250 research outputs found
Probing the Catalytic Roles of Arg548 and Gln552 in the Carboxyl Transferase Domain of the \u3cem\u3eRhizobium etli\u3c/em\u3e Pyruvate Carboxylase by Site-directed Mutagenesis
The roles of Arg548 and Gln552 residues in the active site of the carboxyl transferase domain of Rhizobium etli pyruvate carboxylase were investigated using site-directed mutagenesis. Mutation of Arg548 to alanine or glutamine resulted in the destabilization of the quaternary structure of the enzyme, suggesting that this residue has a structural role. Mutations R548K, Q552N, and Q552A resulted in a loss of the ability to catalyze pyruvate carboxylation, biotin-dependent decarboxylation of oxaloacetate, and the exchange of protons between pyruvate and water. These mutants retained the ability to catalyze reactions that occur at the active site of the biotin carboxylase domain, i.e., bicarbonate-dependent ATP cleavage and ADP phosphorylation by carbamoyl phosphate. The effects of oxamate on the catalysis in the biotin carboxylase domain by the R548K and Q552N mutants were similar to those on the catalysis of reactions by the wild-type enzyme. However, the presence of oxamate had no effect on the reactions catalyzed by the Q552A mutant. We propose that Arg548 and Gln552 facilitate the binding of pyruvate and the subsequent transfer of protons between pyruvate and biotin in the partial reaction catalyzed in the active site of the carboxyl transferase domain of Rhizobium etli pyruvate carboxylase
Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy postmenopausal women at high-risk for ovarian cancer.
OBJECTIVE: To evaluate if serum levels of candidate ovarian cancer biomarkers vary with individual characteristics of healthy women who are likely candidates for an ovarian cancer screening program. METHODS: We analyzed serum CA125, mesothelin, and HE4 levels in a sample of 155 healthy postmenopausal women at increased risk for developing ovarian cancer based on personal and family cancer history. Information on reproductive, family and medical histories, lifestyle factors, and anthropometry was collected by self-report. Twenty-two factors were examined using univariate and multiple linear regression models for the three biomarker levels. RESULTS: In the multivariate models, CA125 levels were significantly higher in women who had used talcum powder (P = 0.02) and were lower in women who were parous (P = 0.05). Mesothelin levels were significantly higher in older women (P = 0.01) and lower in heavier women (P = 0.03). HE4 levels were higher in older women (P = 0.001) and in women who began menstruating at an older age (P = 0.03). CONCLUSIONS: CA125, mesothelin, and HE4 levels in healthy, postmenopausal women at increased risk for ovarian cancer are significantly associated with a few ovarian cancer risk factors. Since the effects of these personal characteristics on these serum markers are not large, their incorporation in screening algorithms may be unnecessary. This is true especially if a longitudinal algorithm is used because the marker level at the previous screen reflects personal characteristics such as age, body mass index, and age of menarche. Understanding the influence of personal factors on levels of novel early detection markers in healthy, unaffected women may have clinical utility in interpreting biomarker levels
Impact of ocean carbon system variability on the detection of temporal increases in anthropogenic CO2
Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 113 (2008): C03019, doi:10.1029/2007JC004153.Estimates of temporal trends in oceanic anthropogenic carbon dioxide (CO2) rely on the ability of empirical methods to remove the large natural variability of the ocean carbon system. A coupled carbon-climate model is used to evaluate these empirical methods. Both the ΔC* and multiple linear regression (MLR) techniques reproduce the predicted increase in dissolved inorganic carbon for the majority of the ocean and have similar average percent errors for decadal differences (24.1% and 25.5%, respectively). However, this study identifies several regions where these methods may introduce errors. Of particular note are mode and deep water formation regions, where changes in air-sea disequilibrium and structure in the MLR residuals introduce errors. These results have significant implications for decadal repeat hydrography programs, indicating the need for subannual sampling in certain regions of the oceans in order to better constrain the natural variability in the system and to robustly estimate the intrusion of anthropogenic CO2.We would like to acknowledge funding
from NSF (OCE02-23869), NCAR, the WHOI Ocean Climate Institute, a
Linden Earth Systems Graduate Fellowship (MIT), and a National Defense
Science and Engineering Graduate Fellowship. NCAR is sponsored by the
National Science Foundation. R.W. is supported by the Office of Oceanic
and Atmospheric Research at NOAA
Autoimmune and autoinflammatory mechanisms in uveitis
The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders
Association Between Race/Ethnicity and COVID-19 Outcomes in Systemic Lupus Erythematosus Patients From the United States: Data From the COVID-19 Global Rheumatology Alliance
