Global trends in carbapenem- and difficult-to-treat-resistance among World Health Organization priority bacterial pathogens: ATLAS surveillance program 2018-2022.

OBJECTIVES: To report trends in carbapenem resistance and difficult-to-treat resistance (DTR) among clinical isolates of Gram-negative priority pathogens collected by the ATLAS global surveillance program from 2018 to 2022. METHODS: Reference broth microdilution testing was performed in a central laboratory for 79,214 Enterobacterales, 30,504 Pseudomonas aeruginosa, and 13,500 Acinetobacter baumannii-calcoaceticus complex isolates collected by a constant set of 157 medical centres in 49 countries in Asia Pacific (APAC), Europe (EUR), Latin America (LATAM), Middle East-Africa (MEA), and North America (NA) regions. MICs were interpreted by 2023 CLSI M100 breakpoints. ß-lactamase genes were identified for meropenem-nonsusceptible (MIC ≥2 mg/L) Enterobacterales isolates. RESULTS: Carbapenem-resistant Enterobacterales (CRE) detection increased (P < 0.05) in APAC, EUR, LATAM, and MEA regions and decreased in NA, while annual DTR percentages increased in all five regions. Carbapenem-resistant P. aeruginosa (CRPA; decreased in MEA region) and carbapenem-resistant A. baumannii-calcoaceticus complex (CRAB; decreased in MEA region and increased in EUR) remained relatively stable over time in all regions, although notably, annual percentages of CRAB and DTR A. baumannii-calcoaceticus complex isolates were consistently >25 percentage points lower in NA than in other regions. For all regions except NA, the majority of changes in CRE percentages could be attributed to hospital-acquired infections. Among meropenem-nonsusceptible Enterobacterales, KPC was the most frequent carbapenemase in NA and EUR each year. NDM was the most prevalent carbapenemase detected in 2022 in other global regions. CONCLUSION: CRE, CRPA, CRAB, and DTR rates vary among global regions over time highlighting the need for continuing surveillance to inform treatment strategies and antimicrobial stewardship.

Rhode Island (RI) Women's Breast Cancer Mammography Use Prior to and After Cancer Diagnosis: Linkage of RI Cancer Registry Data With RI All-Payer Claims Database.

OBJECTIVE: A limitation of the central cancer registries to examine associations between mammography use and cancer diagnosis is their lack of cancer screening history. To fill this measurement gap, Rhode Island Cancer Registry (RICR) breast cancer (BC) records were linked to Rhode Island-all-payer claims database (RI-APCD) to study Rhode Island (RI) women's regular mammography use and identify its predictors. METHODS: From the linked 2011-2019 data, we identified 4 study cohorts: (1) women who ever received mammography by Women's Cancer Screening Program (WCSP) and were diagnosed with BC ("WCSP-BC" cohort: n = 149), (2) women diagnosed with BC outside of WCSP (BC-control cohort: n = 4304), (3) women with a history of mammography use at WCSP but no BC diagnosis (n = 6513), and (4) general RI women with no BC diagnosis (n = 15 121). Logistic regressions were conducted to identify predictors of regular mammography use. RESULTS: The linkage for RI-APCD and RICR for our study had a high matching rate of 82%. Mammography use prior to BC diagnosis was not different between the WCSP-BC cohort and the BC-control cohort (58% vs 57%). Women in the BC-control cohort who had mammography in 2 years prior to their cancer diagnosis were more likely of being diagnosed at an early-stage disease. Among BC-control group, women with no anxiety/depression or with no preventive examinations were less likely of regular mammography use. Among women with no BC, a lower proportion of women with a history of screening at WCSP had regular mammography use, compared with the general RI women (38% vs 66%). CONCLUSION: RI-APCD data linkage with RICR provides excellent opportunities to examine regular mammography use among RI women and compare their outcomes to the general women population in the state. We identified opportunities for improving their mammography use. A measurement gap in the central cancer registries can be effectively reduced by utilizing statewide claims database.

Association of guideline-concordant care with survival, health care utilization, and costs among older women with advanced epithelial ovarian cancer.

