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Background: There is limited research on the racial/ethnic differences in long-term outcomes for men with untreated, localized prostate cancer., Methods: Men diagnosed with localized, Gleason ≤7 prostate cancer who were not treated within 1 year of diagnosis from 1997-2007 were identified. Cumulative incidence rates of the following events were calculated; treatment initiation, metastasis, death due to prostate cancer and all-cause mortality, accounting for competing risks. The Cox model of all-cause mortality and Fine-Gray sub distribution model to account for competing risks were used to test for racial/ethnic differences in outcomes adjusted for clinical factors., Results: There were 3925 men in the study, 749 Hispanic, 2415 non-Hispanic white, 559 non-Hispanic African American, and 202 non-Hispanic Asian/Pacific Islander (API). Median follow-up was 9.3 years. At 19 years, overall cumulative incidence of treatment, metastasis, death due to prostate cancer, and all-cause mortality was 25.0%, 14.7%, 11.7%, and 67.8%, respectively. In adjusted models compared to non-Hispanic whites, African Americans had higher rates of treatment (HR = 1.39, 95% CI = 1.15-1.68); they had an increased risk of metastasis beyond 10 years after diagnosis (HR = 4.70, 95% CI = 2.30-9.61); API and Hispanic had lower rates of all-cause mortality (HR = 0.66, 95% CI = 0.52-0.84, and HR = 0.72, 95% CI = 0.62-0.85, respectively), and API had lower rates of prostate cancer mortality in the first 10 years after diagnosis (HR = 0.29, 95% CI = 0.09-0.90) and elevated risks beyond 10 years (HR = 5.41, 95% CI = 1.39-21.11)., Conclusions: Significant risks of metastasis and prostate cancer mortality exist in untreated men beyond 10 years after diagnosis, but are not equally distributed among racial/ethnic groups., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aim: Given the immunosuppressive nature of pancreatic cancer, we investigated the relationship between epigenetic modification of immune-regulatory cytokine genes and pancreatic cancer outcomes. Materials & methods: We evaluated DNA methylation of 184 pancreatic tumor samples from The Cancer Genome Atlas for 111 CpG loci in seven cytokine genes: IL10 , IL6 , IL8 , TGFβ1 , TGFβ2 , TGFβ3 and TNF . We used Cox regression to evaluate the associations between methylation and overall survival, disease-specific survival and disease progression (α = 0.05). Results: Poorer survival was associated with increased methylation in fifteen CpG probes in TGFβ1 , TGFβ2 , TGFβ3 and TNF . We also detected improved outcomes for three loci in IL10 , IL8 and IL6 . Conclusion: Epigenetic regulation of cytokine-related gene expression may be associated with pancreatic cancer outcomes.

Background & Aims: Observational studies of predominantly white populations have found new-onset diabetes to be associated with increased risk of pancreatic cancer. We sought to determine whether this relationship applies to other races or ethnicities and to identify metabolic profiles associated with increased risk of pancreatic cancer., Methods: We conducted a population-based cohort study of Asian, black, Hispanic and white patients from Kaiser Permanente Southern California from 2006 through 2016 (n = 1,499,627). Patients with diabetes were identified based on glucose and hemoglobin A1c (HbA1c) measurements. We used Cox regression to assess the relationship between diabetes status and duration and pancreatic cancer. For patients with recent diagnoses of diabetes (1 year or less) we compared longitudinal changes in glucose, HbA1c, and weight, from time of diabetes diagnosis through 3 years prior to the diagnosis, in patients with vs without pancreatic cancer., Results: We identified 2,002 incident cases of pancreatic cancer from nearly 7.5 million person-years of follow-up. Compared to patients without diabetes, individuals who received a recent diagnosis of diabetes had an almost 7-fold increase in risk of pancreatic cancer (relative risk, 6.91; 95% CI, 5.76-8.30). Among patients with a recent diagnosis of diabetes, those who developed pancreatic cancer had more rapid increases in levels of glucose (Δslope: cases, 37.47 mg/dL vs non-cases, 27.68 mg/dL) and HbA1c (Δslope: cases, 1.39% vs non-cases, 0.86%) in the month preceding the diagnosis of diabetes, and subtle weight loss in the prior years (slope: cases -0.18 kg/interval vs non-cases 0.33 kg/interval). These longitudinal changes in markers of metabolism were stronger for specific race and ethnic groups., Conclusions: In a study of a large ethnically diverse population, we found risk of pancreatic cancer to be increased among patients with a diagnosis of diabetes in the past year among different races and ethnicities. Weight loss and rapid development of poor glycemic control were associated with increased risk of pancreatic cancer in multiple races., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

It is unknown whether the HPV vaccine is effective in immunocompromised women during catch-up ages. We performed a case-control study of 4,357 women with incident CIN2+ (cases) and 5:1 age-matched, incidence-density selected controls (N = 21,773) enrolled in an integrated health care system from 2006 to 2014. Vaccine effectiveness was estimated from multivariable conditional logistic regression models, with results stratified by immunosuppression history, defined as prior HIV infection, solid organ transplant history, or recently prescribed immunosuppressive medications. HPV vaccination resulted in a 19% reduction in CIN2+ rates for women without an immunosuppression history but a nonsignificant 4% reduction for women with an immunosuppression history. Further research is needed to evaluate whether catch-up HPV vaccine effectiveness varies by immunosuppression status, especially given the recent approval of the HPV vaccine for adults up to 45 years of age., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: We assessed the ability to supplement existing epidemiologic/etiologic studies with data on treatment and clinical outcomes by linking to publicly available cancer registry and administrative databases., Methods: Medical records were retrieved and abstracted for cases enrolled in a Los Angeles County case-control study of non-Hodgkin lymphoma (NHL). Cases were linked to the Los Angeles County cancer registry (CSP), the California state hospitalization discharge database (OSHPD), and the SEER-Medicare database. We assessed sensitivity, specificity, and positive predictive value (PPV) of cancer treatment in linked databases, compared with medical record abstraction., Results: We successfully retrieved medical records for 918 of 1,004 participating NHL cases and abstracted treatment for 698. We linked 59% of cases (96% of cases >65 years old) to SEER-Medicare and 96% to OSHPD. Chemotherapy was the most common treatment and best captured, with the highest sensitivity in SEER-Medicare (80%) and CSP (74%); combining all three data sources together increased sensitivity (92%), at reduced specificity (56%). Sensitivity for radiotherapy was moderate: 77% with aggregated data. Sensitivity of BMT was low in the CSP (42%), but high for the administrative databases, especially OSHPD (98%). Sensitivity for surgery reached 83% when considering all three datasets in aggregate, but PPV was 60%. In general, sensitivity and PPV for chronic lymphocytic leukemia/small lymphocytic lymphoma were low., Conclusions: Chemotherapy was accurately captured by all data sources. Hospitalization data yielded the highest performance values for BMTs. Performance measures for radiotherapy and surgery were moderate., Impact: Various administrative databases can supplement epidemiologic studies, depending on treatment type and NHL subtype of interest., (©2020 American Association for Cancer Research.)