OBJECTIVE: To determine the association between race/ethnicity and COVID-19 outcomes in individuals with systemic lupus erythematosus (SLE). METHODS: Individuals with SLE from the US with data entered into the COVID-19 Global Rheumatology Alliance registry between March 24, 2020 and August 27, 2021 were included. Variables included age, sex, race, and ethnicity (White, Black, Hispanic, other), comorbidities, disease activity, pandemic time period, glucocorticoid dose, antimalarials, and immunosuppressive drug use. The ordinal outcome categories were: not hospitalized, hospitalized with no oxygenation, hospitalized with any ventilation or oxygenation, and death. We constructed ordinal logistic regression models evaluating the relationship between race/ethnicity and COVID-19 severity, adjusting for possible confounders. RESULTS: We included 523 patients; 473 (90.4%) were female and the mean ± SD age was 46.6 ± 14.0 years. A total of 358 patients (74.6%) were not hospitalized; 40 patients (8.3%) were hospitalized without oxygen, 64 patients (13.3%) were hospitalized with any oxygenation, and 18 (3.8%) died. In a multivariable model, Black (odds ratio [OR] 2.73 [95% confidence interval (95% CI) 1.36–5.53]) and Hispanic (OR 2.76 [95% CI 1.34–5.69]) individuals had higher odds of more severe outcomes than White individuals. CONCLUSION: Black and Hispanic individuals with SLE experienced more severe COVID-19 outcomes, which is consistent with findings in the US general population. These results likely reflect socioeconomic and health disparities and suggest that more aggressive efforts are needed to prevent and treat infection in this population
SARS-CoV-2 breakthrough infections among vaccinated individuals with rheumatic disease : Results from the COVID-19 Global Rheumatology Alliance provider registry
Funding Information: members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology (ACR), EULAR, the UK National Health Service (NHS), the National Institute for Health Research (NIHR), the UK Department of Health or any other organisation. Competing interests KLH reports she has received non-personal speaker’s fees from AbbVie and grant income from BMS, UCB and Pfizer, all unrelated to this manuscript; KLH is supported by the NIHR Manchester Biomedical Research Centre. LG reports personal consultant fees from AbbVie, Amgen, BMS, Biogen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis and UCB, and grants from Amgen, Lilly, Janssen, Pfizer, Sandoz, Sanofi and Galapagos, all unrelated to this manuscript. AS reports research grants from a consortium of 14 companies (among them AbbVie, BMS, Celltrion, Fresenius Funding Information: Kabi, Gilead/Galapagos, Lilly, Mylan/Viatris, Hexal, MSD, Pfizer, Roche, Samsung, Sanofi-Aventis and UCB) supporting the German RABBIT register and personal fees from lectures for AbbVie, MSD, Roche, BMS, Lilly and Pfizer, all unrelated to this manuscript. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as AbbVie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi-Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal and UCB Pharma. EF-M reports personal consultant fees from Boehringer Ingelheim Portugal and that LPCDR received support for specific activities: grants from AbbVie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal, MSD, Celgene, Medac, Pharmakern and GAfPA; grants and non-financial support from Pfizer; and non-financial support from Grünenthal, outside the submitted work. IB reports personal consultant fees from AbbVie, Novartis, Pfizer and Janssen, all unrelated to this manuscript. JZ reports speaker fees from AbbVie, Novartis and Janssen/Johnson & Johnson, all unrelated to this manuscript. GR-C reports personal consultant fees from Eli Lilly and Novartis, all unrelated to this manuscript. JS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers: R01 AR077607, P30 AR070253 and P30 AR072577), and the R Bruce and Joan M Mickey Research Scholar Fund. JS has received research support from Amgen and Bristol Myers Squibb and performed consultancy for Bristol Myers Squibb, Gilead, Inova, Janssen and Optum, unrelated to this work. LW receives speaker’s bureau fees from Aurinia Pharma, unrelated to this manuscript. SB reports no competing interests related to this work. He reports non-branded consulting fees for AbbVie, Horizon and Novartis (all <10 000). RG reports no competing interests related to this work. Outside of this work she reports personal and/or speaking fees from AbbVie, Janssen, Novartis, Pfizer and Cornerstones and travel assistance from Pfizer (all <10 000). ESi reports non-financial support from Canadian Arthritis Patient Alliance, outside the submitted work. PS reports personal fees from the American College of Rheumatology/Wiley Publishing, outside the submitted work. ZW reports grant support from Bristol Myers Squibb and Principia/Sanofi and performed consultancy for Viela Bio and MedPace, outside the submitted work. His work is supported by grants from the National Institutes of Health. PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this study. PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). PCR reports no competing interests related to this work. Outside of this work PCR reports personal fees from AbbVie, Atom Bioscience, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Kukdong, Novartis, UCB, Roche and Pfizer; meeting