OBJECTIVES: To examine guideline-concordant care (GCC) for ovarian cancer, identify its predictors, and evaluate the associations between GCC and survival, health care expenditures, and utilization. STUDY DESIGN: A retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare data. METHODS: Women aged 66 to 90 years who received a diagnosis of stage II or higher epithelial ovarian cancer during 2011-2015 were included (N = 3237). The National Comprehensive Cancer Network clinical practice guidelines were used to identify GCC. Logistic regression was conducted to identify predictors of GCC, a Cox proportional hazards model was used to examine mortality, and generalized linear models were used to examine mean monthly Medicare expenditures and health care utilization. RESULTS: Approximately 57% of women received GCC and 11.6% of women did not receive any cancer-specific treatment. Women who were relatively older (adjusted odds ratio [AOR], 0.272; 95% CI, 0.210-0.351), had Census tract income of $50,000 or less (AOR, 0.709; 95% CI, 0.551-0.913), had a psychiatric condition (AOR, 0.655; 95% CI, 0.464-0.923), and had adenocarcinoma histology (AOR, 0.564; 95% CI, 0.441-0.721) were significantly less likely to receive GCC. Race/ethnicity was not found to be a significant predictor of GCC. Women who received surgery only or chemotherapy only had a significant higher hazard of all-cause mortality and ovarian cancer-specific mortality compared with those who received GCC (surgery only: adjusted HR [AHR], 2.307; chemotherapy only: AHR, 1.802). Receiving chemotherapy only was associated with 45% (P < .0001) higher mean monthly expenditures compared with those who received GCC. CONCLUSIONS: Non-GCC was associated with worsened survival, higher health care utilization, and increased expenditures. It is important to highlight that women who received GCC were associated with better survival likely due to favorable prognostic clinical factors.

In vitro activity of aztreonam-avibactam against Enterobacterales isolates collected in Latin America, Africa/Middle East, Asia, and Eurasia for the ATLAS Global Surveillance Program in 2019-2021.

This study aimed to report reference method antimicrobial susceptibility results for 24,937 recent (2019-2021) clinical isolates of Enterobacterales from 27 countries in Latin America, Eurasia, Africa/Middle East, and Asia with a focus on the investigational combination aztreonam-avibactam against metallo-ß-lactamase (MBL) isolates. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution methodology. Minimum inhibitory concentrations (MICs) were interpreted using the CLSI (2022) breakpoints for all agents except aztreonam-avibactam (provisional pharmacokinetic/pharmacodynamic susceptible breakpoint, ≤ 8 mg/L) and tigecycline (US-FDA). Molecular testing for ß-lactamase genes was performed on isolates with meropenem MICs ≥ 2 mg/L, ceftazidime-avibactam MICs ≥ 16 mg/L, and/or aztreonam-avibactam MICs ≥ 16 mg/L, and 50% of isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs ≥ 2 mg/L. Aztreonam-avibactam inhibited 99.8% of all Enterobacterales at ≤ 8 mg/L (MIC90, 0.25 mg/L) and maintained activity against phenotypically resistant subsets of multidrug-resistant (MDR) (99.5% susceptible), extensively drug-resistant (XDR) (98.7%), and carbapenem-resistant Enterobacterales (CRE) (99.1%) isolates. At ≤ 8 mg/L, aztreonam-avibactam inhibited 100%, 99.6%, 99.6%, and 98.8% of KPC-, OXA-48-like-, ESBL-, and MBL-carrying isolates, respectively. MBL-positive isolates were most prevalent in India (20.5%), Guatemala (13.8%), and Jordan (13.2%). No differences in the activity of aztreonam-avibactam were observed across the global regions evaluated. At a concentration of ≤ 8 mg/L, aztreonam-avibactam inhibited almost all Enterobacterales collected from developing countries, including MBL-producing isolates. The widespread dissemination of MBLs among Enterobacterales highlights the unmet need for new agents such as aztreonam-avibactam for the treatment of CRE infections.

Antimicrobial Susceptibility Among Gram-Negative Isolates in Pediatric Patients in Latin America, Africa-Middle East, and Asia From 2016-2020 Compared to 2011-2015: Results From the ATLAS Surveillance Study.