Introduction: Although clinical prognostic indicators exist for follicular lymphoma(FL), patient outcomes remain heterogeneous., Material and Methods: We evaluated the association between survival and a polygenic risk score(PRS) composed of five previously identified FL susceptibility loci(rs12195582, rs13254990, rs17749561, rs4245081, rs4938573) among women who participated in a case-control study of non-Hodgkin lymphoma in Los Angeles County between 2004-2008. Risk associations were estimated through logistic regression, calculating the odds ratios(OR) and 95 % confidence intervals(95 % CI). Survival was estimated under a Cox proportional hazards model and hazard ratios(HR) and 95 % CI were calculated., Results: Among 437 non-Hispanic White controls and 100 non-Hispanic White FL patients, we confirmed a 2.6-fold increased risk of FL associated with the highest PRS tertile (95 % CI:1.35-4.86). After accounting for clinical indicators, the PRS was associated with improved overall survival in non-Hispanic women (HR:0.31; 95 % CI:0.10-0.96)., Conclusion: PRS was associated with increased risk of FL, but improved overall survival., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interests., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer screening is a complex process encompassing risk assessment, the initial screening examination, diagnostic evaluation, and treatment of cancer precursors or early cancers. Metrics that enable comparisons across different screening targets are needed. We present population-based screening metrics for breast, cervical, and colorectal cancers for nine sites participating in the Population-based Research Optimizing Screening through Personalized Regimens consortium., Methods: We describe how selected metrics map to a trans-organ conceptual model of the screening process. For each cancer type, we calculated calendar year 2013 metrics for the screen-eligible target population (breast: ages 40-74 years; cervical: ages 21-64 years; colorectal: ages 50-75 years). Metrics for screening participation, timely diagnostic evaluation, and diagnosed cancers in the screened and total populations are presented for the total eligible population and stratified by age group and cancer type., Results: The overall screening-eligible populations in 2013 were 305 568 participants for breast, 3 160 128 for cervical, and 2 363 922 for colorectal cancer screening. Being up-to-date for testing was common for all three cancer types: breast (63.5%), cervical (84.6%), and colorectal (77.5%). The percentage of abnormal screens ranged from 10.7% for breast, 4.4% for cervical, and 4.5% for colorectal cancer screening. Abnormal breast screens were followed up diagnostically in almost all (96.8%) cases, and cervical and colorectal were similar (76.2% and 76.3%, respectively). Cancer rates per 1000 screens were 5.66, 0.17, and 1.46 for breast, cervical, and colorectal cancer, respectively., Conclusions: Comprehensive assessment of metrics by the Population-based Research Optimizing Screening through Personalized Regimens consortium enabled systematic identification of screening process steps in need of improvement. We encourage widespread use of common metrics to allow interventions to be tested across cancer types and health-care settings., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Population-based cancer registries collect information on first course of treatment that may be utilized in research on cancer care quality, yet few studies have investigated the validity of this information. We examined the accuracy and completeness of registry-based treatment information in a cohort of adolescent and young adult women., Methods: Women diagnosed with breast cancer, lymphoma, thyroid cancer, cervical/uterine cancer or ovarian cancer at ages 15-39 during 2003-2014 were identified using data from the North Carolina Central Cancer Registry (CCR) (N = 2342). CCR data were linked to Medicaid and private insurance claims data, and claims were reviewed for the 12 months following diagnosis to identify cancer treatments received. Using claims data as the gold standard, we calculated the sensitivity and positive predictive value (PPV) of CCR data for receipt of chemotherapy, radiation and hormone therapy. We also compared dates of treatment initiation between the two data sources., Results: For all cancer types combined, the sensitivity of the CCR data was high for chemotherapy (86%) and moderate for radiation (74%). PPVs were 82% and 83% for chemotherapy and radiation, respectively. Both the sensitivity (67%) and PPV (70%) were lower for hormone therapy for breast cancer. For all three treatment types, dates of initiation in the registry and the claims differed by ≤30 days for most women., Conclusions: In this cohort of young women, population-based cancer registry data on chemotherapy receipt was reasonably accurate and complete in comparison with insurance claims. Radiation and hormone therapy appeared to be less complete., Competing Interests: Declarations of Competing Interest None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The 2012 national cervical cancer screening guidelines recommended cessation of screening after age 65 years in women with adequate prior screening. In this retrospective cohort study, adherence to these screening exit guidelines was examined., Methods: Women who turned age 66 years in 2012-2013 at Kaiser Permanente Southern California were followed through age 68 years for cervical cancer screening uptake. Adequacy of prior screening was assessed between age 56 and 65 years using electronic medical records. Guideline adherence was determined based on screening pattern between age 66 and 68 years. Patient- and physician-level correlates for guideline adherence were examined using multivariable logistic regression. Data collection and analyses were conducted in 2018., Results: A total of 14,778 women were included; 24% did not have adequate prior screening by age 65 years. Among those without adequate prior screening, the proportion screened after age 65 years ranged from 71% (177 of 249) in those whose most recent test was abnormal to 3% (34 of 1,330) in those who did not have any testing in 10 years. Prior screening pattern was the only factor associated with screening after age 65 years. Of those with adequate prior screening, 10% (1,135 of 11,295) continued to receive screening after age 65 years. Frequent office visits and having a male primary care physician were associated with continuing screening after age 65 years., Conclusions: A considerable proportion of women did not have adequate prior screening by age 65 years. Of these, a large proportion did not receive screening after age 65 years, except those who had a recent abnormal screening result. Further research is needed to understand barriers for guideline adherence and rationales for clinical decision making., (Copyright © 2019 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Factor that binds to the inducer of short transcripts of the human immunodeficiency virus-1 (FBI-1) represents as a crucial gene regulator in colorectal cancer; however, the correlation between FBI-1 and preoperative radiotherapy (RT) in rectal cancer (RC) has not yet been reported. The aim was to detect FBI-1 expression in patients with RC with or without RT, by immunohistochemistry and quantitative polymerase chain reaction, and to analyze its association with clinicopathological features and response to RT. The results from immunohistochemistry analysis (n=139) and reverse transcription-quantitative polymerase chain reaction (n=55) demonstrated that FBI-1 was overexpressed in patients with RC, whether they had received preoperative RT or not. Subsequently, the association between FBI-1 expression, and the clinicopathological features and response to RT in patients with RC was analyzed. Cytoplasmic FBI-1 was upregulated in non-RT (n=77) and RT (n=62) groups (17.7 vs. 74.0%, P<0.001; 41.1 vs. 69.4%, P=0.002, respectively) of patients with RC compared with normal mucosa. However, nuclear FBI-1 was downregulated (75.8 vs. 22.1%, P<0.001; 83.9 vs. 35.5%, P<0.001, respectively) in both groups. RT had no significant effect on FBI-1 expression in RC tissues. Furthermore, nuclear FBI-1 was positively associated with tumor-node-metastasis stage and distant recurrence (P=0.003 and P=0.010, respectively). In patients with stage I, II or III RC, higher nuclear FBI-1 expression was associated with poorer disease-free survival [hazard ratio (HR)=1.934, 95% confidence interval (CI): 1.055-3.579, P=0.033] and overall survival (HR=2.174, 95% CI: 1.102-4.290, P=0.025), independently of sex, age, growth pattern, differentiation and RT. In addition, FBI-1 was positively correlated with numerous biological factors, including p73 [Spearman's correlation coefficient (r s )=0.332, P=0.007], lysyl oxidase (r s =0.234, P=0.043), Wrap53 (r s =-0.425, P=0.0002) and peroxisome proliferator-activated receptor δ (r s =-0.294, P=0.026). In conclusion, the present study demonstrated that nuclear FBI-1 was an independent prognostic factor in patients with RC and correlated with numerous biological factors, which indicated that it may have multiple roles in RC., (Copyright: © Wang et al.)

Background: Hodgkin lymphoma (HL) is a leading cancer diagnosis for adolescents and young adults (AYAs), with an overall 5-year survival rate of >80%. However, to the authors' knowledge, little is known regarding posttreatment patterns of care. In the current study, the authors characterized the use of guideline-recommended services in a cohort of AYA survivors of HL in Kaiser Permanente Southern California., Methods: Patients with HL who were diagnosed between ages 15 and 39 years between 2000 and 2010 were identified. The authors calculated the number of patients who received recommended short-term care within 2 years after treatment cessation for those who remained enrolled and alive from 2001 through 2015. Use of recommended late-effects screening for breast cancer and cardiovascular disease was examined. Logistic regression was used to evaluate the association between receipt of recommended care and patient, cancer, and treatment characteristics., Results: A total of 354 patients were identified, with a mean age at the time of diagnosis of 26 years (standard deviation, 6.9 years). Approximately 12% of patients had stage I disease, 59% had stage II disease, 17% had stage III disease, and 13% of patients had stage IV disease. Nearly all patients received chemotherapy (95%), 51% received radiotherapy, and 5% received care from a pediatric oncologist. Overall, approximately 49% of patients received recommended short-term care. Of those patients eligible for cardiovascular screening at 10 years posttreatment (60 patients), 53% received at least 1 screening. Of those patients eligible for breast cancer screening (21 patients), approximately 50% underwent at least 1 screening. Regression results indicated that those patients treated by a pediatric oncologist were >3 times as likely to receive recommended short-term care., Conclusions: The results of the current study highlight gaps in the delivery of posttreatment care to AYA survivors of HL. By determining areas in need of improvement, these findings can guide the development of tailored interventions with which to improve care., (© 2019 American Cancer Society.)

Little is known about the effect of evolving risk-based cervical cancer screening and management guidelines on United States (US) clinical practice and patient outcomes. We describe the National Cancer Institute's Population-based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium, methods and baseline findings from its cervical sites: Kaiser Permanente Washington, Kaiser Permanente Northern California, Kaiser Permanente Southern California, Parkland Health & Hospital System/University of Texas Southwestern (Parkland-UTSW) and New Mexico HPV Pap Registry housed by University of New Mexico (UNM-NMHPVPR). Across these diverse healthcare settings, we collected data on human papillomavirus (HPV) vaccinations, screening tests/results, diagnostic and treatment procedures/results and cancer diagnoses on nearly 4.7 million women aged 18-89 years from 2010 to 2014. We calculated baseline (2012 for UNM-NMHPVPR; 2010 for other sites) frequencies for sociodemographics, cervical cancer risk factors and key screening process measures for each site's cohort. Healthcare delivery settings, cervical cancer screening strategy, race/ethnicity and insurance status varied among sites. The proportion of women receiving a Pap test during the baseline year was similar across sites (26.1-36.1%). Most high-risk HPV tests were performed either reflexively or as cotests, and utilization pattern varied by site. Prevalence of colposcopy or biopsy was higher at Parkland-UTSW (3.6%) than other sites (1.3-1.4%). Incident cervical cancer was rare. HPV vaccination among age-eligible women not already immunized was modest across sites (0.1-7.2%). Cervical PROSPR I makes available high-quality, multilevel, longitudinal screening process data from a large and diverse cohort of women to evaluate and improve the effectiveness of US cervical cancer screening delivery., (© 2018 UICC.)

