Objective
The aim of this study was to determine the risk of post‐acute sequelae of COVID‐19 associated with the continuous spectrum of BMI.
Methods
Epidemiology of Long COVID (EPILOC) is a ...population‐based study conducted in Baden‐Württemberg (Germany), including subjects aged 18 to 65 years who tested positive for SARS‐CoV‐2 between October 2020 and April 2021. Eligible subjects answered a standardized questionnaire, including sociodemographic characteristics, lifestyle factors, and the presence of specific symptoms. Participants assessed their current general health recovery and working capacity compared with the pre‐infection situation and provided their body height and weight. Generalized additive models were used to assess the association of BMI with general health recovered, working capacity recovered, and prevalence of fatigue, cognitive impairment, and chest symptoms.
Results
The analyses included 11,296 individuals (41% male), with a mean age of 44.0 (SD 13.7) years. Best general health recovery was observed at BMI of 22.1 (95% CI: 21.0‐27.0) kg/m2 in men and BMI of 21.6 (95% CI: 20.3‐23.1) kg/m2 in women. In addition, we found that increasing BMI was consistently associated with post‐COVID fatigue, neurocognitive impairment, and chest symptoms.
Conclusions
High BMI contributes to impaired recovery after SARS‐CoV‐2 infection; however, a low BMI is associated with impaired recovery as well.
Species within the Enterobacter cloacae complex (ECC) include globally important nosocomial pathogens. A three-year study of ECC in Germany identified Enterobacter xiangfangensis as the most common ...species (65.5%) detected, a result replicated by examining a global pool of 3246 isolates. Antibiotic resistance profiling revealed widespread resistance and heteroresistance to the antibiotic colistin and detected the mobile colistin resistance (mcr)-9 gene in 19.2% of all isolates. We show that resistance and heteroresistance properties depend on the chromosomal arnBCADTEF gene cassette whose products catalyze transfer of L-Ara4N to lipid A. Using comparative genomics, mutational analysis, and quantitative lipid A profiling we demonstrate that intrinsic lipid A modification levels are genospecies-dependent and governed by allelic variations in phoPQ and mgrB, that encode a two-component sensor-activator system and specific inhibitor peptide. By generating phoPQ chimeras and combining them with mgrB alleles, we show that interactions at the pH-sensing interface of the sensory histidine kinase phoQ dictate arnBCADTEF expression levels. To minimize therapeutic failures, we developed an assay that accurately detects colistin resistance levels for any ECC isolate.
Summary Objectives Staphylococcus aureus bacteraemia is a common, often fatal infection. Our aim was to describe how its clinical presentation varies between populations and to identify common ...determinants of outcome. Methods We conducted a pooled analysis on 3395 consecutive adult patients with S. aureus bacteraemia. Patients were enrolled between 2006 and 2011 in five prospective studies in 20 tertiary care centres in Germany, Spain, United Kingdom, and United States. Results The median age of participants was 64 years (interquartile range 50–75 years) and 63.8% were male. 25.4% of infections were associated with diabetes mellitus, 40.7% were nosocomial, 20.6% were caused by methicillin-resistant S. aureus (MRSA), although these proportions varied significantly across studies. Intravenous catheters were the commonest identified infective focus (27.7%); 8.3% had endocarditis. Crude 14 and 90-day mortality was 14.6% and 29.2%, respectively. Age, MRSA bacteraemia, nosocomial acquisition, endocarditis, and pneumonia were independently associated with death, but a strong association was with an unidentified infective focus (adjusted hazard ratio for 90-day mortality 2.92; 95% confidence interval 2.33 to 3.67, p < 0.0001). Conclusion The baseline demographic and clinical features of S. aureus bacteraemia vary significantly between populations. Mortality could be reduced by assiduous MRSA control and early identification of the infective focus.