BACKGROUND: Antimicrobial resistance (AMR) data in the pediatric population are limited, particularly in developing countries. This study assessed the AMR profile and key resistance phenotypes and genotypes for Gram-negative bacteria (GNB) isolates collected as part of the Antimicrobial Testing Leadership and Surveillance program from pediatric patients in Latin America, Africa-Middle East, and Asia in 2016-2020 versus 2011-2015. METHODS: Minimum inhibitory concentrations by broth microdilution methodology were interpreted per the Clinical and Laboratory Standards Institute. European Committee on Antimicrobial Susceptibility Testing breakpoints were used for interpreting colistin activity. ß-lactamase genes were screened by polymerase chain reaction and sequencing. RESULTS: For Acinetobacter baumannii, low susceptibility (<60.0%) was observed for all antimicrobials, except colistin (≥92.9%), across regions and year periods. Ceftazidime-avibactam, amikacin, colistin, and meropenem were mostly active (78.6%-100.0%) against Enterobacter cloacae, Escherichia coli, and Klebsiella pneumoniae. For Pseudomonas aeruginosa, susceptibility to ceftazidime-avibactam, amikacin, and colistin was ≥85.9%. Among resistance phenotypes, carbapenem-resistant (CR, ≥44.8%) and difficult-to-treat resistant (DTR, ≥37.1%) rates were the highest in A. baumannii. A consistent increase in CR and DTR K. pneumoniae was noted across regions over time. Extended-spectrum ß-lactamases (ESBL)-producing K. pneumoniae (32.6%-55.6%) were more frequent than ESBL-producing E. coli (25.3%-37.1%). CTX-M was the dominant ESBL among Enterobacterales. NDM-positive Enterobacterales species and VIM-positive P. aeruginosa were identified across regions. CONCLUSIONS: This study identified high susceptibility to few agents for key GNB in pediatric patients. Continued surveillance of resistance phenotypes and genotypes at regional levels may help to guide appropriate treatment decisions.

Evaluation of the association between health insurance status and healthcare utilization and expenditures among adult cancer survivors in the United States.

BACKGROUND: Health care expenditures for cancer care has increased significantly over the past decade and is further projected to rise. This study examined the associations between health insurance status and total direct health care expenditures and health care utilization among cancer survivors living in the United States. METHODS: A cross-sectional study of cancer survivors aged ≥18 years, identified from the Medical Expenditures Panel Survey (MEPS) during 2017 using International Classification of Diseases, Tenth Revision codes specific for cancer. Health insurance was categorized into Private, Medicare, Medicaid, and uninsured. Multivariable ordinary least squares regression was used to examine the association between log expenditures and health insurance. Negative binomial regression with log link was used to obtain adjusted incident rate ratios (AIRR) for health care utilization. Survey weights were used to produce nationally representative estimates of the US population. RESULTS: A total of 1140 (weighted = 13.9 million) cancer survivors were identified. Compared to the adjusted mean annual health care expenditures for the private group ($14,265; 95% confidence interval (CI): $12,645 to $16,092), the adjusted mean annual health care expenditures for the Medicare group were higher ($15,112; 95%CI: $13,361 to $17,092). As compared to the private group, the average annual expenditures for uninsured cancer survivors ($2315; 95%CI:1038 to $3501) was significantly lower and so was their health care utilization. Adjusted rates of ER visits for Medicaid were twice (AIRR:2.04; SE:0.28; p = 0.001) as compared to privately insured. CONCLUSIONS: A difference in the average total direct expenditures between uninsured and privately insured patients was found. Uninsured had the lowest health care utilization while Medicaid reported significantly higher number of ER visits. Despite differences in program structures, health care expenditures across insurance types were similar. Lower utilization of health care services among uninsured suggests cost maybe a barrier to accessing care.

Real-World Outcomes Associated With Letermovir Use for Cytomegalovirus Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: A Systematic Review and Meta-analysis of Observational Studies.

