Real-world effectiveness of dupilumab in patients with asthma: Findings from the US ADVANTAGE study.

BACKGROUND: Dupilumab is approved as an add-on maintenance therapy for patients (≥6 years) with moderate-to-severe asthma. Better understanding of real-world effectiveness is needed. OBJECTIVE: To characterize the real-world effectiveness of dupilumab in asthma management. METHODS: This retrospective study included patients (≥12 years of age) diagnosed with asthma, initiating dupilumab between November 2018 and September 2020. The study used a US electronic medical record database (TriNetX Dataworks, Cambridge, Massachusetts). Asthma exacerbation rates before and after the initiation of dupilumab were analyzed using generalized estimating equations models with Poisson probabilistic link to estimate incidence rate ratios (IRRs). Sensitivity analyses were conducted based on previous exacerbation data, eosinophil levels, history of atopic dermatitis or chronic rhinosinusitis with nasal polyps, previous use of biologics, and presence of SARS-CoV-2 (COVID-19). RESULTS: A total of 2400 patients initiating dupilumab met all study criteria. After initiation of dupilumab, risk of asthma exacerbation was reduced by 44% (IRR, 0.56; 95% CI, 0.47-0.57; P = <0.0001) and systemic corticosteroid prescriptions by 48% (IRR, 0.52; 95% CI, 0.48, 0.56; P = <0.0001) compared with those before initiation of dupilumab. Adjustment for COVID-19 showed a greater reduction in asthma exacerbations (IRR, 0.50; 95% CI, 0.45-0.55; P = <0.0001). CONCLUSION: Current real-world efficacy evidence indicates that dupilumab reduces asthma exacerbations and total systemic corticosteroid prescriptions in clinical practice. The effectiveness of dupilumab was observed independent of exacerbation history, eosinophil levels, or COVID-19 impact.

Hypereosinophilic syndrome in Europe: Retrospective study of treatment patterns, clinical manifestations, and healthcare resource utilization.

BACKGROUND: The burden of hypereosinophilic syndrome (HES) in Europe is not well characterized. OBJECTIVE: To evaluate real-world patient characteristics, treatment patterns, clinical manifestations, and healthcare resource utilization for patients with HES from France, Germany, Italy, Spain, and the United Kingdom. METHODS: In this retrospective, noninterventional study, data for patients with a physician-confirmed diagnosis of HES were abstracted from medical chart reviews. Patients were aged 6 years or older at the time of HES diagnosis and had 1 or more years of follow-up from the index date (first clinic visit between January 2015 and December 2019). Data on treatment patterns, comorbidities, clinical manifestations, clinical outcomes, and healthcare resource utilization were collected from diagnosis or index date to end of follow-up. RESULTS: Data for 280 patients were abstracted from medical charts by 121 physicians treating HES, with multiple specialties. Most patients (55%) had idiopathic HES, and 24% had myeloid HES; the median number (interquartile range [IQR]) of diagnostic tests per patient was 10 (6-12). The most common comorbidities were asthma (45%) and anxiety or depression (36%). Most patients (89%) used oral corticosteroids; 64% used immunosuppressants or cytotoxic agents, and 44% used biologics. Patients had a median (IQR) of 3 clinical manifestations (1-5), most commonly constitutional (63%), lung (49%), and skin (48%). Twenty-three percent of patients experienced a flare, and 40% had a complete treatment response. Some patients (30%) were hospitalized with a median (IQR) stay of 9 days (5-15) for HES-related issues. CONCLUSION: Patients with HES across 5 European countries had a substantial disease burden despite extensive oral corticosteroids treatment, highlighting the need for additional targeted therapies.

Real-world treatment patterns of OTX-101 ophthalmic solution, cyclosporine ophthalmic emulsion, and lifitegrast ophthalmic solution in patients with dry eye disease: a retrospective analysis.

BACKGROUND: Dry eye disease (DED) is a disorder characterized by loss of tear film homeostasis that causes ocular surface inflammation and damage. The incidence of DED increases with age. Cyclosporine ophthalmic solution 0.09% (CEQUA®; OTX-101), cyclosporine ophthalmic emulsion 0.05% (Restasis®; CsA), and lifitegrast ophthalmic solution 5% (Xiidra®; LFT) are anti-inflammatory agents indicated for DED. This analysis compared treatment patterns in patients with DED receiving OTX-101, CsA, or LFT. METHODS: This real-world, retrospective, longitudinal cohort study utilized Symphony Health Integrated Dataverse claims from July 2019 to June 2021. The dataset included all patients with OTX-101 claims and patients with CsA or LFT claims randomly selected 2:1 to OTX-101. Patients were sorted into 3 cohorts based on index treatment. Index date was that of first treatment claim, and follow-up period was from index date to end of clinical activity or data availability. Time to treatment discontinuation (TTD), probability of discontinuation, and treatment persistence were assessed for OTX-101 vs. CsA, then OTX-101 vs. LFT. Subgroup analysis was performed based on age and prior DED treatment. Kaplan-Meier analysis and log-rank test were used to examine TTD. A logistic model evaluated association between index treatment and discontinuation. Unadjusted and adjusted odds ratios, 95% confidence intervals, and P-values were reported, with statistically significant associations based on P-values < 0.05. RESULTS: Overall, 7102 patients (OTX-101 n = 1846; CsA n = 2248; LFT n = 3008) were eligible. Median TTD was 354 days for patients receiving OTX-101 vs. 241 days for CsA and 269 days for LFT. Log-rank test indicated TTD was significantly longer for patients on OTX-101 vs. CsA (P = 0.033). Patients on CsA were 35% more likely to discontinue treatment than patients on OTX-101; OTX-101 and LFT groups had similar discontinuation rates. After 360 days, 49.8% of patients receiving OTX-101 remained on treatment vs. 39.4% of patients on CsA (P = 0.036) and 44.0% of patients on LFT (P = 0.854). CONCLUSIONS: Patients receiving OTX-101 remained on treatment significantly longer and were significantly less likely to discontinue treatment than patients on CsA. Older patients remained on OTX-101 significantly longer than CsA. These findings highlight treatment pattern differences in patients with DED receiving these anti-inflammatory agents.