Objectives: To compare a traditional ultrasound (US) method for estimated fetal weight (EFW) calculation and fetal growth restriction diagnosis with 2 newer methods for the prediction of small for gestational age (SGA) at birth., Methods: We reviewed deliveries at our institution from January 1, 2013, to March 31, 2017. Singleton, nonanomalous, well-dated fetuses with a US examination within 2 weeks of delivery were included. Estimated fetal weights and percentiles were calculated by a traditional method (Hadlock et al; Radiology 1991; 181:129-133) and 2 newer methods: Intergrowth-21st (INTG; Ultrasound Obstet Gynecol 2017; 49:478-486) and Salomon et al (Ultrasound Obstet Gynecol 2007; 29:550-555). We calculated each method's test characteristics to predict SGA (birth weight < 10th percentile) using both traditional (EFW < 10th percentile) and receiver operating characteristic (ROC)-derived fetal growth restriction cutoffs. Mean percentile discrepancies between EFW and birth weight measurements were calculated to compare method accuracy. We hypothesized that the INTG and Salomon methods would have superior SGA prediction compared with the Hadlock method., Results: Of 831 pregnancies with a US examination within 2 weeks of delivery, 138 (16.7%) were SGA at birth. Hadlock had the smallest US-birth weight percentile discrepancy (P < .001 versus both INTG and Salomon). When comparing ROC curves, the Hadlock and INTG methods performed comparably, with areas under the curve of 0.91 and 0.90 (P = .08) and optimal EFW cutoffs of the 15th and 22nd percentiles, respectively. The Salomon method performed less well, with an area under the curve of 0.82 (P < .001 versus both Hadlock and INTG methods)., Conclusions: In our study cohort, the Hadlock method predicted the birth weight percentile more accurately than the INTG or Salomon methods and performed comparably with INTG to predict SGA when ROC-derived cutoffs were used., (© 2018 by the American Institute of Ultrasound in Medicine.)

Background: The fetal growth standard in widest use was published by Hadlock >25 years ago and was derived from a small, homogeneous cohort. In 2015, The Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Study published updated standards that are specific to race/ethnicity. These do not allow for precise estimated fetal weight percentile calculation, however, and their effectiveness to predict neonatal morbidity and small for gestational age has not yet been compared to the long-standing Hadlock standard., Objective: We compared the ability of the Hadlock standard to predict neonatal morbidity and small for gestational age at birth with that of The Eunice Kennedy Shriver National Institute of Child Health and Human Development race-/ethnicity-specific standard. Our secondary objective was to compare their performance among our Native American population, which is not accounted for in the Eunice Kennedy Shriver National Institute of Child Health and Human Development standard., Study Design: For this retrospective study of diagnostic accuracy, we reviewed deliveries at the University of New Mexico Hospital from Jan. 1, 2013, through March 31, 2017. We included mothers with singleton, well-dated pregnancies and nonanomalous fetuses with an estimated fetal weight within 30 days of delivery. Cubic spline interpolation was performed on the Eunice Kennedy Shriver National Institute of Child Health and Human Development estimated fetal weight-percentile tables to calculate percentiles specific to the gestational day. Estimated fetal weight percentiles were then calculated using both the Hadlock and Eunice Kennedy Shriver National Institute of Child Health and Human Development race-/ethnicity-specific standards according to maternal self-identified race/ethnicity. We calculated the receiver operator area under the curve of each method to predict composite and severe composite neonatal morbidity and small for gestational age at birth (birthweight <10th percentile). As an additional measure of method accuracy, we calculated the mean ultrasound-birthweight percentile discrepancy. For Native Americans, percentiles were calculated using the Hadlock and Eunice Kennedy Shriver National Institute of Child Health and Human Development race/ethnicity standards (white, black, Hispanic, Asian), and test characteristics were calculated for each to predict neonatal morbidity and small for gestational age., Results: We included 1514 women, with a mean ultrasonography-to-delivery interval of 14.4 days (±8.8) and a small for gestational age rate of 13.6% (n = 206). For the prediction of both composite and severe composite neonatal morbidity, the Hadlock method had superior performance, with higher areas under the curve than the Eunice Kennedy Shriver National Institute of Child Health and Human Development method (P < .001 for both), though neither had good discriminatory value (all areas under the curve <0.8). For the prediction of small for gestational age at birth, the Hadlock standard had higher sensitivity (61.1%) than the Eunice Kennedy Shriver National Institute of Child Health and Human Development standard, both when using the interpolated Eunice Kennedy Shriver National Institute of Child Health and Human Development method (36.2%, P < .01) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development whole-week 10th percentile cutoff (46.7%, P < .01). The Hadlock method also had a higher area under the curve than the Eunice Kennedy Shriver National Institute of Child Health and Human Development interpolated method to predict small for gestational age (0.89 vs 0.88, P < .01). The Hadlock method had a lower ultrasound-birthweight percentile discrepancy than the Eunice Kennedy Shriver National Institute of Child Health and Human Development method (6.1 vs 16.5 percentile points, P < .01). Fetuses classified as growth restricted by Hadlock but not Eunice Kennedy Shriver National Institute of Child Health and Human Development had significantly higher composite morbidity than normally grown fetuses. Among Native American women, the Hadlock method had the highest area under the curve to predict composite and severe composite morbidity, while the Hadlock and all Eunice Kennedy Shriver National Institute of Child Health and Human Development race-/ethnicity-specific methods performed comparably to predict small for gestational age., Conclusion: Despite its publication >25 years ago, the Hadlock standard is superior to the Eunice Kennedy Shriver National Institute of Child Health and Human Development race-/ethnicity-specific standard for the prediction of both neonatal morbidity and small for gestational age., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Raltegravir became the first integrase inhibitor to gain FDA approval; but with limited evidence documenting long-term risks in real world care, especially for major health outcomes of interest., Objective: Assess raltegravir safety in clinical practice within an integrated health system., Methods: We conducted a cohort study of HIV-infected adults within Kaiser Permanente California from 2005 to 2013. We compared patients initiating raltegravir during the study period with two groups; a historical cohort (started new antiretroviral regimen [ART] 2005-2007) and a concurrent cohort that did not initiate raltegravir (2007-2013). We used multivariate Cox proportional hazard regression to obtain hazard ratios (HR) for pre-specified incident health outcomes, employing propensity scores to adjust for potential confounding., Results: The population included 8,219 HIV-infected adults (raltegravir cohort N = 1,757; 4,798 patient-years), with greater years known HIV-infected among raltegravir patients. The raltegravir cohort had increased HR for AIDS-defining (HR 2.69 [1.53-4.71]; HR 1.85 [1.21-2.82]) and non-AIDS-defining malignancies (HR 2.26 [1.29-3.94]; HR 1.88 [1.26-2.78]) relative to both comparison cohorts. Compared to the historical cohort we found no significant difference in all-cause mortality; the raltegravir cohort experienced increased HR for all-cause mortality compared to concurrent (HR 1.53 [1.02-2.31]). Raltegravir appeared protective of lipodystrophy when compared to the historical cohort but associated with increased incidence compared to concurrent. There were no significant differences in the incidence of hepatic, skin, or cardiovascular events., Conclusions: The potentially elevated risk for malignancy and mortality with raltegravir and residual confounding merits further investigation. We demonstrate the value of observational cohorts for monitoring post-licensure medication safety.

Several comorbidities have recently been shown to affect risk of chemotherapy-induced febrile neutropenia (FN). Here, we evaluated the added predictive value of these comorbidities beyond established FN risk factors. A retrospective cohort study was conducted among adult patients diagnosed with cancer and treated with chemotherapy at Kaiser Permanente Southern California between 2000 and 2009. The study cohort was equally split into training and validation datasets to develop and evaluate the performance of FN risk prediction models in the first chemotherapy cycle. A reference model was developed based on the model proposed by Lyman et al (Cancer 2011;117:1917). A new model was developed by incorporating the newly identified comorbidities such as rheumatoid conditions and thyroid disorders into the reference model. Area under the receiver operating characteristic curve (AUROCC), risk reclassification, and integrated discrimination improvement (IDI) were used to evaluate the potential improvement of FN risk prediction by incorporating comorbidities. A total of 15 279 patients were included; 4.2% experienced FN in the first chemotherapy cycle. Including comorbidities in FN risk prediction did not improve AUROCC (reference model 0.71 vs new model 0.72). A significant improvement in individual-level FN risk prediction was indicated by IDI (P = .02). However, significant improvement in risk reclassification was not observed overall (although 6% of all patients were more accurately classified for their FN risk level, 5% were less accurately classified) or when examining predicted FN risk among patients who did and did not develop FN. Incorporating several new comorbidities into FN prediction led to improved FN risk prediction in the first chemotherapy cycle, although the observed improvements were small and might not be clinically relevant., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: The Royal College of Obstetricians and Gynaecologists (RCOG) defines fetal growth restriction as ultrasound-estimated fetal weight less than the 10th percentile or abdominal circumference less than the 10th percentile; the American College of Obstetricians and Gynecologists (ACOG) defines fetal growth restriction as estimated fetal weight less than the 10th percentile alone. We compared each method's ability to predict small for gestational age (SGA) at birth., Methods: For this retrospective study of diagnostic accuracy, we reviewed deliveries at the University of New Mexico Hospital from January 1, 2013, to March 31, 2017. We included mothers with singleton, well-dated pregnancies and nonanomalous fetuses undergoing indicated fetal growth restriction surveillance with an ultrasound-estimated fetal weight within 30 days of delivery. Estimated fetal weights and percentiles were calculated using the Hadlock intrauterine growth curve. Small for gestational age was defined as birth weight less than the 10th percentile based on a recent, sex-specific curve. We calculated the area under the curve, sensitivity, specificity, and positive and negative likelihood ratios for various approaches using abdominal circumference and estimated fetal weight to diagnose fetal growth restriction, including the definitions endorsed by ACOG and RCOG., Results: We included 1,704 pregnancies with a mean ultrasonography-to-delivery interval of 14.0 days (±8.6). There were 235 SGA neonates (13.8%). The rate of fetal growth restriction was 13.6% when using ACOG's criteria and 16.9% according to RCOG's criteria (P=.007). The area under the curve of RCOG's diagnostic approach was 0.78 (95% CI 0.76-0.80), which was higher than ACOG's (0.76, 95% CI 0.74-0.78, P=.01). Sensitivities and specificities of the various methods were similar. Adopting estimated fetal weight or abdominal circumference less than the 10th percentile instead of estimated fetal weight alone to predict SGA at birth would correctly identify one additional case of SGA for each 14 patients assessed., Conclusion: The diagnostic approach endorsed by RCOG is a marginally better predictor of SGA at birth compared with the method endorsed by ACOG. Future research should consider the potential benefits and harms of the different methods in different populations.