Background: A systematic review and meta-analysis of real-world observational studies was conducted to summarize the impact of letermovir cytomegalovirus (CMV) primary prophylaxis (PP) among adult allogeneic hematopoietic cell transplant (allo-HCT) recipients. Methods: Systematic searches in Medline/PubMed, Embase, and conferences (from database inception to October 2021) were conducted to identify studies for inclusion. Random-effects models were used to derive pooled estimates on the relative effectiveness of letermovir PP compared to controls. Results: Forty-eight unique studies (N = 7104 patients) were included, most of which were comparative, single-center, and conducted in the United States. Letermovir PP was associated with statistically significant reduction in odds of CMV reactivation (pooled odds ratio [pOR], 0.13 and 0.24; P < .05), clinically significant CMV infection (pOR, 0.09 and 0.19; P < .05), and CMV disease (pOR, 0.31 and 0.35; P < .05) by day +100 and day +200 after allo-HCT, respectively. Letermovir PP was associated with significantly lower odds of all-cause (pOR, 0.73; P < .01) and nonrelapse mortality (pOR, 0.65; P = .01) beyond day 200 after allo-HCT. Conclusions: Letermovir for CMV PP was effective in reducing the risk of CMV-related complications overall and mortality beyond day 200 among adult allo-HCT recipients.

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis.

A systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to examine treatment-related adverse events (TRAEs) for combination of nivolumab (NIVO) and ipilimumab (IPI) compared to NIVO monotherapy among cancer patients. We searched several databases to identify relevant RCTs. Meta-analysis was performed using random-effects model. In fourteen RCTs included in the study, we found that compared to NIVO monotherapy, combination NIVO + IPI increased the risk of any grade (Risk Ratio (RR) = 1.11), and grade 3 or 4 (RR = 1.95) TRAEs. Compared to NIVO, NIVO + IPI had higher risk for any grade colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68).

Ceftazidime-avibactam plus metronidazole vs. meropenem in complicated intra-abdominal infections: Indian subset from RECLAIM.

INTRODUCTION: This study analyzes the safety and efficacy results of the Indian population subset from the RECLAIM trial investigating the non-inferiority of Ceftazidime-Avibactam (CAZ-AVI) plus metronidazole to meropenem and interprets its relevance. METHODOLOGY: The study design, subjects inclusion criteria, dosage, safety and efficacy evaluations in Indian patients have been followed as per the RECLAIM trial protocol. RESULTS: A total of 142 Indian patients with complicated intra-abdominal infection were enrolled across eight centers in India, 125 of them were randomized to either CAZ-AVI + metronidazole (n = 62) or meropenem (n = 63) group. the clinical cure rates in modified intention-to-treat (MITT; all randomized patients who met minimum disease requirements and received any amount of study drug) and clinically evaluable (CE , patients who had an evaluable assessment and no protocol deviations) analysis sets, was numerically comparable to the results of overall population for CAZ-AVI + metronidazole [MITT: 82.5% (Overall, n = 429/520) versus 89.3% (Indian, n = 50/56); CE: 91.7% (Overall, n = 376/410) versus 97.8% (Indian, n = 45/46)] and meropenem [MITT: 84.9% (Overall, n = 444/523) versus 84.7% (Indian, n = 50/59); CE: 92.5% (Overall, n = 385/416) versus 95.5% (Indian, n = 42/44)]. No new safety findings were reported in the Indian population. CONCLUSIONS: CAZ-AVI + metronidazole proved to be an effective option for critical patients with complicated intra-abdominal infection and can be considered as an alternative to carbapenems in the ICU setting for the treatment of resistant pathogens.

In vitro activity of Ceftazidime-Avibactam and its comparators against Carbapenem resistant Enterobacterales collected across India: results from ATLAS surveillance 2018 to 2019.

