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ObjectivesGlucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy.DesignThis multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022.SettingData were collected from the databases of six Teratology Information Services.ParticipantsThis study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women.ResultsExposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses.ConclusionsThis study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.

This study aims to describe the epidemiology of COVID-19 patients in a Swiss university hospital. This retrospective observational study included all adult patients hospitalized with a laboratory confirmed SARS-CoV-2 infection from March 1 to March 25, 2020. We extracted data from electronic health records. The primary outcome was the need to mechanical ventilation at day 14. We used multivariate logistic regression to identify risk factors for mechanical ventilation. Follow-up was of at least 14 days. 145 patients were included in the multivariate model, of whom 36 (24.8%) needed mechanical ventilation at 14 days. The median time from symptoms onset to mechanical ventilation was 9·5 days (IQR 7.00, 12.75). Multivariable regression showed increased odds of mechanical ventilation with age (OR 1.09 per year, 95% CI 1.03-1.16, p = 0.002), in males (OR 6.99, 95% CI 1.68-29.03, p = 0.007), in patients who presented with a qSOFA score ≥2 (OR 7.24, 95% CI 1.64-32.03, p = 0.009), with bilateral infiltrate (OR 18.92, 3.94-98.23, p<0.001) or with a CRP of 40 mg/l or greater (OR 5.44, 1.18-25.25; p = 0.030) on admission. Patients with more than seven days of symptoms on admission had decreased odds of mechanical ventilation (0.087, 95% CI 0.02-0.38, p = 0.001). This study gives some insight in the epidemiology and clinical course of patients admitted in a European tertiary hospital with SARS-CoV-2 infection. Age, male sex, high qSOFA score, CRP of 40 mg/l or greater and a bilateral radiological infiltrate could help clinicians identify patients at high risk for mechanical ventilation.

The reason why most individuals with COVID-19 have relatively limited symptoms while other develop respiratory distress with life-threatening complications remains unknown. Increasing evidence suggests that COVID-19 associated adverse outcomes mainly rely on dysregulated immunity. Here, we compared transcriptomic profiles of blood cells from 103 patients with different severity levels of COVID-19 with that of 27 healthy and 22 influenza-infected individuals. Data provided a complete overview of SARS-CoV-2-induced immune signature, including a dramatic defect in IFN responses, a reduction of toxicity-related molecules in NK cells, an increased degranulation of neutrophils, a dysregulation of T cells, a dramatic increase in B cell function and immunoglobulin production, as well as an important over-expression of genes involved in metabolism and cell cycle in patients infected with SARS-CoV-2 compared to those infected with influenza viruses. These features also differed according to COVID-19 severity. Overall and specific gene expression patterns across groups can be visualized on an interactive website ( https://bix.unil.ch/covid/ ). Collectively, these transcriptomic host responses to SARS-CoV-2 infection are discussed in the context of current studies, thereby improving our understanding of COVID-19 pathogenesis and shaping the severity level of COVID-19.

Aim/Objective: To highlight points to consider to best manage DDIs and ensure safe prescribing. Methods: Two cases of DDIs between anticalcineurins and azoles are presented. Tacrolimus and cyclosporine have a narrow therapeutic index and are metabolized by CYP3A4/5 and CYP3A4, respectively. Azoles are CYP3A inhibitors. Based on these cases, some pitfalls relating to DDIs assessment are reviewed. Results: 41-year-old male with lung transplantation treated with tacrolimus 7 mg po bid resulting in stable tacrolimus trough plasma concentrations (Cmin) within the target range (10-12ng/mL). Two days after introducing isavuconazole, tacrolimus Cmin was [ 30ng/ mL. Isavuconazole is a moderate CYP3A4/5 inhibitor (AUC of sensitive substrates increased by C2-\\5-fold).1,2 In one study, coadministration with isavuconazole increased tacrolimus AUC by 2.2-fold, and cyclosporine AUC by only 1.3-fold.3 Although both anticalcineurins share the same metabolic pathway, they are not equally sensitive to the inhibitory effect of isavuconazole. Thus, DDIs data cannot be automatically inferred from one drug to another. 12-year-old male with allo-SCT treated with cyclosporine 60 mg iv bid. Cyclosporine dose was reduced to 2x48 mg iv bid when posaconazole was introduced. Cyclosporine Cmin remained within the target range (180-250ng/mL) on the subsequent days. Cyclosporine was later switched to oral route and dose was increased to 96 mg bid to account for low oral bioavailability. Two days later, Cmin was 630ng/mL. Posaconazole is a strong CYP3A4 inhibitor (AUC of sensitive substrate increased by C5-fold).2 DDI-based dosage adjustment may differ according to the route of administration, particularly for drugs with high intestinal/hepatic metabolism, such as cyclosporine or tacrolimus (lower dose if po). Conclusion: Managing DDIs requires expertise. In difficult cases, pharmacologists/pharmacists can provide valuable assistance. TDM is useful to check the appropriateness of dosage adjustments. PBPK modeling will enable to better characterize DDIs.

