Metabolites and dead-end products from the microbial oxidation of quaternary ammonium alcohols

Methyl-triethanol-ammonium originates from the hydrolysis of the parent esterquat surfactant, which is used as softener in fabric care. The initial steps of the catabolism were investigated in cell-free extracts of the bacterial strain MM 1 able to grow with methyl-triethanol-ammonium as sole source of carbon, energy and nitrogen. The initial degradation of methyl-triethanol-ammonium is an enzymatically catalyzed reaction, located in the particulate fraction of strain MM 1. The oxygen dependent reaction occurred also in presence of phenazine methosulfate as an alternative electron acceptor. As soon as one ethanol group of methyl-triethanol-ammonium was oxidized to the aldehyde, cyclic hemiacetals were formed by intramolecular cyclization. The third ethanol group of methyl-triethanol-ammonium was oxidized to the aldehyde and the carboxylic acid sequentially. The structurally related compounds dimethyl-diethanol-ammonium and choline were oxidized as well, whereas (±)-2,3-dihydroxypropyl-trimethyl-ammonium was not converted at all. The structures of the metabolites were established by 1D and 2D 1H, 13C and 14N NMR spectroscopy and by capillary electrophoresis mass spectrometr

Dual-energy computed tomography for the differentiation of uric acid stones: ex vivo performance evaluation

We assessed the potential of dual-energy computed tomography (CT) for the differentiation between uric acid (UA)-containing and non-UA-containing urinary stones. Forty urinary stones of 16 different compositions in two sizes (<and≥5mm) were examined in an ex vivo model. Thirty stones consisted of pure calcium oxalate (whewellite or wheddellite), calcium phosphate (apatite, brushite, or vaterite), ammonium magnesium phosphate (struvite), UA, ammonium acid urate, ammonium phosphate, sodium hydrogen urate, or cystine, and ten stones were of mixed composition (UA-sodium hydrogen urate, whewellite-urate, wheddellite-urate, whewellite-brushite, or whewellite-brushite-struvite). Scans were performed using dual-source CT in a dual-energy mode with the tubes simultaneously operating at 80 and 140kV. Two readers analysed the data with respect to stone attenuation at each energy level. The stones were classified as UA- or non-UA-containing using manual attenuation measurements and software analysis results. Sensitivity, specificity, PPV, and NPV were calculated using crystallographic stone analysis as the gold standard. Twenty-six out of 40 stones (65%) contained no UA; 14 stones (35%) contained UA. When compared with UA-containing stones, the differences in attenuation values at 80 and 140kV were significantly (P<0.001) higher in stones containing no UA. The software automatically mapped 39/40 stones (98%). Only one (2%) 2mm UA-stone was missed. The software correctly classified all detected stones as UA- or non-UA-containing. The attenuation values of the missed stone were manually plotted into the analysis sheet which allowed for the correct classification of the stone (containing UA). Therefore, the sensitivity, specificity, PPV, and NPV for the detection of UA-containing stones was 100%. Ex vivo experience indicates that differentiation between UA- and non-UA-containing stones can be accurately performed using dual-source dual-energy C

Glofitamab Treatment in Relapsed or Refractory DLBCL after CAR T-Cell Therapy.

Chimeric antigen receptor T-cells (CAR T) treatment has become a standard option for patients with diffuse large B-cell lymphomas (DLBCL), which are refractory or relapse after two prior lines of therapy. However, little evidence exists for treatment recommendations in patients who relapse after CAR T-cell treatment and the outcome for such patients is poor. In this study, we evaluated the safety and efficacy of a monotherapy with the bispecific CD20xCD3 antibody glofitamab in patients who progressed after CAR T treatment. We report nine consecutive patients with progressive DLBCL after preceding CAR T-cell therapy. The patients received a maximum of 12 cycles of glofitamab after a single obinutuzumab pre-treatment at an academic institution. CRS was observed in two patients (grade 2 in both patients). We observed an overall response rate of 67%, with four patients achieving a complete response and a partial remission in two patients. Interestingly, we identified increased persistence of circulating CAR T-cells in peripheral blood in three of the five patients with measurable CAR T-cells. Our data suggest that glofitamab treatment is well tolerated and effective in patients with DLBCL relapsing after CAR T-cell therapy and can enhance residual CAR T-cell activity

Prognosis of patients with hepatocellular carcinoma. Validation and ranking of established staging-systems in a large western HCC-cohort.