Background: The latest 2012 US Preventive Services Task Force cervical cancer screening guidelines recommended screening initiation at age 21 years. Little is known about the cervical cancer screening initiation practices in the community and whether there are critical gaps with respect to adherence to current clinical guidelines. Despite an overall decline in cervical cancer incidence across women of all ages, the incidence rate has not declined among 24-25 year olds between 2000 (2.79 per 100,000) and 2013 (2.93 per 100,000). Thus, it is important to understand cervical cancer screening initiation in young women and how woman- and provider-level factors affect the timing of screening initiation to identify areas for improving cervical cancer prevention., Objective: We examined patterns and correlates of cervical cancer screening initiation among women turning age 21 years in a large community-based practice., Study Design: Female members of Kaiser Permanente Southern California who turned age 21 years (baseline) during 2013-2015 and had not previously received a Papanicolaou test were included. Cervical cancer screening initiation through October 2016 was captured using electronic health records. Incidence rate and cumulative incidence of screening initiation was calculated. Associations between patient and provider characteristics and screening initiation were evaluated using multivariable Cox models., Results: A total of 38,257 women were included and the Papanicolaou screening initiation rate was 44 per 100 person-years during the study period. Approximately 40% initiated screening within 1 year after turning age 21 years. In multivariable analyses, Asian/Pacific Islanders (hazard ratio, 0.91; confidence interval, 0.86-0.96 compared with non-Hispanic whites); Medicaid enrollees (hazard ratio, 0.90; confidence interval, 0.83, 0.97); those whose primary language is not English (hazard ratio, 0.71; confidence interval, 0.67, 0.75); those who have a historical inpatient visit, primary care physician in pediatrics, internal medicine, or another specialty compared with family practice; and have a male rather than female primary care physician (hazard ratio, 0.46; confidence interval, 0.36, 0.57) less often initiated screening. On the other hand, those who used other preventive services such as getting a human papilloma virus and influenza vaccination and those with a history of pregnancy, contraception use, and sexually transmitted infections more often had timely screening initiation., Conclusion: Less than half of the women insured for preventative services initiated screening at age 21 years. Strategies to improve adherence to screening initiation guidelines should consider a tailored approach for at-risk subgroups and addressing initiation challenges associated with male physicians., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Condyloma Acuminatum is a sexually transmitted viral disease caused by the human papilloma virus (HPV). It is the most common viral sexually transmitted disease. In this randomized controlled trial, cantharidin was found to be more effective and better tolerated than trichloroacetic acid for the treatment of these lesions. Patients treated with cantharidin healed with less scarring than those treated with TCA (P<0.034), had less pain during treatment (P<0.01), and required fewer treatments to eradicate warts (P<0.01) when compared to Trichloroacetic acid.

Animal and human data suggest statins may be protective against developing multiple myeloma; however, findings may be biased by the interrelationship with lipid levels. We investigated the association between statin use and risk of multiple myeloma in a large US population, with an emphasis on accounting for this potential bias. We conducted a case-control study nested within 6 US integrated healthcare systems participating in the National Cancer Institute-funded Cancer Research Network. Adults aged ≥40 years who were diagnosed with multiple myeloma from 1998-2008 were identified through cancer registries (N = 2,532). For each case, five controls were matched on age, sex, health plan, and membership duration prior to diagnosis/index date. Statin prescriptions were ascertained from electronic pharmacy records. To address potential biases related to lipid levels and medication prescribing practices, multivariable marginal structural models were used to model statin use (≥6 cumulative months) and risk of multiple myeloma, with examination of multiple latency periods. Statin use 48-72 months prior to diagnosis/index date was associated with a suggestive 20-28% reduced risk of developing multiple myeloma, compared to non-users. Recent initiation of statins was not associated with myeloma risk (risk ratio range 0.90-0.99 with 0-36 months latency). Older patients had more consistent protective associations across all latency periods (risk ratio range 0.67-0.87). Our results suggest that the association between statin use and multiple myeloma risk may vary by exposure window and age. Future research is warranted to investigate the timing of statin use in relation to myeloma diagnosis., (© 2017 UICC.)

Objective: The objective is to clarify the role of immunodeficiency and pneumonia in elevated lung cancer risk among HIV-infected individuals., Design: Cohort study of HIV-infected and HIV-uninfected adults in a large integrated healthcare system in California during 1996-2011., Methods: We used Poisson models to obtain rate ratios for lung cancer associated with HIV infection, overall and stratified by recent CD4 cells/μl (HIV-uninfected as reference group), with χ tests for trends across CD4 strata. Fully adjusted models included demographics, cancer risk factors (smoking, drug/alcohol abuse, overweight/obesity), and prior pneumonia., Results: Among 24 768 HIV-infected and 257 600 HIV-uninfected individuals, the lung cancer rate per 100 000 person-years was 66 (n = 80 events) for HIV-infected and 33 (n = 506 events) for HIV-uninfected individuals [rate ratio 2.0, 95% confidence interval (CI): 1.7-2.2]. Overall, HIV-infected individuals were at increased risk of lung cancer after adjustment for demographics and cancer risk factors (rate ratio 1.4, 95% CI: 1.1-1.7), but not after additional adjustment for pneumonia (rate ratio 1.2, 95% CI: 0.9-1.6). Lower CD4 cell counts were associated with higher risk of lung cancer in unadjusted and demographics-adjusted models (P < 0.001 for all), but this trend did not remain after adjustment for cancer risk factors and pneumonia. Compared with HIV-uninfected individuals, HIV-infected individuals with CD4 less than 200 cells/μl were not at increased risk of lung cancer in fully adjusted models., Conclusion: The increased lung cancer risk among HIV patients is attributable to differences in demographics, risk factors such as smoking, and history of pneumonia. Immunodeficiency does not appear to have an independent effect on lung cancer risk.

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10 -8 ) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment., Competing Interests: The authors declare no competing financial interests.

Background: Little is known about the care that adolescent and young adult (AYA) patients with cancer receive at the end of life (EOL)., Objective: To examine care in the last month of life among AYA patients with cancer., Design: Medical record review of the last 30 days of life., Setting/subjects: One hundred eleven AYA patients aged 15-39 years at death with either stage I-III cancer and evidence of cancer recurrence or stage IV cancer at diagnosis. Patients received care in Kaiser Permanente Southern California, an integrated healthcare delivery system, and died from 2007 to 2010., Measurements: Use of intensive measures, including chemotherapy in the last 14 days of life and emergency room visits, hospitalizations, and intensive care unit admissions in the last 30 days; documented care preferences; symptom prevalence and treatment; advance care planning; hospice use; and location of death., Results: One hundred seven patients (96%) had documented care preferences in the last month of life. At first documentation, 72% of patients wished for life-prolonging care, 20% wished for care focused on comfort, and 8% were undecided. Forty-seven percent of patients had documented changes in preferences in the last month, with 40% wishing for life-prolonging care when preferences were last noted before death, 56% preferring comfort, and 4% undecided. Seventy-eight percent of patients received at least one form of intensive EOL care, including 75% of those who preferred comfort measures at last documentation., Conclusions: Many AYA patients enter the last month of life wishing for life-prolonging care. While most ultimately wish for comfort, intensive care is prevalent even among such patients., Competing Interests: Author Disclosure Statement No competing financial interests exist.