BackgroundAfter mild COVID-19, some outpatients experience persistent symptoms. However, data are scarce and prospective studies are urgently needed.ObjectivesTo characterize the post-COVID-19 syndrome after mild COVID-19 and identify predictors.ParticipantsOutpatients with symptoms suggestive of COVID-19 with (1) PCR-confirmed COVID-19 (COVID-positive) or (2) SARS-CoV-2 negative PCR (COVID-negative).DesignMonocentric cohort study with prospective phone interview between more than 3 months to 10 months after initial visit to the emergency department and outpatient clinics.Main MeasuresData of the initial visits were extracted from the electronic medical file. Predefined persistent symptoms were assessed through a structured phone interview. Associations between long-term symptoms and PCR results, as well as predictors of persistent symptoms among COVID-positive, were evaluated by multivariate logistic regression adjusted for age, gender, smoking, comorbidities, and timing of the survey.Key ResultsThe study population consisted of 418 COVID-positive and 89 COVID-negative patients, mostly young adults (median age of 41 versus 36 years in COVID-positive and COVID-negative, respectively; p = 0.020) and healthcare workers (67% versus 82%; p = 0.006). Median time between the initial visit and the phone survey was 150 days in COVID-positive and 242 days in COVID-negative patients. Persistent symptoms were reported by 223 (53%) COVID-positive and 33 (37%) COVID-negative patients (p = 0.006) and proportions were stable among the periods of the phone interviews. Overall, 21% COVID-positive and 15% COVID-negative patients (p = 0.182) attended care for this purpose. Four surveyed symptoms were independently associated with COVID-19: fatigue (adjusted odds ratio 2.14, 95% CI 1.04–4.41), smell/taste disorder (26.5, 3.46–202), dyspnea (2.81, 1.10–7.16), and memory impairment (5.71, 1.53–21.3). Among COVID-positive, female gender (1.67, 1.09–2.56) and overweight/obesity (1.67, 1.10–2.56) were predictors of persistent symptoms.ConclusionsMore than half of COVID-positive outpatients report persistent symptoms up to 10 months after a mild disease. Only 4 of 14 symptoms were associated with COVID-19 status. The symptoms and predictors of the post-COVID-19 syndrome need further characterization as this condition places a significant burden on society.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a multifaceted disease potentially responsible for various clinical manifestations including gastro-intestinal symptoms. Several evidences suggest that the intestine is a critical site of immune cell development, gut microbiota could therefore play a key role in lung immune response. We designed a monocentric longitudinal observational study to describe the gut microbiota profile in COVID-19 patients and compare it to a pre-existing cohort of ventilated non-COVID-19 patients. Methods From March to December 2020, we included patients admitted for COVID-19 in medicine (43 not ventilated) or intensive care unit (ICU) (14 ventilated) with a positive SARS-CoV-2 RT-PCR assay in a respiratory tract sample. 16S metagenomics was performed on rectal swabs from these 57 COVID-19 patients, 35 with one and 22 with multiple stool collections. Nineteen non-COVID-19 ICU controls were also enrolled, among which 14 developed ventilator-associated pneumonia (pneumonia group) and five remained without infection (control group). SARS-CoV-2 viral loads in fecal samples were measured by qPCR. Results Although similar at inclusion, Shannon alpha diversity appeared significantly lower in COVID-19 and pneumonia groups than in the control group at day 7. Furthermore, the microbiota composition became distinct between COVID-19 and non-COVID-19 groups. The fecal microbiota of COVID-19 patients was characterized by increased Bacteroides and the pneumonia group by Prevotella . In a distance-based redundancy analysis, only COVID-19 presented significant effects on the microbiota composition. Moreover, patients in ICU harbored increased Campylobacter and decreased butyrate-producing bacteria, such as Lachnospiraceae , Roseburia and Faecalibacterium as compared to patients in medicine. Both the stay in ICU and patient were significant factors affecting the microbiota composition. SARS-CoV-2 viral loads were higher in ICU than in non-ICU patients. Conclusions Overall, we identified distinct characteristics of the gut microbiota in COVID-19 patients compared to control groups. COVID-19 patients were primarily characterized by increased Bacteroides and decreased Prevotella . Moreover, disease severity showed a negative correlation with butyrate-producing bacteria. These features could offer valuable insights into potential targets for modulating the host response through the microbiota and contribute to a better understanding of the disease's pathophysiology. Trial registration CER-VD 2020–00755 (05.05.2020) & 2017–01820 (08.06.2018).