HCC is diagnosed in approximately half a million people per year, worldwide. Staging is a more complex issue than in most other cancer entities and, mainly due to unique geographic characteristics of the disease, no universally accepted staging system exists to date. Focusing on survival rates we analyzed demographic, etiological, clinical, laboratory and tumor characteristics of HCC-patients in our institution and applied the common staging systems. Furthermore we aimed at identifying the most suitable of the current staging systems for predicting survival. Overall, 405 patients with HCC were identified from an electronic medical record database. The following seven staging systems were applied and ranked according to their ability to predict survival by using the Akaike information criterion (AIC) and the concordance-index (c-index): BCLC, CLIP, GETCH, JIS, Okuda, TNM and Child-Pugh. Separately, every single variable of each staging system was tested for prognostic meaning in uni- and multivariate analysis. Alcoholic cirrhosis (44.4%) was the leading etiological factor followed by viral hepatitis C (18.8%). Median survival was 18.1 months (95%-CI: 15.2-22.2). Ascites, bilirubin, alkaline phosphatase, AFP, number of tumor nodes and the BCLC tumor extension remained independent prognostic factors in multivariate analysis. Overall, all of the tested staging systems showed a reasonable discriminatory ability. CLIP (closely followed by JIS) was the top-ranked score in terms of prognostic capability with the best values of the AIC and c-index (AIC 2286, c-index 0.71), surpassing other established staging systems like BCLC (AIC 2343, c-index 0.66). The unidimensional scores TNM (AIC 2342, c-index 0.64) and Child-Pugh (AIC 2369, c-index 0.63) performed in an inferior fashion. Compared with six other staging systems, the CLIP-score was identified as the most suitable staging system for predicting prognosis in a large German cohort of predominantly non-surgical HCC-patients

Improved detection of microbial ureteral stent colonisation by sonication

Purpose: The diagnosis of microbial ureteral stent colonisation (MUSC) is difficult, since routine diagnostic techniques do not accurately detect microorganisms embedded in biofilms. New methods may improve diagnostic yield and understanding the pathophysiology of MUSC. The aim of the present study was to evaluate the potential of sonication in the detection of MUSC and to identify risk factors for device colonisation. Methods: Four hundred and eight polyurethane ureteral stents of 300 consecutive patients were prospectively evaluated. Conventional urine culture (CUC) was obtained prior to stent placement and device removal. Sonication was performed to dislodge adherent microorganisms. Data of patient sex and age, indwelling time and indication for stent placement were recorded. Results: Sonicate-fluid culture detected MUSC in 36%. Ureteral stents inserted during urinary tract infection (UTI) were more frequently colonised (59%) compared to those placed in sterile urine (26%; P<0.001). Female sex (P<0.001) and continuous stenting (P<0.005) were significant risk factors for MUSC; a similar trend was observed in patients older than 50years (P=0.16). MUSC and indwelling time were positively correlated (P<0.005). MUSC was accompanied by positive CUC in 36%. Most commonly isolated microorganisms were Coagulase-negative staphylococci (18.3%), Enterococci (17.9%) and Enterobacteriaceae (16.9%). Conclusions: Sonication is a promising approach in the diagnosis of MUSC. Significant risk factors for MUSC are UTI at the time of stent insertion, female sex, continuous stenting and indwelling time. CUC is a poor predictor of MUSC. The clinical relevance of MUSC needs further evaluation to classify isolated microorganism properly as contaminants or pathogen

Improved detection of microbial ureteral stent colonisation by sonication

Purpose: The diagnosis of microbial ureteral stent colonisation (MUSC) is difficult, since routine diagnostic techniques do not accurately detect microorganisms embedded in biofilms. New methods may improve diagnostic yield and understanding the pathophysiology of MUSC. The aim of the present study was to evaluate the potential of sonication in the detection of MUSC and to identify risk factors for device colonisation. Methods: Four hundred and eight polyurethane ureteral stents of 300 consecutive patients were prospectively evaluated. Conventional urine culture (CUC) was obtained prior to stent placement and device removal. Sonication was performed to dislodge adherent microorganisms. Data of patient sex and age, indwelling time and indication for stent placement were recorded. Results: Sonicate-fluid culture detected MUSC in 36%. Ureteral stents inserted during urinary tract infection (UTI) were more frequently colonised (59%) compared to those placed in sterile urine (26%; P<0.001). Female sex (P<0.001) and continuous stenting (P<0.005) were significant risk factors for MUSC; a similar trend was observed in patients older than 50years (P=0.16). MUSC and indwelling time were positively correlated (P<0.005). MUSC was accompanied by positive CUC in 36%. Most commonly isolated microorganisms were Coagulase-negative staphylococci (18.3%), Enterococci (17.9%) and Enterobacteriaceae (16.9%). Conclusions: Sonication is a promising approach in the diagnosis of MUSC. Significant risk factors for MUSC are UTI at the time of stent insertion, female sex, continuous stenting and indwelling time. CUC is a poor predictor of MUSC. The clinical relevance of MUSC needs further evaluation to classify isolated microorganism properly as contaminants or pathogen