ATLAS (Antimicrobial Testing Leadership and Surveillance) detects trends in multi-drug resistance longitudinally over time. In the present study, the in vitro activity of ceftazidime-avibactam and comparators was analyzed against Escherichia coli (n = 458) and Klebsiella pneumoniae (n = 455)  isolates obtained from 9 centers across India. The overall susceptibility to ceftazidime-avibactam was observed to be 72% among K. pneumoniae isolates and 87% among E. coli isolates. Among the tested carbapenem resistant isolates, 51% of CR-K. pneumoniae and 24% of CR-E. coli were susceptible to ceftazidime- avibactam. OXA-48 like was identified in 52% of the K. pneumoniae isolates followed by co-production of NDM with OXA-48 like in 27%. NDM was predominantly identified in 68% of the E. coli isolates followed by OXA-48 like in 24% isolates. The findings suggest that ceftazidime- avibactam is a reasonable alternative to standard therapy for management of carbapenem resistant Enterobacterales infections particularly with K. pneumoniae and E. coli with the OXA-48 like genotype.

Association of guideline-concordant initial systemic treatment with clinical and economic outcomes among older women with metastatic breast cancer in the United States.

PURPOSE: We examined guideline-concordant initial systemic treatment among women with metastatic breast cancer, its predictors, and if guideline-concordant treatment was associated with mortality, healthcare utilization and Medicare expenditures. METHODS: This retrospective observational cohort study was conducted using the Surveillance, Epidemiology, End Results-Medicare linked database. Women aged 66-90 years diagnosed with metastatic breast cancer during 2010-2013 (N = 1282) were included. The National Comprehensive Cancer Network treatment guidelines were used to determine the guideline-concordant initial systemic treatment following cancer diagnosis. A logistic regression analysis was conducted to examine significant predictors of guideline-concordant treatment. Generalized linear regressions were used to examine the association between guideline-concordant treatment and healthcare utilization and average monthly Medicare expenditures. RESULTS: About 74% of the study cohort received guideline-concordant initial systemic treatment. Women who received guideline-concordant treatment were significantly more likely to be comparatively younger (p < 0.05), were married/partnered (p = 0.0038), had HER2 positive tumors, and had good performance status. Adjusted hazards ratios for all-cause (2.364, p < 0.0001) and breast-cancer specific mortality (2.179, p < 0.0001) were higher for women who did not receive guideline-concordant treatment. Rates of healthcare utilization were also higher for women not receiving guideline-concordant treatment. Average monthly Medicare expenditures were 100.4% higher (95% confidence interval: $77.3%-126.5%) for women who did not receive guideline-concordant treatment compared to those who received guideline-concordant treatment (p < 0.0001). CONCLUSION: One fourth of the study cohort did not receive guideline-concordant initial systemic treatment. Guideline-concordant initial treatment was associated with reduced mortality, and lower healthcare utilization and Medicare expenditures in women with metastatic breast cancer.

Clinical outcomes of ceftazidime-avibactam versus meropenem in Indian patients with nosocomial pneumonia: Subset analysis from the REPROVE study.

The efficacy and safety of Ceftazidime-Avibactam (CAZ-AVI) as compared to meropenem for nosocomial pneumonia was established in a randomized, phase-III, non-inferiority trial REPROVE, which included Indian patients. We determined if the results for the Indian patients were in-line with the results of overall population. Descriptive analysis of efficacy and safety demonstrated ceftazidime-avibactam was comparable to meropenem in the management of nosocomial pneumonia in Indian patients and it may be a useful addition to the armamentarium of antibiotics for management of such infections with Enterobacterales and Pseudomonas.

Trends and Disparities in Quality of Diabetes Care in the US: The National Health and Nutrition Examination Survey, 1999-2016.