Cupriavidus sp. strain Ni-2 resistant to high concentration of nickel and its genes responsible for the tolerance by genome comparison.

The widespread use of metals influenced many researchers to examine the relationship between heavy metal toxicity and bacterial resistance. In this study, we have inoculated heavy metal-contaminated soil from Janghang region of South Korea in the nickel-containing media (20 mM Ni2+) for the enrichment. Among dozens of the colonies acquired from the several transfers and serial dilutions with the same concentrations of Ni, the strain Ni-2 was chosen for further studies. The isolates were identified for their phylogenetic affiliations using 16S rRNA gene analysis. The strain Ni-2 was close to Cupriavidus metallidurans and was found to be resistant to antibiotics of vancomycin, erythromycin, chloramphenicol, ampicillin, gentamicin, streptomycin, and kanamycin by disk diffusion method. Of the isolated strains, Ni-2 was sequenced for the whole genome, since the Ni-resistance seemed to be better than the other strains. From the genome sequence we have found that there was a total of 89 metal-resistance-related genes including 11 Ni-resistance genes, 41 heavy metal (As, Cd, Zn, Hg, Cu, and Co)-resistance genes, 22 cation-efflux genes, 4 metal pumping ATPase genes, and 11 metal transporter genes.

Comparative Genome Analysis of Polar Mesorhizobium sp. PAMC28654 to Gain Insight into Tolerance to Salinity and Trace Element Stress.

In this study, Mesorhizobium sp. PAMC28654 was isolated from a soil sample collected from the polar region of Uganda. Whole-genome sequencing and comparative genomics were performed to better understand the genomic features necessary for Mesorhizobium sp. PAMC28654 to survive and thrive in extreme conditions and stresses. Additionally, diverse sequence analysis tools were employed for genomic investigation. The results of the analysis were then validated using wet-lab experiments. Genome analysis showed trace elements' resistant proteins (CopC, CopD, CzcD, and Acr3), exopolysaccharide (EPS)-producing proteins (ExoF and ExoQ), and nitrogen metabolic proteins (NarG, NarH, and NarI). The strain was positive for nitrate reduction. It was tolerant to 100 mM NaCl at 15 °C and 25 °C temperatures and resistant to multiple trace elements (up to 1 mM CuSO4·5H2O, 2 mM CoCl2·6H2O, 1 mM ZnSO4·7H2O, 0.05 mM Cd(NO3)2·4H2O, and 100 mM Na2HAsO4·7H2O at 15 °C and 0.25 mM CuSO4·5H2O, 2 mM CoCl2·6H2O, 0.5 mM ZnSO4·7H2O, 0.01 mM Cd(NO3)2·4H2O, and 100 mM Na2HAsO4·7H2O at 25 °C). This research contributes to our understanding of bacteria's ability to survive abiotic stresses. The isolated strain can be a potential candidate for implementation for environmental and agricultural purposes.

Treatment patterns and overall survival of patients with double-class and triple-class refractory multiple myeloma: a US electronic health record database study.

Patients with relapsed/refractory multiple myeloma (RRMM) resistant to multiple drug classes remain a high unmet need population. This longitudinal retrospective cohort study assessed real-world treatment patterns and outcomes in adults with RRMM. Patients who had three or more prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (double-exposed) were further categorized as refractory to a PI and an immunomodulatory agent (double-class refractory, n = 381) or additionally to an anti-CD38 monoclonal antibody (triple-class refractory, n = 173). Treatment options are limited for patients with double-class or triple-class refractory disease. Retreatment is a part of standard of care. Bortezomib and lenalidomide had the highest retreatment rates among double-class and triple-class refractory patients. Survival outcomes remain poor among RRMM patients with median overall survival (OS) of 22.3 and 11.6 months for double-class refractory and triple-class refractory patients, respectively. This study highlights the need for novel efficacious therapies in this heavily pretreated RRMM population.

Escherichia coli resistance, treatment patterns and clinical outcomes among females with uUTI in Germany: a retrospective physician-based chart review study.

