Effectiveness and cost-effectiveness of a nurse-delivered intervention to improve adherence to treatment for HIV : a pragmatic, multicentre, open-label, randomised clinical trial

This trial was funded from public money by the Netherlands Organisation for Health Research and Development (ZonMW; grant number 171002208). Aardex provided support on the development of the study website. We thank all the HIV nurses and physicians from the seven HIV clinics involved in the AIMS study for their input and collaboration (Academic Medical Centre, Slotervaart hospital, and St. Lucas-Andreas hospital, all in Amsterdam; the Leiden University Medical Centre, Leiden; HAGA hospital, The Hague; Erasmus Medical Centre, Rotterdam; and Isala clinic, Zwolle), the study participants, and the Stichting HIV Monitoring (SHM) for their support in accessing the SHM database for identifying patient inclusion criteria and developing the Markov model. Finally, we thank and remember Herman Schaalma (deceased) for his contribution to the study design and grant application.Peer reviewedPostprin

Whole genome sequencing of human metapneumoviruses from clinical specimens using MinION nanopore technology

Human metapneumovirus (HMPV), a member of the Pneumoviridae family, is a causative agent of respiratory illness in young children, the elderly, and immunocompromised individuals. Globally, viruses belonging to two main genetic lineages circulate, A and B, which are further divided into four genetic sublineages (A1, A2, B1, B2). Classical genotyping of HMPV is based on the sequence of the fusion (F) and attachment (G) glycoprotein genes, which are under direct antibody-mediated immune pressure. Whole genome sequencing provides more information than sequencing of subgenomic fragments and is therefore a powerful tool for studying virus evolution and disease epidemiology and for identifying transmission events and nosocomial outbreaks. Here, we report a robust method to obtain whole genome sequences for HMPV using MinION Nanopore technology. This assay is able to generate HMPV whole genome sequences from clinical specimens with good coverage of the highly variable G gene and is equally sensitive for strains of all four genetic HMPV sublineages. This method can be used for studying HMPV genetics, epidemiology, and evolutionary dynamics.</p

Ceftriaxone for the Treatment of Chronic Bacterial Prostatitis:A Case Series and Literature Review

Chronic bacterial prostatitis is increasingly difficult to treat due to rising antimicrobial resistance limiting oral treatment options. In this case series, 11 men with CBP (including patients with urological comorbidities) due to multi-resistant E. coli were treated with once-daily ceftriaxone intravenously for 6 weeks. Nine patients were clinically cured at 3 months follow up. No early withdrawal of medication due to side effects occurred. A literature review was conducted to describe the prostate pharmacokinetics of ceftriaxone and its use in prostatic infection. In conclusion, ceftriaxone can be considered an appropriate treatment of chronic bacterial prostatitis

Pharmacokinetics of fosfomycin in patients with prophylactic treatment for recurrent Escherichia coli urinary tract infection

Objectives: To evaluate the pharmacokinetics and clinical effectiveness of IV and oral fosfomycin treatment in patients with recurrent urinary tract infection (rUTI) with Escherichia coli. Patients and methods: Patients with rUTI treated with 3 g of oral fosfomycin every 72 h for at Least 14 days were included in a prospective open-Label single-centre study. Serum samples were taken after oral and IV administration of fosfomycin. Urine was collected for 24 h on 3 consecutive days. Fosfomycin concentrations in serum and urine were analysed using validated LC-MS/MS. Pharmacokinetics were evaluated using a population model. EudraCT number 2018-000616-25. Results: Twelve patients were included, of whom nine were also administered IV fosfomycin. Data were best described by a two-compartment model with Linear elimination and a transit-absorption compartment. Median values for absolute bioavailability and serum half-Life were 18% and 2.13 h, respectively. Geometric mean urine concentrations on Days 1, 2 and 3 were above an MIC of 8 mg/L after both oral and IV administration. Quality of Life reported on a scale of 1-10 increased from 5.1 to 7.4 (P= 0.001). The average score of UTI symptoms decreased after fosfomycin dosing (by 3.1 points, 95% CI = -0.7 to 7.0, P= 0.10). Conclusions: Oral fosfomycin at 3 g every 72 h provides plasma and urine concentrations of fosfomycin above the MIC for E. coli. This pharmacokinetic model can be used to develop optimal dosing regimens of fosfomycin in patients with UTI

4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1

In recent years, especially since the outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic, the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) has gained traction as a potential antiviral agent. Here, we demonstrate that 4-OI inhibits replication of multiple influenza A viruses (IAV) by restricting nuclear export of viral ribonucleoproteins, a key step in the IAV replication cycle. This nuclear retention is achieved by deactivation and subsequent degradation of chromosomal maintenance 1 protein (CRM1), also known as exportin 1 (XPO1), a host cell protein exploited by IAV during replication. 4-OI-mediated deactivation of CRM1 resulted in the accumulation of the IAV nucleoprotein, the Rev protein of feline immunodeficiency virus, as well as the natural CRM1 cargos p53 and p65, in the nucleus of treated cells. Further mechanism of action studies revealed that, similar to known CRM1 inhibitors, 4-OI modifies a key cysteine in the cargo binding pocket of CRM1 at position 528 through an alkylation reaction called 2,3-dicarboxypropylation. Subsequent studies in a cell line in which the cysteine at position 528 in CRM1 protein was substituted by a serine confirmed that modification of this residue was indeed the cause for the observed inhibitory effect induced by 4-OI on CRM1 function. Overall, this study demonstrated a mechanism through which 4-OI directly interferes with the replication cycle of CRM1-dependent viruses, which contributes to the understanding of the antiviral and anti-inflammatory properties of this multifaceted immuno-metabolite. IMPORTANCE Itaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral effects of exogenous 4-octyl itaconate (4-OI), a derivative of itaconate, against the influenza A virus replication is demonstrated. The data indicate that 4-OI targets the cysteine at position 528 of the CRM1 protein, resulting in inhibition of the nuclear export of viral ribonucleoprotein complexes in a similar manner as previously described for other selective inhibitors of nuclear export. These results postulate a mechanism not observed before for this immuno-metabolite derivative. This knowledge is helpful for the development of derivatives of 4-OI as potential antiviral and anti-inflammatory therapeutics.</p

