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Background: Close monitoring of vaccination coverage is important for cervical cancer prevention efforts. The study aims to describe the HPV vaccination coverage by dose in girls eligible for HPV vaccination within Sweden's childhood immunization program and provide an estimate on dose timing compliance., Methods: Vaccination records between 2012 and March 2019 were obtained for girls born in 2000-2006 from the vaccination registers in Sweden. The mid-time population counts for the respective birth cohorts were taken as the denominator. Full-dose coverage and coverage with at least one dose of the vaccine were calculated within the two-dose and three-dose regimen, by region. Dose compliance was calculated within the two-dose regimen., Results: Vaccination coverage with at least one dose of the vaccine was >80% within birth cohorts 2001-2006. Full-dose coverage within a two-dose and three-dose regimen were 73.4% in birth cohorts 2004-2005, and 56.3% in birth cohorts 2000-2001, respectively. Little variation was observed in vaccination coverage between regions. Dose completion was 91.8%, and 72.8% in girls that initiated a two-dose and three-dose regimen, respectively. Among girls receiving a two-dose regimen, 93.0% received the second dose 6-12 months after dose one., Discussion: In conclusion, high levels of HPV vaccination coverage were observed with little variation between regions. Dose timing compliance was particularly high in the two-dose regimen. To fully benefit from the impact of HPV vaccination, it will be important to further push the vaccination coverage and reach the girls that do not or partially engage with HPV vaccination., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The study was funded by Merck and Co., LLC. KS has received unrestricted research grants for other studies on HPV-vaccination in Sweden. SH and CV are employees of Merck and Co., LLC. CK was previously an employee of the study Sponsor., (© 2023 Published by Elsevier Inc.)

Objectives: To monitor pregnancy occurrence and outcomes among Nexplanon users in the United States during standard clinical practice., Study Design: The Nexplanon Observational Risk Assessment (NORA) study was a large prospective cohort study conducted in the United States (US). Study participants with a newly inserted Nexplanon implant were recruited by health care professionals (HCPs) who had completed the Nexplanon clinical training. Via a survey, study participants were followed up at 6-month intervals for 36 months and 6 months after implant removal. Reported unintended pregnancies were validated and classified as noninsertion, preinsertion, during-use, or postremoval., Results: Four hundred and twenty-eight HCPs in 47 states recruited 7364 Nexplanon users. Pregnancies included one noninsertion, eight preinsertion, three during-use, and 14 postremoval pregnancies; of these 26 pregnancies, 22 resulted in the birth of a healthy child, two resulted in an induced abortion, one resulted in a spontaneous abortion, and one resulted in an ectopic pregnancy. Six pregnancies occurred during-use (n = 3) or within 7 days following implant removal (n = 3), yielding a Pearl Index of 0.04 (95% CI, 0.02-0.09)., Conclusions: Nexplanon is an effective contraceptive in real-world users; the Pearl Index was 0.02 (95% CI, 0.00-0.06) for during-use pregnancies, and 0.04 when including pregnancies that occurred within 7 days following implant removal., Implications: This large real-world-use study indicates that Nexplanon is as effective as shown in the preapproval clinical trials., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Human papillomavirus (HPV) infection, which poses significant disease burden, is decreasing following implementation of vaccination programs. Synthesized evidence on HPV vaccine real-world benefit was published in 2016. However, long-term impact of vaccination, and how vaccination programs influence infection rates and disease outcomes, requires further examination., Areas Covered: We systematically reviewed observational studies on HPV vaccination within MEDLINE, EMBASE, and Google Scholar from 2016 to 2020, involving 14 years of follow-up data. We identified 138 peer-reviewed publications reporting HPV vaccine impact or effectiveness. Outcomes of interest included rates of infection at different anatomical sites and incidence of several HPV-related disease endpoints., Expert Opinion: The expansion of HPV vaccination programs worldwide has led to a reduction in genital infection and significant decreases in incidence of HPV-related disease outcomes. Therefore, the WHO has set goals for the elimination of cervical cancer as a public health concern. To track progress toward this requires an understanding of the effectiveness of different vaccination initiatives. However, the impact on males, and potential benefit of gender-neutral vaccination programs have not been fully explored. To present an accurate commentary on the current outlook of vaccination and to help shape policy therefore requires a systematic review of available data.