It is unclear whether HIV-infected individuals remain at higher risk of invasive pneumococcal disease (IPD) compared with HIV-uninfected individuals. We conducted a cohort study of HIV-infected and demographically matched HIV-uninfected adults within Kaiser Permanente Northern California during the period 1996-2011. We used Poisson models to obtain rate ratios (RRs) for incident IPD associated with HIV infection and other risk factors. Among 13,079 HIV-infected and 137,643 HIV-uninfected adults, the IPD rate per 100,000 person-years was 160 (n = 109 events) for HIV-infected and 8 (n = 75 events) for HIV-uninfected subjects, with an adjusted RR of 13.0 [95% confidence interval (CI): 9.1-18.7]. For HIV-infected individuals, IPD incidence per 100,000 person-years decreased by 71% during study follow-up, from 305 in 1996-1999 to 88 in 2010-2011 (p < 0.001), with an adjusted RR of 6.6 (95% CI: 2.7-16.1) compared with HIV-uninfected subjects in 2010-2011. Risk factors for IPD among HIV-infected individuals included black compared with white race/ethnicity, smoking, cancer, and higher HIV RNA levels. The 23-valent pneumococcal polysaccharide vaccination was not associated with a reduced risk of IPD in HIV-infected or HIV-uninfected individuals. Among HIV-infected IPD cases, the most common serotype was 19A (33%), and 59% of serotypes were covered by the 13-valent pneumococcal conjugate vaccine (PCV13). Despite a dramatic decline in IPD incidence for HIV-infected adults since 1996, IPD rates were nearly sevenfold higher compared with HIV-uninfected adults in recent years, even after adjustment for risk factors. Timely antiretroviral therapy initiation, risk reduction strategies, and recent guidelines recommending PCV13 use may further reduce IPD incidence among HIV patients.

Background: It is unknown if a survival gap remains between HIV-infected and HIV-uninfected individuals with access to care., Methods: We conducted a cohort study within Kaiser Permanente California during 1996-2011, using abridged life tables to estimate the expected years of life remaining ("life expectancy") at age 20., Results: Among 24,768 HIV-infected and 257,600 HIV-uninfected individuals, there were 2229 and 4970 deaths, with mortality rates of 1827 and 326 per 100,000 person-years, respectively. In 1996-1997, life expectancies at age 20 for HIV-infected and HIV-uninfected individuals were 19.1 and 63.4 years, respectively, corresponding with a gap of 44.3 years (95% confidence interval: 38.4 to 50.2). Life expectancy at age 20 for HIV-infected individuals increased to 47.1 years in 2008 and 53.1 years by 2011, narrowing the gap to 11.8 years (8.9-14.8 years) in 2011. In 2008-2011, life expectancies at age 20 for HIV-infected individuals ranged from a low of 45.8 years for blacks and 46.0 years for those with a history of injection drug use to a high of 52.2 years for Hispanics. HIV-infected individuals who initiated antiretroviral therapy with CD4 ≥500 cells per microliter had a life expectancy at age 20 of 54.5 years in 2008-2011, narrowing the gap relative to HIV-uninfected individuals to 7.9 years (5.1-10.6 years). For these HIV-infected individuals, the gap narrowed further in subgroups with no history of hepatitis B or C infection, smoking, drug/alcohol abuse, or any of these risk factors., Conclusions: Even with early treatment and access to care, an 8-year gap in life expectancy remains for HIV-infected compared with HIV-uninfected individuals.

Background: Evidence is conflicting about the association of abacavir use and cardiovascular disease (CVD) among HIV-infected individuals. Previous studies may have been biased by the preferential initiation or continuation of abacavir in patients with renal dysfunction., Methods: We conducted a cohort study in Kaiser Permanente California during 1998-2011, following HIV-infected adults initiating antiretroviral therapy until the earliest of CVD (ie, coronary heart disease or ischemic stroke), health plan disenrollment, death, or end of study. We used inverse-probability weighting to fit marginal structural models to estimate hazard ratios (HRs) for CVD comparing regimens with and without abacavir. Propensity score models included demographics, HIV-specific factors, and CVD risk factors, including alcohol/drug use, smoking, overweight/obesity, diabetes, lipid-lowering and hypertension therapy, and renal dysfunction (ie, estimated glomerular filtration rate <60 mL·min·1.73 m)., Results: Among 8154 subjects, 178 had ≥1 CVD event, with 24/704 (3.4%) in the abacavir group and 154/7450 (2.1%) in the group initiating regimens without abacavir. Abacavir users had more renal dysfunction at antiretroviral therapy initiation (7.0% vs. 3.3%, P < 0.001). Compared with patients initiating regimens without abacavir, abacavir users had a 2.2-fold higher risk of CVD in intention-to-treat analysis [HR 2.2, 95% confidence interval (CI): 1.4 to 3.5], a 2.7-fold higher risk when remaining on their initial regimens for ≥1 year (HR 2.7, 95% CI: 1.5 to 5.0), and a 2.1-fold higher risk in per-protocol analysis (HR 2.1, 95% CI: 0.9 to 5.0)., Conclusions: Abacavir was associated with an over 2-fold increased risk of CVD, which was not explained by renal dysfunction or other CVD risk factors.

Objectives: We examined the trends and correlates of quadrivalent human papillomavirus vaccine (HPV4) initiation in insured boys during the periods before and after routine use recommendation., Methods: We grouped data from electronic medical records of boys aged 9 to 17 years from the Kaiser Permanente Southern California prepaid health plan into 3 open cohorts: permissive use: 2009 to 2010; anal cancer indication added: 2010 to 2011; and routine use: 2011 to 2013. We estimated adjusted risk ratios (ARRs) between demographics and vaccination initiation using Poisson regression., Results: HPV4 initiation increased across cohorts--1.6%, 3.4%, and 18.5%--with the greatest increase among boys aged 11 to 12 years in cohort 3. Initiation was associated with receiving influenza vaccination in the previous year in all cohorts (cohort 3: ARR = 1.48; 95% confidence interval [CI] = 1.46, 1.51) and with non-White race/ethnicity following routine recommendation (cohort 3, non-Hispanic Black: ARR = 1.18; 95% CI = 1.08, 1.30; Hispanic: ARR = 1.23; 95% CI = 1.17, 1.29; Asian/Pacific Islanders: ARR = 1.16; 95% CI = 1.11, 1.20)., Conclusions: Routine use recommendation increased the uptake of HPV4 in boys. System-level interventions to encourage providers to routinely recommend HPV4 vaccination may help increase HPV4 uptake in boys.

Background: In observational vaccine safety studies, diagnosis codes assigned prior to or on the day of vaccination (Day 0) are often excluded from analysis of safety signals since they usually represent pre-existing conditions. The limitations of this approach have been described for autoimmune conditions but not for other chronic conditions. We draw on our experience in a post-licensure quadrivalent human papillomavirus vaccine (HPV4) safety study to examine the effectiveness of exclusion of pre-existing and Day 0 diagnoses of type 2 diabetes mellitus (T2DM) in excluding prevalent T2DM., Methods: Subjects included all 117,402 females ages 9-26 years who received HPV4 August 2006-March 2008 in Kaiser Permanente Southern California. We identified potential incident T2DM cases using ICD9 code 250.xx associated with inpatient and emergency room visits during the 60 days following each HPV4 dose, excluding those with this code prior to their first HPV4 dose. Electronic medical records were reviewed to determine the dates of symptom onset, diagnostic labs, vaccine administration and T2DM diagnosis., Results: Of 33 potential incident T2DM cases identified using automated data, 4 (12%) were confirmed to have new onset T2DM after medical record review. Nineteen cases were excluded that did not have T2DM or had T2DM diagnosed before Day 0; nine had an abnormal fasting blood sugar (FBS) ordered on Day 0, prompting subsequent evaluation and diagnosis of T2DM; and one had elevated FBS and glucosuria prior to the first dose of HPV4 but T2DM diagnosed at a visit following vaccination., Conclusion: These results suggest that among adolescents and young adults, the workup and subsequent diagnosis of pre-existing conditions may result from a visit at which a vaccination is administered. This "unmasking" phenomenon is not entirely eliminated by exclusion of pre-existing and Day 0 diagnoses. Medical record review should be considered in the evaluation of potential safety signals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Importance: Cancer is the leading disease-related cause of death among adolescents and young adults (AYAs), but little is known about the care that AYA patients with cancer receive at the end of life (EOL)., Objective: To evaluate the intensity of EOL care among AYA patients with cancer., Design, Setting, and Participants: Cross-sectional study of Kaiser Permanente Southern California (KSPC) cancer registry data and electronic health records for 663 AYA patients with either stage I to III cancer and evidence of cancer recurrence or stage IV cancer at diagnosis. All patients were treated within KSPC, an integrated health care delivery system, and died between 2001 and 2010 before age 40 years (age range at time of death, 15-39 years)., Main Outcomes and Measures: (1) Chemotherapy use in the last 14 days of life; (2) intensive care unit (ICU) care in the last 30 days of life; (3) more than 1 emergency department (ED) visit in the last 30 days of life; (4) hospitalization in the last 30 days of life; and (5) a composite measure of medically intensive EOL care including any of the aforementioned measures., Results: Eleven percent of patients (72 of 663) received chemotherapy within 14 days of death. In the last 30 days of life, 22% of patients (144 of 663) were admitted to the ICU; 22% (147 of 663) had more than 1 ED visit; and 62% (413 of 663) were hospitalized. Overall, 68% of patients (449 of 663) received at least 1 medically intensive EOL care measure., Conclusions and Relevance: Most AYA patients received at least 1 form of medically intensive EOL care. These findings suggest the need to better understand EOL care preferences and decision making in this young population.

