Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials. Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as 2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load.

ABSTRACT:1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (Lu AA21004) is a novel antidepressant that is currently in late-stage clinical development for major depressive disorder. In the present study, the metabolism of Lu AA21004 was investigated using human liver microsomes (HLM), human liver S9 fraction, and recombinant enzymes. Lu AA21004 was found in vitro to be oxidized to a 4-hydroxy-phenyl metabolite, a sulfoxide, an N-hydroxylated piperazine, and a benzylic alcohol, which was further oxidized to the corresponding benzoic acid [3-methyl-4-(2-piperazin-1-yl-phenysulfanyl)-benzoic acid (Lu AA34443)]. The formation of the 4-hydroxy-phenyl metabolite was catalyzed by CYP2D6 with some contribution from CYP2C9, whereas the formation of the sulfoxide was mediated by CYP3A4/5 and CYP2A6. CYP2C9 and CYP2C19 were the primary enzymes responsible for formation of the N-hydroxylated metabolite. The benzylic alcohol was formed by CYP2D6 only. The oxidation of the benzylic alcohol to the corresponding benzoic acid of Lu AA21004 was catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, with some contribution from aldehyde oxidase. CYP2D6 was also capable of catalyzing the formation of the benzoic acid of Lu AA21004; however, its overall contribution to this pathway was negligible. Enzyme kinetic parameters revealed that the rate-limiting step in the formation of the benzoic acid from Lu AA21004 is the formation of the corresponding alcohol. Thus, the intrinsic clearance (V max /K m ) in HLM for metabolism of Lu AA21004 to the benzylic alcohol was 1.13 ؋ 10, whereas the subsequent metabolism of the benzylic alcohol to the benzoic acid of Lu AA21004 is characterized by an intrinsic clearance (V max /K m ) in S9 fraction of 922 ؋ 10 ؊6 l ⅐ min ؊1 ⅐ mg ؊1.

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Background and ObjectivesInfections are common complications among patients on chronic hemodialysis. This population-based cohort study aims to estimate risk and case fatality of bloodstream infection among chronic hemodialysis patients.MethodsIn this population-based cohort study we identified residents with end-stage renal disease in Central and North Jutland, Denmark who had hemodialysis as first renal replacement therapy (hemodialysis patients) during 1995–2010. For each hemodialysis patient, we sampled 19 persons from the general population matched on age, gender, and municipality. Information on positive blood cultures was obtained from regional microbiology databases. All persons were observed from cohort entry until first episode of bloodstream infection, emigration, death, or end of hemodialysis treatment, whichever came first. Incidence-rates and incidence-rate ratios were computed and risk factors for bloodstream infection assessed by Poisson regression. Case fatality was compared by Cox regression.ResultsAmong 1792 hemodialysis patients and 33 618 matched population controls, we identified 461 and 1126 first episodes of bloodstream infection, respectively. Incidence rates of first episode of bloodstream infection were 13.7 (95% confidence interval (CI), 12.5–15.0) per 100 person-years among hemodialysis patients and 0.53 (95% CI, 0.50–0.56) per 100 person-years among population controls. In hemodialysis patients, the most common causative microorganisms were Staphylococcus aureus (43.8%) and Escherichia coli (12.6%). The 30-day case fatality was similar among hemodialysis patients and population controls 16% (95% CI, 13%–20%) vs. 18% (95% CI, 15%–20%).ConclusionsHemodialysis patients have extraordinary high risk of bloodstream infection while short-term case fatality following is similar to that of population controls.

In this study, we identified all adults living in Denmark diagnosed with common variable immunodeficiency (CVID) and characterized them according to clinical presentation and EUROclass classification. Using a retrospective, cross-sectional design, possible CVID patients were identified in the Danish National Patient Register and Centers in Denmark treating patients with primary immunodeficiencies. The CVID diagnosis was verified by review of medical records. One-hundred-seventy-nine adults with CVID were identified. This corresponds to a prevalence of 1:26,000. The median age at onset of symptoms was 29 years with no sex difference. The median age at diagnosis was 40 years. Males were diagnosed earlier with a peak in the fourth decade of life, whereas females were diagnosed later with a peak in the sixth decade. The median diagnostic delay was seven years. Recurrent sinopulmonary infections were seen in 92.7% of the patients. The prevalence of non-infectious complications was similar to that of previously reported cohorts: bronchiectasis (35.8%), splenomegaly (22.4%), lymphadenopathy (26.3%), granulomatous inflammation (3.9%) and idiopathic thrombocytopenic purpura (14.5%). Non-infectious complications were strongly associated with B cell phenotype, with all having a reduced number of isotype-switched memory B cells. One-hundred-seventy (95%) were treated with immunoglobulin replacement therapy, primarily administered subcutaneously. According to international guidelines, diagnostic evaluation was inadequate in most cases. This study emphasizes the need for improved diagnostic criteria and more awareness of CVID as a differential diagnosis. Diagnosis and management of CVID patients is a challenge requiring specialists with experience in the field of PID.