Objective: To assess and compare the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in NOMAC-E2 users with levonorgestrel-containing combined oral contraceptive (COCLNG) users., Study Design: This large, prospective, observational active surveillance study used a non-inferiority design. New users of NOMAC-E2 and COCLNG were recruited in 12 countries in Australia, Europe, and Latin America. Women were followed up directly and self-reported outcomes of interest were validated via treating physicians. The main outcome of interest was VTE, specifically deep venous thrombosis of the lower extremities (DVT) and pulmonary embolism (PE). Secondary outcomes included all VTE and ATE. Data on confounders were captured and independent blinded adjudication assessed the classification of events. Incidence rates, crude (HRcrude), and adjusted (HRadj) hazard ratios were calculated., Results: A total of 101,498 women (49,598 NOMAC-E2 users and 51,900 COCLNG users) were enrolled and followed for up to 2 years (144,901 WY of observation). NOMAC-E2 users had a higher mean age (31.0 ± 8.63 years) than COCLNG users (29.3 ± 8.53 years) but other baseline characteristics were similar between the cohorts. The main analysis comparing the risk of DVT of the lower extremities and PE in NOMAC-E2 users versus COCLNG users yielded an HRadj of 0.59 (95% CI, 0.25-1.35) (adjusted for age, BMI, family history of VTE, and current duration of use). The risk of all VTE and ATE was not higher in NOMAC-E2 users compared with COCLNG users., Conclusion(s): NOMAC-E2 use was not associated with a higher risk of VTE or ATE compared with COCLNG.

Objective: To assess and compare the risk of unintended pregnancy in NOMAC-E2 users with levonorgestrel-containing COC (COC LNG ) users in clinical practice., Study Design: In this observational study, new users 1 of NOMAC-E2 and COC LNG were recruited in Europe, Australia, and Latin America and followed for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (contraceptive failures per 100 women-years [WY]), crude hazard ratios (HR crude ) and adjusted hazard ratios (HR adj )., Results: Overall, 44,559 and 46,754 users were recruited to the NOMAC-E2 and COC LNG user cohorts, respectively. There were 64 unintended pregnancies in NOMAC-E2 users (0.15 per 100 WY; 95% CI, 0.11-0.19) and 200 in COC LNG users (0.41 per 100 WY; 95% CI, 0.35-0.47). The unintended pregnancy risk was statistically significantly lower in the NOMAC-E2 cohort (p<.0001) compared to the COC LNG user cohort. The HR adj of NOMAC-E2 vs COC LNG was 0.45 (95% CI, 0.34-0.60; adjusted for age, body mass index, gravidity, COC user status, education level)., Conclusions: NOMAC-E2 demonstrated superior contraceptive effectiveness compared to COC LNG , likely due to the comparatively short hormone-free interval and possibly reinforced by the long half-life of NOMAC.

Background: Sugammadex (Bridion) was approved by the US Food and Drug Administration (FDA) in December 2015 for the reversal of neuromuscular block (NMB) induced by rocuronium and vecuronium bromide in adults undergoing surgery and approved for use in both adults and children in the European Union in 2008. Sugammadex use in children has been reported in the United States, but to what extent is not clear. Aims: The aim was to describe the utilization pattern of NMB agents and factors associated with the use of reversal agents (neostigmine and sugammadex) in US children. Methods: Cross-sectional study of children with exposure to NMB agents between 2015 and 2017 in the Cerner Health Facts ® database, which is an electronic health record (EHR) database across 600 facilities in the United States. Logistic regression estimated factors associated with the use of sugammadex vs neostigmine. Results: A total of 27 094 pediatric clinical encounters were exposed to neuromuscular blocking agents (NMBAs), in which 21 845 were exposed to rocuronium (76%), vecuronium (18%), or both (6%). Among children with exposure to rocuronium and vecuronium, the use of sugammadex was 1.7% in 2016 and 7.6% in 2017. The multivariable logistic model suggested that children who were older (age 12-17 years vs 0-1 year; odds ratio [OR] 1.96; 95% confidence interval [CI], 1.36-2.83), Hispanic or Latino ethnicity and other ethnicities (vs non-Hispanic or Latino; OR 2.03 and 1.56; 95% CI, 1.55-2.67 and 1.15-2.13, respectively), in teaching facilities (OR 1.26; 95% CI, 1.00-1.59), or admitted through emergency departments (OR 1.65; 95% CI, 1.06-2.58) were independently more likely to receive sugammadex than neostigmine after controlling for other covariates. Conclusions: In Cerner Health Facts database 2015 to 2017, among children, rocuronium was more commonly used than vecuronium, and sugammadex use was observed since 2016. Sugammadex and neostigmine users varied by demographic, clinical, and site-level characteristics., Competing Interests: Authors’ Note: Jay Horrow is now retired from Merck. Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All the authors are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc, Kenilworth, NJ, USA, all of whom may own stock and/or hold stock options in the Company., (© The Author(s) 2020.)

