, 8.3-60), peak inspiratory pressure of 14.3 cm H2O (95% CI, 8.6-19.9), and improvement in pH of 0.17 (0.346-0.002) within 6 hours of administration. Only one patient presented hypotension responsive to volume administration at the beginning of the treatment. All patients could be extubated within a median time of 120 hours (interquartile range, 46-216). CONCLUSIONS: Inhaled sevoflurane therapy decreases the levels of PaCO2 and peak inspiratory pressure values, and it may be considered as a rescue therapy in patients with life-threatening bronchospasm refractory to conventional therapy.

A Multisite, Randomized Controlled Clinical Trial of Computerized Cognitive Remediation Therapy for Schizophrenia.

The effectiveness of cognitive remediation therapy (CRT) for the neuropsychological deficits seen in schizophrenia is supported by meta-analysis. However, a recent methodologically rigorous trial had negative findings. In this study, 130 chronic schizophrenic patients were randomly assigned to computerized CRT, an active computerized control condition (CC) or treatment as usual (TAU). Primary outcome measures were 2 ecologically valid batteries of executive function and memory, rated under blind conditions; other executive and memory tests and a measure of overall cognitive function were also employed. Carer ratings of executive and memory failures in daily life were obtained before and after treatment. Computerized CRT was found to produce improvement on the training tasks, but this did not transfer to gains on the primary outcome measures and most other neuropsychological tests in comparison to either CC or TAU conditions. Nor did the intervention result in benefits on carer ratings of daily life cognitive failures. According to this study, computerized CRT is not effective in schizophrenia. The use of both active and passive CCs suggests that nature of the control group is not an important factor influencing results.

Effectiveness of liposomal amphotericin B in patients admitted to the ICU on renal replacement therapy.

INTRODUCTION: This study was designed to compare the effectiveness of liposomal amphotericin B (L-AmB) in ICU patients with and without renal replacement therapy (RRT). METHODS: Observational, retrospective, comparative and multicenter study conducted in critically ill patients treated with L-AmB for 3 or more days, divided into two cohorts depending on the use of RRT before or within the first 48 hours after starting L-AmB. Clinical and microbiological response at the end of treatment was evaluated. RESULTS: A total of 158 patients met the inclusion criteria, 36 (22.8%) of which required RRT during the ICU stay. Patients with RRT as compared with those without RRT showed a higher APACHE II score on admission (21.4 vs 18.4, P = 0.041), greater systemic response against infection (P = 0.047) and higher need of supportive techniques (P = 0.002). In both groups, main reasons for the use of L-AmB were broad spectrum and hemodynamic instability. A higher daily dose of L-AmB was used in the RRT group (4.30 vs 3.84 mg/kg, P = 0.030) without differences in the total cumulative dose or treatment duration. There were no differences in the clinical response (61.1% vs 56.6%, P = 0.953) or microbiological eradication rate (74.1% vs 64.6%, P = 0.382). In patients with proven invasive fungal infection, satisfactory clinical response was obtained in 74.1% and microbiological eradication 85.7%. CONCLUSIONS: Although the study sample is small, this study shows that L-AmB is effective in critically ill patients admitted to the ICU requiring RRT.