Gram-negative bacteria partly rely on efflux pumps to facilitate growth under stressful conditions and to increase resistance to a wide variety of commonly used drugs. In recent years,
sequence type ...131 (ST131) has emerged as a major cause of extraintestinal infection frequently exhibiting a multidrug resistance (MDR) phenotype. The contribution of efflux to MDR in emerging
MDR clones, however, is not well studied. We characterized strains from an international collection of clinical MDR
isolates by MIC testing with and without the addition of the AcrAB-TolC efflux inhibitor 1-(1-naphthylmethyl)-piperazine (NMP). MIC data for 6 antimicrobial agents and their reversion by NMP were analyzed by principal-component analysis (PCA). PCA revealed a group of 17 MDR
isolates (
= 34) exhibiting increased susceptibility to treatment with NMP, suggesting an enhanced contribution of efflux pumps to antimicrobial resistance in these strains (termed enhanced efflux phenotype EEP strains). Only 1/17 EEP strains versus 12/17 non-EEP MDR strains belonged to the ST131 clonal group. Whole-genome sequencing revealed marked differences in efflux-related genes between EEP and control strains, with the majority of notable amino acid substitutions occurring in AcrR, MarR, and SoxR. Quantitative reverse transcription-PCR (qRT-PCR) of multiple efflux-related genes showed significant overexpression of the AcrAB-TolC system in EEP strains, whereas in the remaining strains, we found enhanced expression of alternative efflux proteins. We conclude that a proportion of MDR
strains exhibit an EEP, which is linked to an overexpression of the AcrAB-TolC efflux pump and a distinct array of genomic variations. Members of ST131, although highly successful, are less likely to exhibit the EEP.
Phe-Arg-β-naphthylamide (PAβN) has been characterized as an efflux pump inhibitor (EPI) acting on the major multidrug resistance efflux transporters of Gram-negative bacteria, such as AcrB in
. In ...the present study, in vitro random mutagenesis was used to evolve resistance to the sensitizing activity of PAβN with the aim of elucidating its mechanism of action. A strain was obtained that was phenotypically similar to a previously reported mutant from a serial selection approach that had no efflux-associated mutations. We could confirm that
mutations in the new mutant were unrelated to PAβN resistance. The next-generation sequencing of the two mutants revealed loss-of-function mutations in
. An engineered
knockout strain showed up to 16-fold decreased PAβN activity with large lipophilic drugs, while its efflux capacity, as well as the efficacy of other EPIs, remained unchanged. LpxM is responsible for the last acylation step in lipopolysaccharide (LPS) synthesis, and
deficiency has been shown to result in penta-acylated instead of hexa-acylated lipid A. Modeling the two lipid A types revealed steric conformational changes due to underacylation. The findings provide evidence of a target site of PAβN in the LPS layer, and prove membrane activity contributing to its drug-sensitizing potency.
Quinolones have recently been reevaluated based on new possible side effects and new risk assessments of known side effects. Several of the recently reported untoward effects are not new to the ...class, and they are very rare compared with the relatively common neuropsychiatric adverse events. New associations are aortic aneurysm/dissection and long-standing peripheral neuropathy, muscle weakness, mobility and gait disorders with unclear causal relationship to fluoroquinolone treatment and no known effective therapeutic interventions. Based on estimates from comparative data there could be slightly more than 1000 additional cases of adverse drug effects associated with fluoroquinolone treatment versus other common antibiotics per 100 000 treatment episodes - most of them being neuropsychiatric side effects in primary care, tendinopathy and - more rarely and uncertain - liver toxicity. Consequences were safety alerts in the USA and in European countries with recommendations that the use of the marketed fluoroquinolone antibiotics should be restricted and other antibacterial medicines be preferred if possible. The prophylactic use should be abandoned (travellers' diarrhea and prevention of relapsing cystitis) or critically reevaluated and individualized (prevention of neutropenic fever and of spontaneous bacterial peritonitis).
HIV Gene Therapy: An Update Cornu, Tatjana I; Mussolino, Claudio; Müller, Matthias C ...