Prohormones in the early diagnosis of cardiac syncope

Background--The early detection of cardiac syncope is challenging. We aimed to evaluate the diagnostic value of 4 novel prohormones, quantifying different neurohumoral pathways, possibly involved in the pathophysiological features of cardiac syncope: midregional-pro-A-type natriuretic peptide (MRproANP), C-terminal proendothelin 1, copeptin, and midregionalproadrenomedullin. Methods and Results--We prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. ED probability of cardiac syncope was quantified by the treating ED physician using a visual analogue scale. Prohormones were measured in a blinded manner. Two independent cardiologists adjudicated the final diagnosis on the basis of all clinical information, including 1-year follow-up. Among 689 patients, cardiac syncope was the adjudicated final diagnosis in 125 (18%). Plasma concentrations of MRproANP, C-terminal proendothelin 1, copeptin, and midregional-proadrenomedullin were all significantly higher in patients with cardiac syncope compared with patients with other causes (P < 0.001). The diagnostic accuracies for cardiac syncope, as quantified by the area under the curve, were 0.80 (95% confidence interval [CI], 0.76-0.84), 0.69 (95% CI, 0.64-0.74), 0.58 (95% CI, 0.52-0.63), and 0.68 (95% CI, 0.63-0.73), respectively. In conjunction with the ED probability (0.86; 95% CI, 0.82-0.90), MRproANP, but not the other prohormone, improved the area under the curve to 0.90 (95% CI, 0.87-0.93), which was significantly higher than for the ED probability alone (P=0.003). An algorithm to rule out cardiac syncope combining an MRproANP level of < 77 pmol/L and an ED probability of < 20% had a sensitivity and a negative predictive value of 99%. Conclusions--The use of MRproANP significantly improves the early detection of cardiac syncope among unselected patients presenting to the ED with syncope

Social determinants of pertussis and influenza vaccine uptake in pregnancy: a national cohort study in England using electronic health records.

OBJECTIVE: To examine the social determinants of influenza and pertussis vaccine uptake among pregnant women in England. DESIGN: Nationwide population-based cohort study. SETTING: The study used anonymised primary care data from the Clinical Practice Research Datalink and linked Hospital Episode Statistics secondary care data. PARTICIPANTS: Pregnant women eligible for pertussis (2012-2015, n=68 090) or influenza (2010/2011-2015/2016, n=152 132) vaccination in England. MAIN OUTCOME MEASURES: Influenza and pertussis vaccine uptake. RESULTS: Vaccine uptake was 67.3% for pertussis and 39.1% for influenza. Uptake of both vaccines varied by region, with the lowest uptakes in London and the North East. Lower vaccine uptake was associated with greater deprivation: almost 10% lower in the most deprived quintiles compared with the least deprived for influenza (34.5% vs 44.0%), and almost 20% lower for pertussis (57.7% vs 76.0%). Lower uptake for both vaccines was also associated with non-white ethnicity (lowest among women of black ethnicity), maternal age under 20 years and a greater number of children in the household. The associations between all social factors and vaccine uptake were broadly unchanged in fully adjusted models, suggesting the social determinants of uptake were largely independent of one another. Among 3111 women vaccinated against pertussis in their first eligible pregnancy and pregnant again, 1234 (40%) were not vaccinated in their second eligible pregnancy. CONCLUSIONS: Targeting promotional campaigns to pregnant women who are younger, of non-white ethnicity, with more children, living in areas of greater deprivation or the London or North East regions, has potential to reduce vaccine-preventable disease among infants and pregnant women, and to reduce health inequalities. Vaccination promotion needs to be sustained across successive pregnancies. Further research is needed into whether the effectiveness of vaccine promotion strategies may vary according to social factors

Geographic and temporal variation in racial and ethnic disparities in SARS-CoV-2 positivity between February 2020 and August 2021 in the United States.

The coronavirus pandemic has disproportionally impacted racial and ethnic minority communities in the United States. Patterns of these disparities may be changing over time as outbreaks occur in different communities. Utilizing electronic health record data from the US Department of Veterans Affairs (VA), we estimated odds ratios, stratified by time period and region, for testing positive among 1,313,402 individuals tested for SARS-CoV-2 between February 12, 2020 and August 16, 2021 at VA medical facilities. We adjusted for personal characteristics (sex, age, rural/urban residence, VA facility) and a wide range of clinical characteristics that have been evaluated in prior SARS-CoV-2 reports and could potentially explain racial/ethnic disparities in SARS-CoV-2. Our study found racial and ethnic disparities for testing positive were most pronounced at the beginning of the pandemic and decreased over time. A key finding was that the disparity among Hispanic individuals attenuated but remained elevated, while disparities among Asian individuals reversed by March 1, 2021. The variation in racial and ethnic disparities in SARS-CoV-2 positivity by time and region, independent of underlying health status and other demographic characteristics in a nationwide cohort, provides important insight for strategies to prevent further outbreaks