Unlabelled: A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004)., Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations., (©2015 American Association for Cancer Research.)

Hepatitis C virus (HCV) co-infection and biological sex may each affect response to antiretroviral therapy (ART), yet no studies have examined HIV-associated outcomes by both HCV status and sex. We conducted a cohort study of HIV-infected adults initiating ART in Kaiser Permanente California during 1996-2011. We used piecewise linear regression to assess CD4 changes by sex and HCV status over 5 years. We used Cox regression to estimate hazard ratios (HR) by sex and HCV status for HIV RNA <500 copies/mL over 1 year, and for AIDS and death over the follow-up period. Among 12,865 subjects, there were 154 HIV/HCV-co-infected women, 1000 HIV/HCV-co-infected men, 1088 HIV-mono-infected women, and 10,623 HIV-mono-infected men. CD4 increases were slower in the first year for HIV/HCV-co-infected women (75 cells/μL) and men (70 cells/μL) compared with HIV-mono-infected women (145 cells/μL) and men (120 cells/μL; p<0.001). After 5 years, women had higher CD4 than men in both HIV-mono-infected (598 vs. 562 cells/μL, p=0.003) and HIV/HCV-co-infected individuals (567 vs. 509 cells/μL, p=0.003). Regardless of sex, HIV/HCV co-infection was associated with 40% higher mortality [95% confidence interval (CI): 1.2-1.6] compared with HIV mono-infection, but was not associated with AIDS (HR 1.1, 95% CI: 0.9-1.3) or achieving HIV RNA <500 copies/mL (HR 1.0, 95% CI: 0.9-1.1). HIV/HCV-co-infected men and women have slower CD4 recovery after starting ART and have increased mortality compared with HIV-mono-infected men and women. HCV should be aggressively treated in HIV/HCV-co-infected adults, regardless of sex.

Concerns remain for an increased myocardial infarction (MI) risk among individuals infected with human immunodeficiency virus (HIV). We conducted a cohort study evaluating MI risk from 1996 to 2011 by HIV status. The adjusted MI rate ratio for HIV status declined over time, reaching 1.0 (95% confidence interval, .7-1.4) in 2010-2011, the most recent study period., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine the association of HIV infection and immunodeficiency with incidence of ischemic stroke., Design: Cohort study of HIV-positive and matched HIV-negative adult Kaiser Permanente Northern and Southern California (KPNC and KPSC, respectively) members during 1996-2011 (KPNC) or 2000-2011 (KPSC)., Methods: We used Poisson models to obtain rate ratios for incident ischemic stroke associated with HIV infection, both overall and stratified by CD4 cell counts (cells/μl) and HIV RNA copies (copies/ml), with HIV-negative individuals as the reference group. We also obtained rate ratios for risk factors in the HIV-positive subset., Results: Among 24,768 HIV-positive and 257,600 HIV-negative individuals, the ischemic stroke rate per 100,000 person-years was 125 (n = 151 events) for HIV-positive and 74 (n = 1128 events) for HIV-negative individuals, with an adjusted rate ratio of 1.4 [95% confidence interval (CI) 1.2-1.7). Compared with HIV-negative individuals, HIV-positive individuals with recent CD4 cell counts of 500 cells/μl at least (rate ratio 1.0, 95% CI 0.8-1.4) or recent HIV RNA less than 500 copies/ml (rate ratio 1.1, 95% CI 0.9-1.4) had no excess risk of ischemic stroke, with similar results for HIV-positive individuals with nadir CD4 cell counts of 500 cells/μl at least (rate ratio 1.4, 95% CI 0.8-2.2) or 200-499 cells/μl (rate ratio 1.2, 95% CI 0.9-1.5). Among HIV-positive individuals only, recent CD4 cell count less than 200 cells/μl (rate ratio 2.5, 95% CI 1.3-4.6) was associated with an increased risk of ischemic stroke after adjustment for recent HIV RNA and nadir CD4 cell count, whereas recent HIV RNA and nadir CD4 were not independent risk factors., Conclusion: Ischemic stroke incidence in HIV-positive individuals with high CD4 cell count or low HIV RNA is similar to that of HIV-negative individuals.

Background: We investigated whether the reported lower incidence of prostate cancer in HIV-positive men is a result of confounding factors or reduced screening., Methods: We conducted a cohort study of 17,424 HIV-positive and 182,799 HIV-negative men enrolled in Kaiser Permanente (KP). Subjects were followed from the first KP enrollment after January 01, 1996 for KP Northern California (KPNC) and January 01, 2000 for KP Southern California until the earliest of prostate cancer diagnosis, loss to follow-up, or December 31, 2007. Poisson regression was used to compare cancer rates by HIV status adjusting for age, race, smoking, alcohol/drug abuse, overweight/obesity, and diabetes. For the KPNC subset, we analyzed additional available data by HIV status on testosterone deficiency, and on prostate-specific antigen (PSA) tests as a proxy for cancer screening., Results: The prostate cancer incidence rate was 102/100,000 person-years in HIV-positive men (n = 74 cases) and 131/100,000 person-years in HIV-negative men (n = 1195 cases), with an adjusted rate ratio of 0.73 (95% confidence interval: 0.57 to 0.92; P = 0.008). The reduced risk among HIV-positive men was greater for higher-stage cancers, which are less likely to be biased by screening differences than lower-stage cancers. In the KPNC subset, more HIV-positive (90.8%) than HIV-negative men (86.2%) received a PSA test by age 55 (P < 0.001). Decreased risk for HIV-positive men remained when examined only among those with a previous PSA test, and with adjustment for testosterone deficiency (rate ratio = 0.55; 95% confidence interval: 0.39 to 0.80; P = 0.001)., Conclusions: Prostate cancer incidence rates are lower in HIV-positive compared with HIV-negative men, which is not explained by screening differences or the risk factors evaluated.

Background: We sought to clarify the association of HIV infection and immunodeficiency on myocardial infarction (MI) risk., Methods: We conducted a cohort study from 1996 to 2009 of HIV-positive (HIV) and demographically matched HIV-negative (HIV) Kaiser Permanente California health plan members. Rate ratios (RRs) were obtained from Poisson regression models comparing MI incidence rates between HIV (overall and stratified by recent and nadir CD4 count, and recent HIV RNA levels) and HIV subjects, adjusting for age, sex, calendar era, race/ethnicity, census-based socioeconomic status, smoking, alcohol/drug abuse, overweight/obesity, diabetes, hypertension, and lipid-lowering therapy. Among HIV subjects, we also evaluated the independent association of CD4, HIV RNA, and antiretroviral therapy (ART) use., Results: The study population included 22,081 HIV and 230,069 HIV subjects. The crude MI incidence rate per 100,000 person-years was 283 and 165 for HIV and HIV subjects, respectively, with an adjusted RR of 1.4 [95% confidence interval (CI): 1.3 to 1.6]. Compared with HIV subjects (reference), MI rates were similar for HIV subjects with recent CD4 ≥500 cells per microliter (RR = 1.18; 95% CI: 0.96 to 1.45) and those with nadir CD4 ≥500 cells per microliter (RR = 0.85; 95% CI: 0.55 to 1.33). Among HIV subjects, nadir CD4 was the only HIV-specific factor associated with MIs (RR per 100 cells = 0.88; 95% CI: 0.81 to 0.96), whereas recent CD4 and HIV RNA, prior ART use, and duration of protease inhibitors and nonnucleoside reverse transcriptase inhibitors were not associated with MIs., Conclusion: HIV subjects with recent or nadir CD4 ≥500 cells per microliter had similar MI rates compared with HIV subjects. Lower nadir CD4, in particular, seems to be independently associated with MIs. These results strengthen recommendations for earlier ART initiation.

The accuracy of smoking history documentation in the electronic medical records was examined at a large managed care organization among 36,494 male members who self-reported smoking history in mailed surveys. The sensitivity of electronic smoking history documentation for ever-smoking status was 0.19 in years 2003-2005 (using ICD-9/CPT code only), 0.80 in 2006-2008 and 0.84 in 2009-2010 (combination of ICD-9/CPT codes and risk factor module used after 2006). The positive predictive value was 0.96, 0.90, and 0.95 in these periods, respectively. Among self-reported ever-smokers, increased healthcare utilization and smoking intensity/duration were associated with higher likelihood of having electronic smoking history documentation, while Asian race and Spanish language preference were associated with lower likelihood. These data suggest that enhanced efforts may be needed to screen for and document smoking among racial/ethnic minorities.