Background: BRIDION ® (sugammadex sodium) is an agent for the reversal of neuromuscular blockade (NMB) induced by rocuronium and vecuronium in general anesthesia. Following the approval of sugammadex in Canada (February 2016), Health Canada required a survey to assess the knowledge and understanding of the safety and efficacy aspects of sugammadex among anesthesiologists in Canada., Objective: Our objective was to evaluate how well the anesthesiologists in Canada understood the safety and efficacy aspects of sugammadex., Methods: A survey was implemented among anesthesiologists in Canada via internet/phone. The survey was organized to test the knowledge of anesthesiologists by utilizing 11 key questions regarding the safety and efficacy of sugammadex. Five additional safety questions that were not considered part of the key messages but were important concepts for anesthesiologists to know when administering sugammadex were also included., Results: A total of 202 completed surveys were collected. Based on an a priori threshold of understanding of 75%, 9 out of 11 key messages scored at or above this threshold. The two messages that scored below this threshold involved (1) knowledge that sugammadex is not indicated for use in children aged < 18 years (71.8%; 95% confidence interval [CI] 65.0-77.9) and (2) that monitoring is required for recurrence of NMB after reversal with sugammadex (73.3%; 95% CI 66.6-79.2). Of the five additional safety questions, four had an understanding rate of ≥ 88.1%. One question scored 60.4%; this question covered the concept that sugammadex is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min), including those requiring dialysis., Conclusion: In general, the survey results suggested that anesthesiologists understood the use, safety, and efficacy of sugammadex for the reversal of moderate to deep NMB induced by rocuronium or vecuronium in adults undergoing surgery.

Objectives: We conducted this study to characterize the frequency of insertion-, localization- and removal-related events and their clinically significant consequences among Nexplanon® (etonogestrel radiopaque contraceptive implant) users in the United States during standard clinical practice., Study Design: The Nexplanon Observational Risk Assessment (NORA) study was a large, prospective cohort study conducted in the United States. A total of 428 Health Care Professionals (HCPs) who had completed the Nexplanon clinical training program recruited women who were newly prescribed Nexplanon. We collected data on insertion-, localization- and removal-related events experienced during routine clinical practice via questionnaires completed by patients and HCPs. Recruitment began in December 2011 and follow-up ended in October 2017. Data analysis characterized the frequency of procedure-related events., Results: We collected data on 7364 insertion procedures. The incidence of incorrect insertion (i.e., initially unrecognized non-insertion, partial insertion or deep insertion) was 12.6 per 1000 insertions (95% CI, 10.2-15.5). Pins and needles/numbness in the arm/hand/fingers was the most common patient-reported event. We obtained data on 5159 removal procedures, of which all were successful but one (due to the location of the implant in deep muscle tissue). No implants were localized outside the arm. The most common challenge reported by HCPs during implant removal was encasement of the implant within fibrotic tissue., Conclusions: Events associated with the insertion, localization and removal of the Nexplanon contraceptive implant were rare and their clinical consequences were generally not suggestive of serious injury., Implications: This study is the largest prospective evaluation of events associated with insertion and removal of Nexplanon during routine clinical practice. It demonstrates that complications associated with insertion and removal of Nexplanon are rare when performed by trained clinicians., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: Data on prevalence of chronic kidney disease (CKD) among US adults with type 2 diabetes (T2D) and cardiovascular diseases (CVD) are limited. The aim of this study was to provide such estimates for T2D, both overall and in those with CVD., Materials and Methods: Using the NHANES 2007-2014 data, we conducted a cross-sectional analysis of an adult sample with diagnosed and undiagnosed T2D, aged ≥18 years. CVD was defined based on self-reported personal interview data on a broad range of health conditions-congestive heart failure, coronary heart disease, angina, stroke, or heart attack. T2D was defined as diagnosed T2D (self-reported provider diagnosis) and undiagnosed T2D (FPG ≥126 mg/dL or HbA1c ≥ 6.5% without self-reported diagnosis). Participants who started insulin within a year of T2D diagnosis, or were pregnant