attendance support from BMS, Pfizer and UCB; and grant funding from Janssen, Novartis, Pfizer and UCB Pharma (all <$10 000). JY reports no competing interests related to this work. Her work is supported by grants from the National Institutes of Health (K24 AR074534 and P30 AR070155). Outside of this work, she has received research grants or performed consulting for Gilead, BMS Foundation, Pfizer, Aurinia and AstraZeneca. Funding Information: Twitter Jean Liew @rheum_cat, Loreto Carmona @carmona_loreto, Pedro M Machado @pedrommcmachado and Philip C Robinson @philipcrobinson Contributors All authors contributed to the study design, data collection, interpretation of results and review/approval of the final submitted manuscript. JL and MG are guarantors for this manuscript. Funding MG reports grants from the National Institutes of Health, NIAMS, outside the submitted work. KLH is supported by the NIHR Manchester Biomedical Research Centre. JS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers: R01 AR077607, P30 AR070253 and P30 AR072577), and the R Bruce and Joan M Mickey Research Scholar Fund. JH is supported by grants from the Rheumatology Research Foundation. ZW is supported by grants from the National Institutes of Health. PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). JY is supported by grants from the National Institutes of Health (K24 AR074534 and P30 AR070155). Publisher Copyright: ©Objective. While COVID-19 vaccination prevents severe infections, poor immunogenicity in immunocompromised people threatens vaccine effectiveness. We analysed the clinical characteristics of patients with rheumatic disease who developed breakthrough COVID-19 after vaccination against SARS-CoV-2. Methods. We included people partially or fully vaccinated against SARS-CoV-2 who developed COVID-19 between 5 January and 30 September 2021 and were reported to the Global Rheumatology Alliance registry. Breakthrough infections were defined as occurring ≥14 days after completion of the vaccination series, specifically 14 days after the second dose in a two-dose series or 14 days after a single-dose vaccine. We analysed patients' demographic and clinical characteristics and COVID-19 symptoms and outcomes. Results SARS-CoV-2 infection was reported in 197 partially or fully vaccinated people with rheumatic disease (mean age 54 years, 77% female, 56% white). The majority (n=140/197, 71%) received messenger RNA vaccines. Among the fully vaccinated (n=87), infection occurred a mean of 112 (±60) days after the second vaccine dose. Among those fully vaccinated and hospitalised (n=22, age range 36-83 years), nine had used B cell-depleting therapy (BCDT), with six as monotherapy, at the time of vaccination. Three were on mycophenolate. The majority (n=14/22, 64%) were not taking systemic glucocorticoids. Eight patients had pre-existing lung disease and five patients died. Conclusion. More than half of fully vaccinated individuals with breakthrough infections requiring hospitalisation were on BCDT or mycophenolate. Further risk mitigation strategies are likely needed to protect this selected high-risk population.publishersversionPeer reviewe
Effects of Short-Term Continuous Montmorency Tart Cherry Juice Supplementation in Participants with Metabolic Syndrome
© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s00394-020-02355-5Purpose: Metabolic Syndrome (MetS) augments the incidence of cardiovascular disease by two-fold and type II diabetes mellitus by five-fold. Montmorency tart cherries are rich in phytochemicals shown to improve biomarkers related to cardio-metabolic health in humans. This study aimed to examine cardio-metabolic responses after 7-days Montmorency tart cherry juice (MTCJ) supplementation and also acute on short-term supplementation responses to a single bolus, in humans with MetS. Methods: In a randomised, single-blind, placebo-controlled, crossover trial, 12 participants with MetS (50 ± 10 years; 6M/6F), consumed MTCJ or placebo (PLA) for 7 days. Blood-based and functional cardio-metabolic biomarkers were measured pre- and post-supplementation, and acute responses measured pre-bolus and up to 5 h post-bolus on the 7th day. Results: 24-h ambulatory systolic (P = 0.016), diastolic (P = 0.009) blood pressure and mean arterial pressure (P = 0.041) were significantly lower after 7-days MTCJ supplementation compared to PLA. Glucose (P = 0.038), total cholesterol (P = 0.036), LDL (P = 0.023) concentrations, total cholesterol:HDL ratio (P = 0.004) and respiratory exchange ratio values (P = 0.009) were significantly lower after 6-days MTCJ consumption compared to PLA. Conclusions: This study revealed for the first time in humans that MTCJ significantly improved 24-h BP, fasting glucose, total cholesterol and total cholesterol:HDL ratio, and also lowered resting respiratory exchange ratio compared to a control group. Responses demonstrated clinically relevant improvements on aspects of cardio-metabolic function, emphasising the potential efficacy of MTCJ in preventing further cardio-metabolic dysregulation in participants with MetS. Registered at clinicaltrials.gov (NCT03619941).Peer reviewedFinal Accepted Versio
Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy
Background
A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets.