Захист суспільної моралі в інформаційному суспільстві

До питання ролі держави та її інституцій в захисті суспільної моралі, в удосконаленні чинного законодавства з питань захисту суспільної моралі.К вопросу роли государства и его институций в защите общественной морали, в усовершенствовании действующего законодательства по вопросам защиты общественной морали.As to the role of the state and its institutions in the protection of social morality, in improvement of current legislation on protection of social morality

Cost-effectiveness and Cost-utility of the Adherence Improving Self-management Strategy in Human Immunodeficiency Virus Care : A Trial-based Economic Evaluation

This study was funded by ZonMw (the Netherlands), program Doelmatigheidsonderzoek (grant number 171002208). This funding source had no role in study design, data collection, analysis, interpretation, or writing of the report. All authors declare that they have no competing interests. We thank the HIV-nurses and physicians from the seven HIV-clinics who were involved in the AIMSstudy (Academic Medical Center, Amsterdam; Slotervaart Hospital, Amsterdam; St. Lucas-Andreas Hospital, Amsterdam; the Leiden University Medical Center, Leiden; Haga Teaching Hospital, Den Haag; Erasmus Medical Center, Rotterdam; Isala Clinics, Zwolle) for their input and collaboration. We also would like to express our gratitude to the study participants. Written informed consent was obtained from each patient. The study has been approved by the ethics committee of each participating center.Peer reviewedPostprin

Current Pyuria Cutoffs Promote Inappropriate Urinary Tract Infection Diagnosis in Older Women

Background: Pre-existing lower urinary tract symptoms (LUTS), cognitive impairment, and the high prevalence of asymptomatic bacteriuria (ASB) complicate the diagnosis of urinary tract infection (UTI) in older women. The presence of pyuria remains the cornerstone of UTI diagnosis. However, >90% of ASB patients have pyuria, prompting unnecessary treatment. We quantified pyuria by automated microscopy and flowcytometry to determine the diagnostic accuracy for UTI and to derive pyuria thresholds for UTI in older women. Methods: Women ≥65 years with ≥2 new-onset LUTS and 1 uropathogen ≥104 colony-forming units (CFU)/mL were included in the UTI group. Controls were asymptomatic and classified as ASB (1 uropathogen ≥105 CFU/mL), negative culture, or mixed flora. Patients with an indwelling catheter or antimicrobial pretreatment were excluded. Leukocyte medians were compared and sensitivity–specificity pairs were derived from a receiver operating characteristic curve. Results: We included 164 participants. UTI patients had higher median urinary leukocytes compared with control patients (microscopy: 900 vs 26 leukocytes/µL; flowcytometry: 1575 vs 23 leukocytes/µL; P < .001). Area under the curve was 0.93 for both methods. At a cutoff of 264 leukocytes/µL, sensitivity and specificity of microscopy were 88% (positive and negative likelihood ratio: 7.2 and 0.1, respectively). The commonly used cutoff of 10 leukocytes/µL had a poor specificity (36%) and a sensitivity of 100%. Conclusions: The degree of pyuria can help to distinguish UTI in older women from ASB and asymptomatic controls with pyuria. Current pyuria cutoffs are too low and promote inappropriate UTI diagnosis in older women

Direct-Acting Antiviral Treatment for Hepatitis C Genotypes Uncommon in High-Income Countries:A Dutch Nationwide Cohort Study

Background. The majority of hepatitis C virus (HCV) infections are found in low- and middle-income countries, which harbor many region-specific HCV subtypes. Nevertheless, direct-acting antiviral (DAA) trials have almost exclusively been conducted in high-income countries, where mainly epidemically spread HCV subtypes are present. Recently, several studies have demonstrated suboptimal DAA efficacy for certain nonepidemic subtypes, which could hamper global HCV elimination. Therefore, we aimed to evaluate DAA efficacy in patients treated for a nonepidemic HCV genotype infection in the Netherlands. Methods. We performed a nationwide retrospective study including patients treated with interferon-free DAAs for an HCV genotype other than 1a/1b/2a/2b/3a/4a/4d. The genotype was determined by NS5B region phylogenetic analysis. The primary end point was SVR-12. If stored samples were available, NS5A and NS5B sequences were obtained for resistance-associated substitutions (RAS) evaluation. Results. We included 160 patients, mainly infected with nonepidemic genotype 2 (41%) and 4 (31%) subtypes. Most patients were from Africa (45%) or South America (24%); 51 (32%) were cirrhotic. SVR-12 was achieved in 92% (140/152) of patients with available SVR-12 data. Only 73% (8/11) genotype 3-infected patients achieved SVR-12, the majority being genotype 3b patients with 63% (5/8) SVR. Regardless of SVR, all genotype 3b patients had 30K and 31M RAS. Conclusions. (T)he DAA efficacy we observed in most nonepidemic genotypes in the Netherlands seems reassuring. However, the low SVR-12 rate in subtype 3b infections is alarming, especially as it is common in several HCV-endemic countries. Alongside earlier results, our results indicate that a remaining challenge for global HCV elimination is confirming and monitoring DAA efficacy in nonepidemic genotypes