at the time of health examination were excluded. Appropriate sample weights were used to provide a national estimate., Results: The prevalence of moderate to severe renal impairment based on eGFR below 60 ml/min/1.73 m 2 among T2D was 18.0%. The prevalence of mild renal impairment was 36.9%: 28.3% with UACR<30 mg/g, 7.0% with UACR ≥30-300 mg/g and 1.6% with UACR >300 mg/g. For T2D and CVD subgroup, the prevalence was 33.6% for moderate to severe renal impairment and 42.8% for mild renal impairment., Conclusions: This study confirms the high prevalence of CKD in patients with multiple comorbidities: T2D and CVD. It also provides estimates of the prevalence of CKD categories based on KDIGO 2012 classification for US adults with T2D., (Copyright © 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Background: The risk of pancreatitis and potential risk of medullary thyroid carcinoma associated with glucagon-like peptide-1 receptor agonists prompted the US Food and Drug Administration to require a Risk Evaluation and Mitigation Strategy for albiglutide, including education for prescribers and subsequent assessment of their knowledge of the risks and safe use of albiglutide via a quantitative survey., Objective: The objective of this study was to assess prescribers' knowledge of the risks related to medullary thyroid carcinoma, pancreatitis, and the appropriate patient population for albiglutide., Methods: Two Risk Evaluation and Mitigation Strategy surveys were conducted 18 months and 3 years after albiglutide was launched. Primary analyses evaluated correct response rates for each question. Secondary analyses evaluated the number of correct responses and the percentage of respondents scoring at/above the target comprehension thresholds (75% at 18 months; 80% at 3 years), which were selected based on discussion with the Food and Drug Administration and current standards for Risk Evaluation and Mitigation Strategy assessments, for each key risk message., Results: The correct response rate for individual questions ranged from 68.2 to 97.9% (18-month survey) and from 69.4 to 98.1% (3-year survey). For the secondary analysis, 79.5, 86.7, and 86.7% of respondents in the 18-month survey answered ≥ 75% of the questions correctly and 70.8, 90.9, and 54.1% of respondents in the 3-year survey answered ≥ 80% of the questions correctly for key risk messages related to medullary thyroid carcinoma, pancreatitis, and appropriate patient population, respectively., Conclusions: Survey results indicated most, but not all, prescribers are knowledgeable regarding the risks and safe use of albiglutide. Additional education to address gaps in knowledge could further improve risk mitigation.

Objectives: Herein, we investigate the presence and prognostic value of autoantibodies against carbamylated proteins (anti-CarP) in the serum of patients with primary Sjögren's syndrome (pSS)., Patients and Methods: Serum levels of anti-CarP antibodies were measured in Norwegian patients with pSS (n=78) and corresponding controls (n=74) using ELISA and analysed in relation with exocrine gland function, degree of salivary gland inflammation, signs of ectopic germinal centre (GC) formation and immunological markers. For univariate comparisons, the Mann-Whitney U test and χ(2) or Fisher's exact tests were used. Correlations were assessed with Spearman's rank testing. Multivariate regression analyses were used to assess the effect of anti-CarP positivity on clinical manifestations., Results: Of the patients with pSS, 27% were positive for anti-CarP IgG antibodies. Levels of anti-CarP correlated positively with total IgG, IgM, rheumatoid factor and β2-microglobulin. Importantly, after adjusting for confounding factors, patients positive for anti-CarP had significantly higher focus score. Furthermore, positive anti-CarP status coincided with 9.2-fold higher odds of having developed GC-like structures in the minor salivary glands. As a patient group considered having worse disease outcome, individuals with ectopic GC-like structures also presented with significantly higher levels of anti-CarP antibodies., Conclusions: Presence of anti-CarP in patients with pSS is strongly associated with increased focal lymphocytic infiltration, formation of ectopic GC-like structures in minor salivary glands, and diminished salivary gland function. Even taking into consideration our relatively small cohort we believe that anti-CarP antibodies offer new possibilities for identifying patients with more active disease and at risk of developing additional comorbidity., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Periodontitis is characterized by chronic inflammation and osteoclast-mediated bone loss regulated by the receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). The aim of this study was to