Objectives: To examine trends and disparities in the quality of diabetes care among US adults with diabetes. Methods: Individuals aged 20 years or older with diabetes from NHANES (1999-2016) were included in the study. Quality indicators for diabetes care included Hemoglobin A1c (HbA1c) < 8%, Blood Pressure (BP) < 130/80 mm Hg, Low-Density Lipoprotein (LDL-C) < 100 mg/dL, triglycerides < 150 mg/dL, receiving eye and foot examinations in the past year, and meeting with a diabetes educator in the past year. Results: A total of 7,521 adults with diabetes were identified. During the 18-year study period, significant improvements in diabetes care were observed in the overall study sample. Adjusted regression analyses showed that compared with their White counterparts, Blacks were more likely to have received eye (OR=1.37; P=0.01) and foot (OR=1.42;P=0.01) examinations and met a diabetes educator (OR=1.40;P<0.01) over the past year. However, Blacks were significantly less likely to achieve treatment goals for HbA1c (OR=0.77, P=0.02), BP (OR=0.75, P<0.01), LDL-C (OR=0.68, P<0.01). Hispanics in general had suboptimal healthcare utilization for diabetes but the Hispanic-white disparities in diabetes care outcomes were attenuated after controlling for patient sociodemographic, clinical and utilization characteristics. Overall, suboptimal quality of diabetes care were particularly prominent among adults without health insurance and those with lower educational attainment. Conclusions: In the United States, despite persistent efforts, racial disparities in quality of diabetes care still persist. Lack of health insurance and lower socioeconomic status are among the strongest predictors of poor quality of diabetes care. These findings provide valuable information in developing policies and practices to promote racial equity in diabetes care.

In-vitro activity of tigecycline and comparator agents against common pathogens: Indian experience.

INTRODUCTION: Tigecycline Evaluation and Surveillance Trail (TEST) study is an on-going global surveillance. The study was performed to determine the susceptibility of common pathogens to tigecycline and comparator antibiotics by broth microdilution (BMD) at two tertiary care centres in India from 2015 to 2017. METHODOLOGY: Total of 989 isolates collected from various clinical specimens between January 2015 and September 2017 from two centres in India were included. BMD was performed to determine the minimum inhibitory concentration (MIC) for tigecycline and comparator antibiotics. RESULTS: Among Gram-negative bacteria, susceptibility to tigecycline was lowest among Klebsiella spp. being 84% while others such as E. coli, Enterobacter spp., Serratia spp. and H. influenzae showed susceptibility of 98%, 95%, 98% and 100% respectively. Overall, 99 isolates among Enterobacteriaceae (E. coli, Klebsiella spp. and Enterobacter spp.) were ESBL producers, susceptible to tigecycline. Among the 101 meropenem resistant Enterobacteriaceae, 85 were susceptible to tigecycline (84%). Among the Gram-positive bacteria, S. aureus and Enterococcus spp. were 99% and 98% susceptible to tigecycline respectively. Among 68 MRSA isolates in the study, 66 (97%) were susceptible to tigecycline. Seven vancomycin resistant E. faecalis were isolated and all were susceptible to tigecycline. CONCLUSION: Tigecycline has retained activity over both Gram-positive and Gram-negative organisms with MIC values comparable to global reports. About 98% of the MDR Gram-positive and Gram-negative bacteria in the study are susceptible to tigecycline. With increased incidence of extensively drug resistant organisms, tigecycline is a potential reserve drug.

Echinocandins: Their role in the management of Candida biofilms.

The importance of antifungal agents and their clinical implications has received little attention in comparison to antibiotics, particularly in the health-care setting. However, apart from bacterial infections rising in hospitals, the incidences of fungal infections are growing with the development of resistance to conventional antifungal agents. Newer antifungal agents such as echinocandins (ECs) have been extensively studied over the past decade and are recognised as a superior treatment compared with prior antifungals as a first line of therapy in tertiary institutions. Caspofungin (CAS), micafungin (MICA) and anidulafungin (ANID) are the three most widely used EC antifungal agents. The treatment of biofilm-associated fungal infections affecting patients in tertiary health-care facilities has been identified as a challenge, particularly in Indian Intensive Care Unit (ICU) settings. With the rising number of critically ill patients requiring invasive devices such as central venous catheters for treatment, especially in ICUs, these devices serve as a potential source of nosocomial infections. Candida spp. colonisation is a major precursor of these infections and further complicates and prolongs treatment procedures, adding to increasing costs both for hospitals and the patient. Analysing studies involving the use of these agents can help in making critical decisions for antifungal therapy in the event of a fungal infection in the ICU. In addition, the development of resistance to antifungal agents is a crucial factor for assessing the appropriate antifungals that can be used for treatment. This review provides an overview of ANID in biofilms, along with CAS and MICA, in terms of clinical efficacy, resistance development and potency, primarily against Candida spp.