Objective: To determine whether the rate of change in total serum prostate-specific antigen (PSA) levels accurately detects prostate cancer and to evaluate whether it adds any predictive value to a single measurement of serum PSA alone, in general practice settings., Materials and Methods: A retrospective cohort of 219,388 community-dwelling men, aged ≥45 years, enrolled in the Kaiser Permanente Southern California health plan, with no history of prostate cancer and at least three PSA measurements, were followed from 1 January 1998 to 31 December 2007, for the development of biopsy-confirmed prostate cancer. Annual percent changes in total serum PSA levels were estimated using linear mixed models. The accuracy of prostate cancer prediction was assessed for prostate cancer overall and for aggressive disease (Gleason score ≥7) and compared with that of a single measure of PSA level using area under the receiver-operating characteristic curves (AUCs)., Results: The men in this cohort experienced a mean change of 2.9% in PSA levels per year and the rate of change in PSA increased modestly with age (P ≤ 0.001). Annual percent changes in PSA accurately predicted the presence of prostate cancer (AUC = 0.963) and aggressive disease (AUC = 0.955) and had more predictive accuracy for aggressive disease than did a single measurement of PSA alone (AUC = 0.727)., Conclusions: Longitudinal measures of PSA improve the accuracy of aggressive prostate cancer detection when compared with a single measurement of PSA alone. Findings from this study provide insight into the usefulness of PSA velocity as a detection marker for aggressive prostate cancer., (© 2013 BJU International.)

Objective: Significant limitations exist in the timely and complete identification of primary and recurrent cancers for clinical and epidemiologic research. A SAS-based coding, extraction, and nomenclature tool (SCENT) was developed to address this problem., Materials and Methods: SCENT employs hierarchical classification rules to identify and extract information from electronic pathology reports. Reports are analyzed and coded using a dictionary of clinical concepts and associated SNOMED codes. To assess the accuracy of SCENT, validation was conducted using manual review of pathology reports from a random sample of 400 breast and 400 prostate cancer patients diagnosed at Kaiser Permanente Southern California. Trained abstractors classified the malignancy status of each report., Results: Classifications of SCENT were highly concordant with those of abstractors, achieving κ of 0.96 and 0.95 in the breast and prostate cancer groups, respectively. SCENT identified 51 of 54 new primary and 60 of 61 recurrent cancer cases across both groups, with only three false positives in 792 true benign cases. Measures of sensitivity, specificity, positive predictive value, and negative predictive value exceeded 94% in both cancer groups., Discussion: Favorable validation results suggest that SCENT can be used to identify, extract, and code information from pathology report text. Consequently, SCENT has wide applicability in research and clinical care. Further assessment will be needed to validate performance with other clinical text sources, particularly those with greater linguistic variability., Conclusion: SCENT is proof of concept for SAS-based natural language processing applications that can be easily shared between institutions and used to support clinical and epidemiologic research.

Background: Limited data exists regarding the effect of chronic HIV infection on the liver. We sought to characterize the hepatic risks of HIV infection, immunodeficiency, and cumulative use of antiretroviral therapy (ART)., Methods: Adult HIV infected and 10:1 age-matched and sex-matched HIV-uninfected individuals were followed for incident hepatic dysfunction or hepatic dysfunction-related death. Multivariable Poisson regression models were used to obtain incident rate ratios, adjusting for multiple hepatic risk factors including alcohol/drug abuse, hepatitis B and C, and diabetes., Results: We identified 20,775 HIV-infected and 215,158 HIV-uninfected individuals. HIV-infected individuals had a significantly greater overall risk compared with HIV-uninfected individuals of both hepatic dysfunction and hepatic dysfunction-related death. The highest risk was seen in patients with low CD4 cell counts not on ART [adjusted rate ratio of hepatic dysfunction-related death 59.4; (95% confidence interval: 39.3 to 89.7), P < 0.001; hepatic dysfunction, adjusted rate ratio 15.7 (95% confidence interval: 11.4 to 21.6), P < 0.001]. In an HIV-infected only model, factors that increased risk included low CD4 cell count, high HIV RNA level, alcohol/drug abuse, hepatitis B or C coinfection, and diabetes. Longer cumulative exposure to ART did not increase risk, regardless of therapy class., Conclusions: HIV-infected individuals have a higher risk of hepatic dysfunction and hepatic dysfunction-related death compared with HIV-uninfected individuals, even with adjustment for known hepatic risk factors. Hepatic outcomes were associated with lower CD4+ T-cell counts but not with longer cumulative ART exposure. These findings provide indirect evidence supporting early use of ART to reduce the risk for hepatic-related complications.

Our recent experience in a post-licensure safety study of autoimmune conditions following the quadrivalent human papillomavirus vaccine in 189,629 girls and young women ages 9-26 years led us to question the adequacy of the exclusion of Day 0 events to prevent the erroneous association of prevalent conditions with vaccination. Of the 18 confirmed cases of Graves' disease diagnosed in days 1-60 following vaccination, only 6 cases appeared to be truly new onset. Among the remaining 12 cases, 2 cases had abnormal thyroid stimulating hormone or thyroxine labs drawn prior to or on Day 0 but had no documented pre-existing symptoms. The other 10 cases had mention of symptoms of hyperthyroidism referencing a period prior to first HPV-4 dose. This 'unmasking' phenomenon, due to health care visits that include vaccination and new workups of preexisting symptoms, may not be adequately controlled through the exclusion of Day 0 events., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Data from the memberships of large, integrated health care systems can be valuable for clinical, epidemiologic, and health services research, but a potential selection bias may threaten the inference to the population of interest., Methods: We reviewed administrative records of members of Kaiser Permanente Southern California (KPSC) in 2000 and 2010, and we compared their sociodemographic characteristics with those of the underlying population in the coverage area on the basis of US Census Bureau data., Results: We identified 3,328,579 KPSC members in 2000 and 3,357,959 KPSC members in 2010, representing approximately 16% of the population in the coverage area. The distribution of sex and age of KPSC members appeared to be similar to the census reference population in 2000 and 2010 except with a slightly higher proportion of 40 to 64 year olds. The proportion of Hispanics/Latinos was comparable between KPSC and the census reference population (37.5% vs 38.2%, respectively, in 2000 and 45.2% vs 43.3% in 2010). However, KPSC members included more blacks (14.9% vs 7.0% in 2000 and 10.8% vs 6.5% in 2010). Neighborhood educational levels and neighborhood household incomes were generally similar between KPSC members and the census reference population, but with a marginal underrepresentation of individuals with extremely low income and high education., Conclusions: The membership of KPSC reflects the socioeconomic diversity of the Southern California census population, suggesting that findings from this setting may provide valid inference for clinical, epidemiologic, and health services research.

Background: Previous studies of varicella-zoster virus reactivation in children have provided little information on potential risk factors. The aim of this study was to investigate the effects of race, chronic medical conditions and treatments, and recent vaccination, on the risk of herpes zoster (HZ) in children vaccinated with one dose of varicella vaccine., Methods: Case subjects were identified from a cohort of subjects who were members of the Southern California Kaiser Permanente Health Plan and received primary immunization with a single-antigen live varicella vaccine at age < or = 12 years from 2002 to 2008. Control subjects free of HZ during the study period were matched at a 5:1 ratio to each case subject on date of birth and sex. Race information was obtained from membership files, health records, and phone interview. Immunization history, medical history, and health care utilization were identified from Southern California Kaiser Permanente Health Plan electronic records., Results: During this time, 122 children were diagnosed with HZ. With adjustment for the number of hospitalizations, outpatient visits, and length of time between vaccination with varicella vaccine and the onset of HZ, Black children were at lower risk of developing HZ than were White (OR=0.41, 95% CI=0.17-0.98) and Asian children (OR=0.30, 95% CI=0.11-0.84)., Conclusions: These data suggest that the racial differences in the risk of developing HZ seen in adults are manifest in children as well. As children are not subject to the majority of factors hypothesized to underlie HZ in adults and as this study was conducted in a setting which affords equal access to health care, it is possible that genetic variation may explain some portion of varicella-zoster virus reactivation.

Background: In adult rats, N-methyl-D-aspartate (NMDA) receptors have been implicated in the central control of body fluid homeostasis, as intracerebroventricular (ICV) injection of NMDA receptor antagonists suppresses stimulated drinking behavior. Fetal swallowing occurs at a significantly higher rate as compared to adult drinking, contributing to amniotic fluid volume regulation and fetal gastrointestinal development. The aim of present study was to determine the role of central NMDA receptors in the modulation of fetal swallowing activity., Methods: Eight time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and ICV catheters, electrocorticogram (ECoG), and esophageal electromyogram electrodes and studied at 130 +/- 1 days' gestation. Following an initial 2-hour baseline period (time 2 h), the NMDA receptor antagonist, dizocipline (1 mg), was injected ICV. At time 4 h, the dose of dizocipline was repeated, together with angiotensin II (AngII, 6.4 microg). Fetal swallowing was monitored for 2 hours after each injection. Four of these fetuses also received an identical control study (on an alternate day) in which dizocipline was replaced with artificial cerebrospinal fluid (aCSF)., Results: ICV dizocipline injection nearly abolished spontaneous fetal swallowing activities (0.6 +/- 0.1 to 0.2 +/- 0.1 swallows/min; P < .001). ICV AngII in the presence of dizocipline did not demonstrate a dipsogenic effect on fetal swallowing (0.1 +/- 0.1; P < .001). In the control study, ICV injection of aCSF did not change fetal swallowing activity (1.0 +/- 0.1 swallows/min), while ICV AngII resulted in a significant increase in fetal swallowing (2.0 +/- 0.1 swallows/min; P < .001)., Conclusions: This study demonstrates that central NMDA-glutamate receptor-mediated activity contributes to the high rate of spontaneous and AngII-stimulated fetal swallowing. We speculate that reduced NMDA receptor expression within the forebrain dipsogenic neurons may account for observed differences in drinking activities between the fetus/neonate and the adult.