investigate the effect of aminothiazoles targeting prostaglandin E synthase-1 (mPGES-1) on RANKL- and lipopolysaccharide (LPS)-mediated osteoclastogenesis and prostaglandin E2 (PGE2 ) production in vitro using the osteoclast precursor RAW 264.7 cells. RAW 264.7 cells were treated with RANKL or LPS alone or in combination with the aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) or 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644). Aminothiazoles significantly decreased the number of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells in cultures of RANKL- and LPS-stimulated RAW 264.7 cells, as well as reduced the production of PGE2 in culture supernatants. LPS-treatment induced mPGES-1 mRNA expression at 16 hrs and the subsequent PGE2 production at 72 hrs. Conversely, RANKL did not affect PGE2 secretion but markedly reduced mPGES-1 at mRNA level. Furthermore, mRNA expression of TRAP and cathepsin K (CTSK) was reduced by aminothiazoles in RAW 264.7 cells activated by LPS, whereas RANK, OPG or tumour necrosis factor α mRNA expression was not significantly affected. In RANKL-activated RAW 264.7 cells, TH-848 and TH-644 down-regulated CTSK but not TRAP mRNA expression. Moreover, the inhibitory effect of aminothiazoles on PGE2 production was also confirmed in LPS-stimulated human peripheral blood mononuclear cell cultures. In conclusion, the aminothiazoles reduced both LPS- and RANKL-mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells, suggesting these compounds as potential inhibitors for treatment of chronic inflammatory bone resorption, such as periodontitis., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: Although prior studies report a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident cardiovascular disease, the prospective association of Lp-PLA2 with incident peripheral arterial disease (PAD) has not been studied. We investigated the association between Lp-PLA2 mass and activity and the risk of developing clinical PAD and low ankle-brachial index (ABI)., Approach and Results: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged ≥65 years enrolled in 1989 to 1990, Lp-PLA2 mass and activity were measured in 4537 individuals without baseline PAD. Clinical PAD, defined as leg artery revascularization or diagnosed claudication, was ascertained through 2011. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15, was assessed among 3537 individuals who had an ABI >0.9 at baseline and a second ABI measurement 3 or 6 years later. Analyses were adjusted for demographics, cholesterol, smoking, comorbidities, and C-reactive protein. Each standard deviation increment in Lp-PLA2 mass (117 ng/mL) was associated with a higher risk of developing clinical PAD (hazard ratio 1.28; 95% confidence interval 1.13, 1.45) and incident low ABI (odds ratio 1.16; 95% confidence interval 1.00, 1.33). Results per standard deviation increment in Lp-PLA2 activity (13 nmol/min per mL) were similar for clinical PAD (hazard ratio 1.24; 95% confidence interval 1.07, 1.44) and low ABI (odds ratio 1.28; 95% confidence interval 1.09, 1.50)., Conclusions: Higher Lp-PLA2 mass and activity were associated with development of both incident clinical PAD and low ABI. Future studies are needed to determine whether pharmacological inhibition of Lp-PLA2 reduces the incidence of PAD., (© 2016 American Heart Association, Inc.)

Carbamylation of lysine residues and protein N-termini is an ubiquitous, non-enzymatic post-translational modification. Carbamylation at sites of inflammation is due to cyanate formation during the neutrophil oxidative burst and may target lysine residues within the antimicrobial peptide LL-37. The bactericidal and immunomodulatory properties of LL-37 depend on its secondary structure and cationic nature, which are conferred by arginine and lysine residues. Therefore, carbamylation may affect the biological functions of LL-37. The present study examined the kinetics and pattern of LL-37 carbamylation to investigate how this modification affects the bactericidal, cytotoxic and immunomodulatory function of the peptide. The results indicated that LL-37 undergoes rapid modification in the presence of physiological concentrations of cyanate, yielding a spectrum of diverse carbamylated peptides. Mass spectrometry analyses revealed that theN-terminal amino group of Leu-1 was highly reactive and was modified almost instantly by cyanate to generate the predominant form of the modified peptide, named LL-37(C1) This was followed by the sequential carbamylation of Lys-8, Lys-12, and Lys-15 to yield LL-37(C8), and Lys-15 to yield LL-37(C12,15) Carbamylation had profound and diverse effects on the structure and biological properties of LL-37. In some cases, anti-inflammatory LL-37 was rapidly converted to pro-inflammatory LL-37., (© The Author(s) 2016.)