Human gene therapy,
01/2021, Letnik:
32, Številka:
1-2
Journal Article
Recenzirano
Progress in antiretroviral therapy has considerably reduced mortality and notably improved the quality of life of individuals infected with HIV since the pandemic began some 40 years ago. However, ...drug resistance, treatment-associated toxicity, adherence to medication, and the need for lifelong therapy have remained major challenges. While the development of an HIV vaccine has remained elusive, considerable progress in developing innovative cell and gene therapies to treat HIV infection has been made. This includes immune cell therapies, such as chimeric antigen receptor T cells to target HIV infected cells, as well as gene therapies and genome editing strategies to render the patient's immune system resistant to HIV. Nonetheless, all of these attempts to achieve a functional cure in HIV patients have failed thus far. This review introduces the clinical as well as the technical challenges of treating HIV infection, and summarizes the most promising cell and gene therapy concepts that have aspired to bring about functional cure for people living with HIV. It further discusses socioeconomic aspects as well as future directions for developing cell and gene therapies with a potential to be an effective one-time treatment with minimal toxicity.
To investigate whether Staphylococcus aureus bloodstream infection (SAB) patients at high risk for complications or relapse benefit from combination therapy with adjunctive rifampicin or fosfomycin.
...In this post hoc analysis, SAB patients with native valve infective endocarditis, osteoarticular infections or implanted foreign devices were included. The co-primary endpoints were all-cause 90 day mortality and death or SAB-related late complications within 180 days. To overcome treatment selection bias and account for its time dependence, inverse probability of treatment weights were calculated and included in marginal structural Cox proportional hazard models (MSCMs).
A total of 578 patients were included in the analysis, of which 313 (54%) received combination therapy with either rifampicin (n = 242) or fosfomycin (n = 58). In the multivariable MSCM, combination therapy was associated with a better outcome, that is, a lower rate of death or SAB-related late complications within 180 days (HR 0.65, 95% CI 0.46-0.92). This beneficial effect was primarily seen in patients with implanted foreign devices, in which combination therapy was associated with a lower rate of death or SAB-related late complications within 180 days (HR 0.53, 95% CI 0.35-0.79) and a lower 90 day mortality (HR 0.57, 95% CI 0.36-0.91). Upon agent-specific stratification, we found no significant differences in outcomes between combination therapy containing rifampicin and fosfomycin; however, the number of patients in most subgroups was not large enough to draw firm conclusions.
In patients with implanted foreign devices, combination therapy was associated with a better long-term outcome. Larger prospective studies are needed to validate these findings.
The goal of the present study was to estimate the prevalence of patient and physician related variables associated with antibiotic prescriptions in patients diagnosed with acute lower and upper ...respiratory tract infections (ALURTI), treated in general practices (GP) and pediatric practices, in Germany.
The analysis included 1,140,095 adult individuals in 1237 general practices and 309,059 children and adolescents in 236 pediatric practices, from the Disease Analyzer database (IQVIA), who had received at least one diagnosis of an ALURTI between 1 January 2015 and 31 March 2019. We estimated the association between 35 predefined variables and antibiotic prescription using multivariate logistic regression models, separately for general and pediatric practices. The variables included the proportion (as a percentage) of antibiotics or phytopharmaceuticals on all prescriptions per practice, as an indicator of physician prescription preference.
The prevalence of antibiotic prescription was higher in patients treated in GP (31.2%) than in pediatric practices (9.1%). In GP, the strongest association with antibiotic prescription was seen in the practice preference for antibiotic use, followed by specific diagnoses (acute bronchitis, sinusitis, pharyngitis, laryngitis, and tracheitis), and higher patient age. In pediatric practices, acute sinusitis and bronchitis were the variables with the strongest association, followed by practice preference for antibiotic prescription. The strongest association with the non-prescription of antibiotics was practice preference for phytopharmaceuticals and the specific diagnosis of a viral infection.
This study shows a high prevalence of antibiotic prescribing for patients with ALURTI in a primary care setting, especially in adult patients; physician related factors play an important role that should be addressed in interventions to reduce potentially inappropriate antibiotic prescribing.
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