Methods
Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis.
Results
A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001).
Conclusion
We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty
Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis : Results from the COVID-19 Global Rheumatology Alliance physician registry
Funding Information: Competing interests JAS is supported by the National Institute of Arthritis and Funding Information: Musculoskeletal and Skin Diseases (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253 and P30 AR072577), the Rheumatology Research Foundation (K Supplement Award and R Bridge Award), the Brigham Research Institute, and the R Bruce and Joan M Mickey Research Scholar Fund. JAS has received research support from Amgen and Bristol-Myers Squibb and performed consultancy for Bristol-Myers Squibb, Gilead, Inova, Janssen and Optum, unrelated to this work. ZSW reports grant support from Bristol-Myers Squibb and Principia/ Sanofi and performed consultancy for Viela Bio and MedPace, outside the submitted work. His work is supported by grants from the National Institutes of Health. MG is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K01 AR070585 and K24 AR074534; JY). KLH reports she has received speaker’s fees from AbbVie and grant income from BMS, UCB and Pfizer, all unrelated to this study. KLH is also supported by the NIHR Manchester Biomedical Research Centre. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories such as, among other institutions, AbbVie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal and UCB Pharma. LG reports research grants from Amgen, Galapagos, Janssen, Lilly, Pfizer, Sandoz and Sanofi; consulting fees from AbbVie, Amgen, BMS, Biogen, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi Aventis and UCB, all unrelated to this study. EFM reports that LPCDR received support for specific activities: grants from AbbVie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal, MSD, Celgene, Medac, Pharma Kern and GAfPA; grants and non-financial support from Pfizer; and non-financial support from Grünenthal, outside the submitted work. AS reports grants from a consortium of 13 companies (among them AbbVie, BMS, Celltrion, Fresenius Kabi, Lilly, Mylan, Hexal, MSD, Pfizer, Roche, Samsung, Sanofi Aventis and UCB) supporting the German RABBIT register, and personal fees from lectures for AbbVie, MSD, Roche, BMS and Pfizer, outside the submitted work. AD-G has no disclosures relevant to this study. His work is supported by grants from the Centers for Disease Control and Prevention and the Rheumatology Research Foundation. KMD is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32-AR-007258) and the Rheumatology Research Foundation. NJP is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32-AR-007258). PD has received research support from Bristol-Myers Squibb, Chugai and Pfizer, and performed consultancy for Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Sanofi, Pfizer, Chugai, Roche and Janssen, unrelated to this work. NS is supported by the RRF Investigator Award and the American Heart Association. MFU-G reports grant support from Janssen and Pfizer. SB reports no competing interests related to this work. He reports non-branded consulting fees for AbbVie, Horizon, Novartis and Pfizer (all <10 000). JH reports no competing interests related to this work. He is supported by grants from the Rheumatology Research Foundation and the Childhood Arthritis and Rheumatology Research Alliance. He has performed consulting for Novartis, Sobi and Biogen, all unrelated to this work (<10 000). PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this study (all <10 000). JY reports no competing interests related to this work. Her work is supported by grants from the National Institutes of Health, Centers for Disease Control, and the Agency for Healthcare Research and Quality. She has performed consulting for Eli Lilly and AstraZeneca, unrelated to this project. Publisher Copyright: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.Objective To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). Methods We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. Results Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. Conclusions People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.publishersversionPeer reviewe
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