The multifactorial chronic inflammatory disease periodontitis, which is characterized by destruction of tooth-supporting tissues, has also been implicated as a risk factor for various systemic diseases. Although periodontitis has been studied extensively, neither disease-specific biomarkers nor therapeutic targets have been identified, nor its link with systemic diseases. Here, we analyzed the global transcriptome of periodontitis and compared its gene expression profile with those of other inflammatory conditions, including cardiovascular disease (CVD), rheumatoid arthritis (RA), and ulcerative colitis (UC). Gingival biopsies from 62 patients with periodontitis and 62 healthy subjects were subjected to RNA sequencing. The up-regulated genes in periodontitis were related to inflammation, wounding and defense response, and apoptosis, whereas down-regulated genes were related to extracellular matrix organization and structural support. The most highly up-regulated gene was mucin 4 (MUC4), and its protein product was confirmed to be over-expressed in periodontitis. When comparing the expression profile of periodontitis with other inflammatory diseases, several gene ontology categories, including inflammatory response, cell death, cell motion, and homeostatic processes, were identified as common to all diseases. Only one gene, pleckstrin (PLEK), was significantly overexpressed in periodontitis, CVD, RA, and UC, implicating this gene as an important networking link between these chronic inflammatory diseases.

Post-translational modifications of proteins significantly affect their structure and function. The carbamylation of positively charged lysine residues to form neutral homoitrulline occurs primarily under inflammatory conditions through myeloperoxidase-dependent cyanate (CNO-) formation. We analyzed the pattern of human IgG1 carbamylation under inflammatory conditions and the effects that this modification has on the ability of antibodies to trigger complement activation via the classical pathway. We found that the lysine residues of IgG1 are rapidly modified after brief exposure to CNO- . Interestingly, modifications were not random, but instead limited to only few lysines within the hinge area and the N-terminal fragment of the CH2 domain. A complement activation assay combined with mass spectrometry analysis revealed a highly significant inverse correlation between carbamylation of several key lysine residues within the hinge region and N-terminus of the CH2 domain and the proper binding of C1q to human IgG1 followed by subsequent complement activation. This severely hindered complement-dependent cytotoxicity of therapeutic IgG1 . The reaction can apparently occur in vivo, as we found carbamylated antibodies in synovial fluid from rheumatoid arthritis patients. Taken together, our data suggest that carbamylation has a profound impact on the complement-activating ability of IgG1 and reveals a pivotal role for previously uncharacterized lysine residues in this process., (© 2014 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To evaluate associations between Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with risk of dementia and its subtypes., Methods: Analysis were completed on 3320 participants of the Cardiovascular Health Study (CHS), a population-based longitudinal study of community-dwelling adults age ≥65 years followed for an average of 5.4 years. Baseline serum Lp-PLA2 mass was measured using a sandwich enzyme immunoassay and Lp-PLA2 activity utilized a tritiated-platelet activating factor activity assay. Cox proportional hazards regression assessed the relative risk of incident dementia with higher baseline Lp-PLA2 adjusting for demographics, cardiovascular disease (CVD) and risk factors, inflammation markers and apolipoprotein E (APOE) genotype., Results: Each standard deviation higher Lp-PLA2 mass and activity were related to increased risk of dementia (fully adjusted HR: 1.11 per SD, 95% CI: 1.00-1.24 for mass; HR: 1.12 per SD, 95% CI: 1.00-1.26 for activity). Persons in the highest quartile of Lp-PLA2 mass were 50% more likely to develop dementia than those in the lowest quartile in adjusted models (HR: 1.49; 95% CI: 1.08-2.06). Among dementia subtypes, the risk of AD was increased two-fold in the highest compared to lowest quartile of Lp-PLA2 mass (adjusted HR: 1.98, 95% CI: 1.22-3.21). Results were attenuated in models of mixed dementia and VaD. Lp-PLA2 activity also doubled the risk of mixed dementia in the highest compared to lowest quartile (HR: 2.21, 95% CI: 1.12-4.373)., Interpretation: These data support Lp-PLA2 as a risk factor for dementia independent of CVD and its risk factors. Further study is required to clarify the role of Lp-PLA2-related mechanisms in dementia subtypes., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Lipoprotein association phospholipase A2 (Lp-PLA(2)), an enzyme which has been found in atherosclerotic plaque is currently under