Trends and disparities in statin use and low-density lipoprotein cholesterol levels among US patients with diabetes, 1999-2014.

AIMS: The 2013 American College of Cardiology/American Heart Association Guideline defined patients with diabetes aged 40-75 years as a major statin benefit group. We explored the temporal trends and disparities in statin utilization and LDL-C levels among patients with diabetes aged 40-75 years. METHODS: A total of 4860 patients from the National Health and Nutrition Examination Survey 1999 to 2014 were included in this study. Differences in statin use and LDL-C levels were explored by patient characteristics. RESULTS: From 1999-2002 to 2011-2014, the prevalence of statin use increased from 26.2% to 49.5% (Ptrend < 0.001). This was accompanied by a continuous decrease in the mean LDL-C level (from 115.8 mg/dL to 103.3 mg/dL, Ptrend < 0.001). The use of guideline-defined high-potency statin medications (atorvastatin and rosuvastatin) remained largely unchanged (from 14.0% to 17.9%, Ptrend = 0.55). Statin utilization increased with age. Women and blacks were 10% and 16% less likely to receive statin treatment compared with men and whites, respectively. In comparison with other statin treatment, use of atorvastatin or rosuvastatin was associated with average LDL-C reduction of 8.0 mg/dL. LDL-C levels were significantly higher among women and black patients. After adjustment for potential confounders, age and Hispanic-white differences in statin use and LDL-C levels were substantially attenuated. CONCLUSIONS: Despite a steady increase in statin use during the 16-year study period, statin therapy remains underutilized in certain subgroups of patients. Confounding factors related to healthcare utilization account for some of the disparities in statin use and LDL-C levels.

Hepatitis B Virus (HBV) Infection in Liver Disease Patients in Mumbai, India with Special Reference to Hepatitis B Surface Antigen (HBsAg) Mutant Detection.

OBJECTIVES: To determine the prevalence of Hepatitis B Surface antigen (HBsAg) in patients attending the Hepatology Out Patient Department (OPD) of a tertiary care hospital and to compare the routinely used HBsAg detection kit with the mutant detection kit to find out the presence of mutants in a given setting. MATERIALS AND METHODS: A cross-sectional study was carried out in adult patients with liver disease attending the Hepatology OPD, of a tertiary care hospital in Mumbai, India. Age, gender and clinical history of the patient were recorded. Blood specimen was tested for HBsAg (Microscreen(TM) ELISA, Span diagnostics, India) and HBsAg mutants (Hepanostika HBsAg Ultra(TM) ELISA, Biomerieux, France). The samples with discordant results between these two ELISAs were confirmed by Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Polymerase Chain Reaction (PCR) (Cobas Taqman(TM), Roche Molecular Systems, USA). RESULTS: Seven hundred and eighteen patients were enrolled in the study. The mean age of patients in the study group was 41 years (range 17 to 69 years). Four hundred and ninety seven (69.22%) were males and remaining were females. The prevalence of HBsAg was found to be 17.4%. The positivity amongst the male population was 18.1% which was higher than the female population (15.8%). Of the 718 samples tested, 120 were positive for HBsAg by Microscreen(TM) ELISA and 132 were positive by Hepanostika HBsAg ultra(TM). Of the 12 discordant samples, HBV DNA was detected in five samples indicating 0.7% prevalence of mutants. CONCLUSION: Hepatitis B is prevalent in liver disease patients. The mutant detecting assay is recommended in set-ups where missing HBsAg in patients would have tremendous impact on the outcome such as in blood donors, organ or tissue donors and antenatal screening of mothers. It is also helpful in chronic liver disease patients where the routine HBsAg detection test is negative and the other causes of chronic liver disease have been ruled out. However, it is not recommended for use in routine diagnostic set-ups where high false positivity would lead to over-diagnosis of the condition.

Focal cortical dysplasias in autism spectrum disorders.