Background: Extracorporeal membrane oxygenation (ECMO) can affect the disposition of drugs, notably by sequestering them in a circuit. This review aimed to provide a comprehensive summary of existing ex vivo studies investigating the impact of contemporary ECMO circuits on drug sequestration, and to examine the associations between the physicochemical properties of drugs, the features and settings of ECMO devices, and the extent of drug sequestration. Method: A comprehensive search was conducted to identify ex vivo studies that determined drug concentrations in ECMO circuits. Studies that did not allow for the proper assessment of drug loss by degradation were excluded. Drug characteristics and experimental conditions were recorded. Drug sequestration in the circuit was calculated as the difference between the drug loss measured in the ECMO circuit and the drug loss due to spontaneous degradation measured under control conditions. To identify predictors of drug sequestration, a stepwise multiple linear meta-regression was applied by testing the physicochemical properties of drugs and ECMO device features/settings. Results: A total of 40 studies were identified, of which 21 were included in the analysis, covering 41 drugs. The Maquet membrane oxygenator was the most used brand (73%). About half of the circuits were adult and half were pediatric. Our final regression model retained lipophilicity, and to a lesser extent ionization at a physiological pH, as significant predictors of drug sequestration (R2 0.44, relative standard error 23%). Protein binding had no additional effect. Anti-infectives were the most studied class of drugs (n = 28). Antibiotics were overall not significantly sequestered, while lipophilic drugs such as posaconazole, voriconazole, paracetamol, fentanyl, sufentanil, propofol, thiopental, dexmedetomidine and amiodarone were highly sequestered (≥50%). However, this sequestration occurred mainly within the first few hours of the experiments, possibly reflecting a saturation effect. Conclusions: Lipophilic drugs are significantly sequestered in ex vivo ECMO circuits, although this effect may be limited by early saturation.

DNA methylation is the most stable type of epigenetic modification modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of six annotation categories showed that evolutionarily conserved regions are the predominant sites for differential DNA methylation and that a core region surrounding the transcriptional start site is an informative surrogate for promoter methylation. We find that 17% of the 873 analyzed genes are differentially methylated in their 5′ UTRs and that about one-third of the differentially methylated 5′ UTRs are inversely correlated with transcription. Despite the fact that our study controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.

To investigate the function of Cx43 during hypertension, we studied the mouse line Cx43KI32 (KI32), in which the coding region of Cx32 replaces that of Cx43. Within the kidneys of homozygous KI32 mice, Cx32 was expressed in cortical and medullary tubules, as well as in some extra- and intraglomerular vessels, i.e., at sites where Cx32 and Cx43 are found in WT mice. Under such conditions, renin expression was much reduced compared with that observed in the kidneys of WT and heterozygous KI32 littermates. After exposure to a high-salt diet, all mice retained a normal blood pressure. However, whereas the levels of renin were significantly reduced in the kidneys of WT and heterozygous KI32 mice, reaching levels comparable to those observed in homozygous littermates, they were not further affected in the latter animals. Four weeks after the clipping of a renal artery (the 2-kidney, 1-clip [2K1C] model), 2K1C WT and heterozygous mice showed an increase in blood pressure and in the circulating levels of renin, whereas 2K1C homozygous littermates remained normotensive and showed unchanged plasma renin activity. Hypertensive, but not normotensive, mice also developed cardiac hypertrophy. The data indicate that replacement of Cx43 by Cx32 is associated with decreased expression and secretion of renin, thus preventing the renin-dependent hypertension that is normally induced in the 2K1C model.

Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guérin (BCG) vaccine. In a prospective longitudinal study, we took advantage of BCG instillations, which increase local immune infiltration, to characterize immune cell populations in the urine of patients with NMIBC as a surrogate for the bladder tumor microenvironment. We observed an infiltration of neutrophils, T cells, monocytic myeloid-derived suppressor cells (M-MDSCs), and group 2 innate lymphoid cells (ILC2). Notably, patients with a T cell-to-MDSC ratio of less than 1 showed dramatically lower recurrence-free survival than did patients with a ratio of greater than 1. Analysis of early and later time points indicated that this patient dichotomy existed prior to BCG treatment. ILC2 frequency was associated with detectable IL-13 in the urine and correlated with the level of recruited M-MDSCs, which highly expressed IL-13 receptor α1. In vitro, ILC2 were increased and potently expressed IL-13 in the presence of BCG or tumor cells. IL-13 induced the preferential recruitment and suppressive function of monocytes. Thus, the T cell-to-MDSC balance, associated with a skewing toward type 2 immunity, may predict bladder tumor recurrence and influence the mortality of patients with muscle-invasive cancer. Moreover, these results underline the ILC2/IL-13 axis as a targetable pathway to curtail the M-MDSC compartment and improve bladder cancer treatment.