investigation in large Phase III clinical trials of vascular disease prevention. We assessed in a variety of different population settings variation of Lp-PLA(2) mass and activity across gender, ethnicity, diabetes, kidney disease and metabolic syndrome. We also assessed correlations with measures of circulating lipids, systemic inflammation and adiposity., Methods: Systematic review of studies measuring Lp-PLA(2) and at least one of the relevant characteristics in >50 participants., Results: We identified a total of 77 studies involving 102,499 participants meeting the inclusion criteria. Lp-PLA(2) mass and activity were consistently approximately 10% higher in males than females and 15% higher in Caucasians than African Americans or Hispanics. There were no clear associations of Lp-PLA(2) mass or activity with type II diabetes, markers of systemic inflammation (C-reactive protein, fibrinogen) or with body mass index. Correlations of Lp-PLA(2) mass or activity with low density lipoprotein cholesterol and apolipoprotein B were moderate and positive, whilst correlations with high density lipoprotein cholesterol were negative and moderate to weak. There was no clear differences in associations with any of the above characteristics in groups defined based upon prevalent cardiovascular disease or its risk factors., Conclusions: Despite considerable variability in absolute levels of Lp-PLA(2) across studies, the variability of Lp-PLA(2) across gender, ethnicity, and levels of circulating lipids and markers of systemic inflammation are more consistent and appear not to vary importantly across categories defined by CVD or its risk factors., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels are associated with kidney function decline has not been well studied., Methods: We investigated associations of Lp-PLA(2) antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m(2) per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m(2))., Results: Mean age was 72 ± 5 years. Average eGFRcys decline was -1.79 ml/min/1.73 m(2) (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA(2) antigen, eGFRcys decline was faster among persons in the second, β -0.31 (95% CI -0.52, -0.10), third -0.19 (-0.41, 0.02) and fourth quartiles -0.26 (-0.48, -0.04) after full adjustment. Persons in the highest quartile of Lp-PLA(2) antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA(2) activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m(2)) at baseline., Conclusion: Higher levels of Lp-PLA(2) antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression., (Copyright © 2011 S. Karger AG, Basel.)

Objective: The aim of this study was to describe glycemic control levels (fasting plasma glucose [FPG] and glycosylated hemoglobin [HbA(1c)]) and pharma-cotherapy change patterns among a cohort of patients with type 2 diabetes mellitus (T2DM) receiving various antidiabetic agents., Methods: This study, a retrospective analysis conducted from a large electronic medical record database, identified T2DM patients with > or =1 prescription for metformin, sulfonylureas, or thiazolidinediones from January 23, 1997, through March 15, 2006. The database contained medical and clinical records of patients-including diagnoses, medications, laboratory results, and physician orders-linked through encrypted patient identifiers. This study calculated the mean and median FPG and HbA(1c) values (performed within 30 days before or after a pharmacotherapy change) and the percentage of patients with values above those recommended by the American Diabetes Association (ADA) and the American College of Endocrinology (ACE)/American Association of Clinical Endocrinologists(AACE)., Results: The study included a total of 7769 T2DM patients (3942 female/3827 male; 56.9% were aged 50-69 years). For patients with no pharmacotherapy change, most did not achieve the ADA recommendations for FPG (56.4% [1917/3398]) or HbA(1c) (48.6% [952/1958]) or the ACE/AACE recommendations forFPG (79.4% [2698/3398]) or HbA(1c) (65.4% [1281/1958]). These patients' mean FPG level was 151.9 mg/ dL (95% CI, 150.0-153.9 mg/dL) and their mean HbA(1c) value was 7.51% (95% CI, 7.43%-7.60%). For patients with a pharmacotherapy change, the mean FPG level was 191.1 mg/dL (95% CI, 186.7-195.4 mg/dL) and the mean HbA(1c) value was 8.85% (95% CI, 8.70%-9.00%). Similar to those with no pharmacotherapy change, a large percentage of patients with a pharmacotherapy change did not achieve the ADA recommendations for FPG (77.7% [1107/1425]) or HbA(1c) (76.2% [753/988]) or the ACE/AACE recommendations for FPG (90.1% [1284/1425]) or HbA(1c) (88.5% [874/988])., Conclusion: Despite the proven benefits of maintaining glycemic control and its impact on reducing long-term risk of diabetes complications, these results indicate that the mean FPG and HbA(1c) values for a large percentage of diabetic patients included in this study remained above those recommended by the ADA and the ACE/AACE.