Real-world data were collected to examine antimicrobial resistance (AMR) prevalence, treatment patterns, and clinical outcomes among female patients with uncomplicated urinary tract infection (uUTI) in Germany. Data were from a retrospective physician-based chart review completed by physicians treating patients with uUTI. Non-pregnant women aged ≥ 12 years, with a uUTI diagnosis, an E. coli-positive urine culture between January 2017-December 2019, and susceptibility test results for ≥ 4 drug classes were eligible. Patients were stratified into three cohorts by drug class susceptibility: susceptible to all (SUS), resistant to one or two drug classes (DR1/2), and resistant to ≥ 3 (MDR) drug classes tested. Among 386 eligible patients [SUS (67.1%); DR1/2 (29.0%); MDR (3.9%)], AMR prevalence was highest for FMIs (18.3%) and lowest for fluoroquinolones (5.2%). The most prescribed drugs were fosfomycin in SUS (44.0%), DR1/2 (41.4%), and fluoroquinolones in MDR (40.0%). Treatment for uUTI failed for 8.8% of patients; failure was more likely in MDR versus SUS [adjusted odds ratio [95% CI] = 4.21 [1.14-1.50]; P = 0.031); incidence of recurrent infection in the 6-months post-index period was higher in DR1/2 versus SUS. These findings may have implications for empiric prescribing, suggesting an unmet need for new treatments.

Direct and Indirect Reduction of Cr(VI) by Fermentative Fe(III)-Reducing Cellulomonas sp. Strain Cellu-2a.

Hexavalent chromium (Cr(VI)) is recognized to be carcinogenic and toxic and registered as a contaminant in many drinking water regulations. It occurs naturally and is also produced by industrial processes. The reduction of Cr(VI) to Cr(III) has been a central topic for chromium remediation since Cr(III) is less toxic and less mobile. In this study, fermentative Fe(III)-reducing bacterial strains (Cellu-2a, Cellu-5a, and Cellu-5b) were isolated from a groundwater sample and were phylogenetically related to species of Cellulomonas by 16S rRNA gene analysis. One selected strain, Cellu-2a showed its capacity of reduction of both soluble iron (ferric citrate) and solid iron (hydrous ferric oxide, HFO), as well as aqueous Cr(VI). The strain Cellu-2a was able to reduce 15 µM Cr(VI) directly with glucose or sucrose as a sole carbon source under the anaerobic condition and indirectly with one of the substrates and HFO in the same incubations. The heterogeneous reduction of Cr(VI) by the surface-associated reduced iron from HFO by Cellu-2a likely assisted the Cr(VI) reduction. Fermentative features such as large-scale cell growth may impose advantages on the application of bacterial Cr(VI) reduction over anaerobic respiratory reduction.

The role of acyl-coenzyme A carboxylase complex in lipstatin biosynthesis of Streptomyces toxytricini.

Streptomyces toxytricini produces lipstatin, a specific inhibitor of pancreatic lipase, which is derived from two fatty acid moieties with eight and 14 carbon atoms. The pccB gene locus in 10.6 kb fragment of S. toxytricini chromosomal DNA contains three genes for acyl-coenzyme A carboxylase (ACCase) complex accA3, pccB, and pccE that are presumed to be involved in secondary metabolism. The pccB gene encoding a beta subunit of ACCase [carboxyltransferase (CT)] was identified upstream of pccE gene for a small protein of epsilon subunit. The accA3 encoding the alpha subunit of ACCase [biotin carboxylase (BC)] was also identified downstream of pccB gene. When the pccB and pccE genes were inactivated by homologous recombination, the lipstatin production was reduced as much as 80%. In contrast, the accumulation of another compound, tetradeca-5.8-dienoic acid (the major lipstatin precursor), was 4.5-fold increased in disruptant compared with wild-type. It implies that PccB of S. toxytricini is involved in the activation of octanoic acid to hexylmalonic acid for lipstatin biosynthesis.

Biochemical characteristization of propionyl-coenzyme a carboxylase complex of Streptomyces toxytricini.

Acyl-CoA carboxylases (ACC) are involved in important primary or secondary metabolic pathways such as fatty acid and/or polyketides synthesis. In the 62 kb fragment of pccB gene locus of Streptomyces toxytricini producing a pancreatic inhibitor lipstatin, 3 distinct subunit genes of presumable propionyl-CoA carboxylase (PCCase) complex, assumed to be one of ACC responsible for the secondary metabolism, were identified along with gene for a biotin protein ligase (Bpl). The subunits of PCCase complex were a subunit (AccA3), P subunit (PccB), and auxiliary ɛ subunit (PccE). In order to disclose the involvement of the PCCase complex in secondary metabolism, some biochemical characteristics of each subunit as well as their complex were examined. In the test of substrate specificity of the PCCase complex, it was confirmed that this complex showed much higher conversion of propionyl-CoA rather than acetyl-CoA. It implies the enzyme complex could play a main role in the production of methylmalonyl-CoA from propionyl-CoA, which is a precursor of secondary polyketide biosynthesis.