BACKGROUND: Previous reports indicate the presence of histological abnormalities in the brains of individuals with autism spectrum disorders (ASD) suggestive of a dysplastic process. In this study we identified areas of abnormal cortical thinning within the cerebral cortex of ASD individuals and examined the same for neuronal morphometric abnormalities by using computerized image analysis. RESULTS: The study analyzed celloidin-embedded and Nissl-stained serial full coronal brain sections of 7 autistic (ADI-R diagnosed) and 7 age/sex-matched neurotypicals. Sections were scanned and manually segmented before implementing an algorithm using Laplace's equation to measure cortical width. Identified areas were then subjected to analysis for neuronal morphometry. Results of our study indicate the presence within our ASD population of circumscribed foci of diminished cortical width that varied among affected individuals both in terms of location and overall size with the frontal lobes being particularly involved. Spatial statistic indicated a reduction in size of neurons within affected areas. Granulometry confirmed the presence of smaller pyramidal cells and suggested a concomitant reduction in the total number of interneurons. CONCLUSIONS: The neuropathology is consistent with a diagnosis of focal cortical dysplasia (FCD). Results from the medical literature (e.g., heterotopias) and our own study suggest that the genesis of this cortical malformation seemingly resides in the heterochronic divisions of periventricular germinal cells. The end result is that during corticogenesis radially migrating neuroblasts (future pyramidal cells) are desynchronized in their development from those that follow a tangential route (interneurons). The possible presence of a pathological mechanism in common among different conditions expressing an autism-like phenotype argue in favor of considering ASD a "sequence" rather than a syndrome. Focal cortical dysplasias in ASD may serve to explain the high prevalence of seizures and sensory abnormalities in this patient population.

B cells from patients with Graves' disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis.

Graves' disease (GD) is an autoimmune process involving the thyroid and connective tissues in the orbit and pretibial skin. Activating anti-thyrotropin receptor Abs are responsible for hyperthyroidism in GD. However, neither these autoAbs nor the receptor they are directed against have been convincingly implicated in the connective tissue manifestations. Insulin-like growth factor-1 receptor (IGF-1R)-bearing fibroblasts overpopulate connective tissues in GD and when ligated with IgGs from these patients, express the T cell chemoattractants, IL-16, and RANTES. Disproportionately large fractions of peripheral blood T cells also express IGF-1R in patients with GD and may account, at least in part, for expansion of IGF-1R(+) memory T cells. We now report a similarly skewed B cell population exhibiting the IGF-1R(+) phenotype from the blood, orbit, and bone marrow of patients with GD. This expression profile exhibits durability in culture and is maintained or increased with CpG activation. Moreover, IGF-1R(+) B cells produce pathogenic Abs against the thyrotropin receptor. In lymphocytes from patients with GD, IGF-1 enhanced IgG production (p < 0.05) and increased B cell expansion (p < 0.02) in vitro while those from control donors failed to respond. These findings suggest a potentially important role for IGF-1R display by B lymphocytes in patients with GD in supporting their expansion and abnormal Ig production.

Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy.

Tissue remodeling associated with thyroid-associated ophthalmopathy (TAO) involves the complex interplay between resident cells (endothelium, vascular smooth muscle, extraocular muscle, and fibroblasts) and those recruited to the orbit, including members of the "professional" immune system. Inflammation early in the disease can later culminate in fibrosis and diminished extraocular muscle motility. TAO remains a poorly understood process, in large part because access to tissues early in the disease is limited and because no robust and complete animal models of Graves' disease have yet been devised. Remaining uncertainty as to the identity of a pathogenic autoantigen(s) that underlies lymphocyte trafficking to the orbit complicates matters. These limitations in our understanding of extrathyroidal Graves' disease have resulted in poorly served patients with severe TAO. Therapies have targeted symptoms rather than the underlying disease processes. Our laboratory group has focused over the last several years on defining the peculiarities of the human orbital fibroblasts as a strategy for shedding more light on the pathologies occurring in TAO. We have reasoned that unique properties of these cells might ultimately prove the basis for why the manifestations of Graves' disease occur in an anatomically selective manner. In this brief review we attempt to survey our findings. We believe that they might provide a "roadmap" for further discovery into the pathogenesis of TAO. Clearly, more questions remain than those thus far answered.