Background: There is conflicting evidence on the reduction of cardiovascular risk in diabetic patients treated with oral antidiabetic agents., Objectives: To compare the risk of myocardial infarction (MI) and coronary revascularization (CR) in type 2 diabetic patients treated with rosiglitazone, metformin, or sulfonylurea., Methods: Using data from a large US insurer, we created propensity-matched cohorts. We identified hospitalizations for MI or CR. We calculated incidence rates and 95% confidence intervals for the outcomes and estimated risks from Cox proportional hazards models., Results: We identified 26,931 initiators of monotherapy, 4,086 initiators of dual-therapy, and 2,346 initiators of combination with insulin therapy. There was no difference between the risk of the composite outcome with rosiglitazone monotherapy compared to metformin monotherapy (HR 1.07, 95% CI: 0.85, 1.34), and similarly with rosiglitazone monotherapy compared to sulfonylurea monotherapy (HR 0.82, 95% CI: 0.67, 1.02). There was no difference in the risk of outcome with rosiglitazone in combination with insulin therapy compared to other oral antidiabetic agents in combination with insulin (HR 0.88, 95% CI: 0.59, 1.32). Overall, there was little difference in the risk of the composite outcome or of the individual outcomes of MI and CR comparing rosiglitazone therapies to non-rosiglitazone therapies (HR for composite outcome 0.93, 95% CI: 0.80, 1.10)., Conclusions: The results from the monotherapy and the dual-therapy comparisons, though not individually significant, are consistent in suggesting that the risk of cardiovascular outcome events in patients using rosiglitazone may lie between the risks associated with sulfonylureas (higher incidence) and metformin (lower incidence).

Purpose: We conducted three nested case-control studies to evaluate the risk of breast, colon, and prostate cancers developing in patients exposed to thiazolidinediones (TZDs) compared with other anti-diabetic agents., Methods: Cancer cases were matched to five controls by age, gender, calendar year, and time in the database from a cohort of 1 26 971 diabetic patients taking anti-diabetic medication in the US Integrated Healthcare Information Services database. Five hundred thirteen breast cancer cases were matched with 2557 controls, 408 cases of colon cancer were matched with 2027 controls and 643 cases of prostate cancer were matched with 3176 controls. Exposure to an anti-diabetic agent within 90 days preceding the index date was defined as recent exposure and at any time during the follow-up was defined as ever exposed., Results: The adjusted odds ratios and 95%CI of cancer from ever exposure to TZDs compared to oral monotherapy, oral dual therapy, oral triple therapy, insulin monotherapy, insulin and oral therapy and all non-TZD anti-diabetic agents were, respectively for breast cancer: 0.91 (0.69-1.20), 0.80 (0.56-1.14), 0.87 (0.32-2.35), 1.27 (0.61-2.67), 0.71 (0.36-1.37), 0.89 (0.68-1.15); for colon cancer: 1.06 (0.80-1.40), 1.12 (0.77-1.63), 1.73 (0.39-7.78), 4.46 (1.05-19.00), 1.06 (0.50-2.26) 1.03 (0.80-1.32) and for prostate cancer: 1.08 (0.85-1.37), 0.89 (0.66-1.21); 0.82 (0.33-2.06); 1.80 (0.79-4.07), 1.10 (0.55-2.18), 1.04 (0.83-1.31). Results for exposure within 90 days of the date of the cancer were similar., Conclusions: Our findings suggest that the effect of TZDs on the likelihood of development of the cancers studied (colon, prostate and breast) appears to be neutral and do not support a beneficial or deleterious effect of TZD on the cancers studied., (Copyright 2006 John Wiley & Sons, Ltd.)

Objective: This study describes the clinical management of type 2 diabetes among a cohort of patients receiving oral antidiabetic monotherapy., Study Design and Setting: A retrospective study was conducted within an integrated Midwestern health system that included all individuals receiving oral antidiabetic monotherapy during the period June 1, 1999 to November 30, 2002 (n = 9335). Among patients with elevated hemoglobin A(1c) (HbA(1c)) test result(s), Kaplan-Meier estimates of median time until pharmacotherapy change were calculated., Results: Among the 8068 patients who had > or = 1 HbA(1c) measurement during the study period, 21.4% were at goal (i.e. HbA(1c) < 7%). Among patients with at least one elevated test result (> or = 7%), the median time to pharmacotherapy change following an HbA(1c) test result of between 7-10% was just over 1 year (372 days, 95% confidence interval [CI] 358-393 days) and 160 days for patients with HbA(1c) > 10%. Among patients with at least two elevated tests, the median time to pharmacotherapy change was 275 days from the second test result of between 7-10%, and 70 days among patients with a second HbA(1c) > 10%. The median time between HbA(1c) testing was 166 days overall, and 154 days among patients with at least one elevated result., Conclusion: Despite the known benefits of glycemic control among patients with diabetes, the time between elevated HbA(1c) results and pharmacotherapy change exceeds 12 months for those with HbA(1c) test results between 7-10% and 9 months for those with results over 10%.