The purpose of this study was to examine cardiovascular responses to fourth cerebral ventricle (4V) administration of nitroglycerin (NTG) or an inhibitor of nitric oxide (NO) synthase (NOS) in the near-term ovine and to determine whether, during birth, neuronal NOS (nNOS) is induced in noradrenergic A1 neurons in the medial nucleus tractus solitarius (mNTS). In chronically instrumented fetal sheep, 4V injection of NTG (1.2 nmol), an NO donor, produced an arterial blood depressor and a moderate decrease in heart rate. Arterial blood pressure is increased by 4V administration of NG-nitro-L-arginine methyl ester (10 nmnol), an inhibitor of NOS, in fetuses. Sections of the medulla from fetuses and newborn lambs were examined by using immunolabeling with tyrosine hydroxylase (TH) antibody combined with NADPH diaphorase (NADPHd) histochemistry, a marker of nNOS activity. The NADPHd-positive cells and TH-positive cells containing NADPHd reactivity were significantly increased in the mNTS of newborns compared with the fetuses. The results suggest that during birth, there is upregulation of NADPHd/nNOS in the noradrenergic neurons of mNTS resulting in a centrally mediated reduction of fetal arterial blood pressure.

Spontaneous fetal swallowing occurs at a markedly higher rate compared with spontaneous adult drinking activity. This high rate of fetal swallowing is critical for amniotic fluid volume regulation. Central NO is critical for maintaining the normal rate of fetal swallowing, as nonselective inhibition of NO (with central N(G)-nitro-L-arginine methyl ester) suppresses spontaneous and angiotensin II (ANG II)-stimulated swallowing. We sought to differentiate the contributions of central endothelial vs. neuronal NO in the regulation of spontaneous and stimulated fetal swallowing, using a selective neuronal NO synthase (nNOS) inhibitor. Six time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and intracerebroventricular (i.c.v.) catheters and electrocorticogram (ECoG) and esophageal electromyogram electrodes and studied at 130 +/- 1 days of gestation. After an initial 2-h baseline period (0-2 h), the selective nNOS inhibitor N-propyl-L-arginine (NPLA) was injected i.c.v. (2-4 h). At 4 h, the dose of NPLA was repeated, together with ANG II, and fetal swallowing was monitored for a final 2 h. Four fetuses also received an identical control study (on an alternate day) in which NPLA was replaced with artificial cerebrospinal fluid (aCSF). Suppression of nNOS by i.c.v. NPLA significantly reduced mean (+/- SE) spontaneous fetal swallowing (1.35 +/- 0.12 to 0.50 +/- 0.07 swallows/min; P < 0.001). Injection of ANG II in the presence of NPLA had no dipsogenic effect on fetal swallowing (0.68 +/- 0.09 swallows/min). In the aCSF study, i.c.v. aCSF did not change fetal swallowing (0.93 +/- 0.10 vs. 0.95 +/- 0.09 swallows/min), whereas i.c.v. ANG II resulted in a significant increase in the rate of fetal swallowing (2.0 +/- 0.04 swallows/min; P = 0.001). We speculate that the suppressive dipsogenic effects of central NPLA indicate that spontaneous and ANG II- stimulated fetal swallowing is dependent on central nNOS activity.

Objective: Intravenous magnesium sulfate is widely used in obstetrics for the treatment of both preterm labor and preeclampsia. Although therapeutic levels of total magnesium have been proposed, the levels remain controversial. Because the active form of magnesium is the free or ionized form, it is essential to determine whether ionized magnesium and total magnesium levels are highly correlated in vivo. We sought to examine the correlation between ionized magnesium and total magnesium under basal and therapeutic conditions and to define the initiation and elimination pharmacokinetics of both forms during intravenous magnesium sulfate infusion., Study Design: Twenty-four singleton pregnant patients who were candidates for magnesium sulfate were studied (preterm labor, 15; preeclampsia, 9). Serial blood samples were taken before the magnesium sulfate infusion, during the first 4 hours after the initiation of magnesium sulfate infusion and for 4 hours after the discontinuation of the infusion., Results: Baseline levels of total magnesium and ionized magnesium were not different between patients with preterm labor and with preeclampsia. Among patients with preeclampsia, although not patients with preterm labor, the initial apparent volume of distribution was significantly smaller for total magnesium than for ionized magnesium (16,397 +/- 1441 vs 23,856 +/- 2745 mL, respectively; P =.03), and the elimination half-life was greater for total magnesium as compared to ionized magnesium (707 +/- 160 vs 313 +/- 29 minutes;P <.05). Linear regression analysis demonstrated a lack of correlation between ionized magnesium and total magnesium during the pretreatment period and during the steady state infusion for both preterm labor and preeclampsia., Conclusion: The measurement of total magnesium may not be adequate for the titration of therapeutic magnesium infusions in patients with preeclampsia or preterm labor because of the lack of correlation between total magnesium and the physiologically active ionized magnesium. Further studies may determine whether the measurement of ionized magnesium is a superior method for following the adequacy and safety of the treatment of preeclampsia and preterm labor.

Objective: This study was designed to compare the values of blood gases in local scalp blood, obtained by scalp blood sampling, with direct measurements of fetal preductal arterial blood in fetal sheep., Methods: Six fetal lambs were catheterized in the brachial artery and vein. Maternal oxygenation was reduced in steps from a fractional inspired oxygen concentration (FiO2) of 20 to 5% by addition of nitrogen to the inhaled gas mixture. Fetal scalp and arterial blood were sampled simultaneously at maternal FiO2 step intervals after maternal FiO2 and oxygen were stable for > 5 min. Blood pH, pO2 and oxygen saturation were measured and linear regression was performed to determine the correlation between these values., Results: Scalp pH correlated well with arterial pH, whereas scalp pO2, pCO2 and oxygen saturation did not. However, when a secondary analysis was performed taking into account the effects of aerobic contamination, scalp pCO2, pO2 and oxygen saturation became highly correlated with arterial values., Conclusions: Local scalp blood oxygen saturation correlates highly with fetal preductal arterial values, when physiological artifacts are eliminated. The technique of scalp blood sampling introduces error into oxygenation saturation measurements, owing to difficulties in anaerobic sample collection. These results suggest that continuous measurement of fetal scalp oxygenation by noninvasive oximetry may be superior to direct sampling of scalp blood.

Objective: Fetal plasma angiotensin II levels are 10 times the levels found in adults. Despite these high levels, central injection of angiotensin II may stimulate fetal swallowing and increase fetal arterial blood pressure. We postulated that the high rate of spontaneous fetal swallowing and normal fetal pressor regulation may be dependent, in part, on central angiotensin II. In view of the potential dipsogenic role of both type 1 and type 2 angiotensin II receptors, we examined the central effect of the nonselective angiotensin II receptor antagonist saralasin on fetal swallowing and cardiovascular responses., Study Design: Six time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and intracerebroventricular catheters, electrocorticograms, and esophageal electromyogram electrodes and studied at 130 +/- 1 days' gestation. After an initial 2-hour baseline period (0 to 2 hours), saralasin (1 mL, 64 microg) was injected intracerebroventricularly (2 to 4 hours). After 4 hours the dose of saralasin was repeated together with angiotensin II (1 mL, 6.4 microg), and the fetuses were monitored for a final 2 hours. Four fetuses also underwent an identical control study (on an alternate day) in which saralasin was replaced with artificial cerebrospinal fluid., Results: Blockade of central angiotensin II receptors by intracerebroventricular saralasin significantly reduced mean (+/- SEM) spontaneous fetal swallowing (1.3 +/- 0.1 to 0.4 +/- 0.1 swallows per minute; P <.001) but did not alter fetal mean blood pressure (50 +/- 5 versus 56 +/- 5 mm Hg). Intracerebroventricular angiotensin II, in the presence of saralasin, did not affect swallowing (0.6 +/- 0.1 swallows per minute) or fetal blood pressure. In the control study, intracerebroventricular artificial cerebrospinal fluid did not change fetal swallowing (0.9 +/- 0.1 versus 1.0 +/- 0.1 swallows per minute), whereas intracerebroventricular angiotensin II significantly increased swallowing activity (1.0 +/- 0.1 versus 2.0 +/- 0.1 swallows per minute; P <.001) and fetal blood pressure (51 +/- 2 to 59 +/- 3 mm Hg; P =.003)., Conclusions: Tonic activity of central angiotensin II receptor stimulation contributed to the high rate of basal ovine fetal swallowing but not fetal basal blood pressure. Angiotensin II-mediated fetal dipsogenic and pressor responses are a result of specific angiotensin II receptor binding in central brain regions. These results indicate that fetal exposure to angiotensin II antagonists or angiotensin-converting enzyme inhibitors may have adverse effects on fetal and amniotic fluid homeostasis.

Background: We compared outcomes between neonates receiving either single course, multiple courses, or no antenatal glucocorticoid exposure., Methods: We retrospectively identified neonates whose mothers received a single course (SIN) of dexamethasone, multiple (2-3) weekly courses (MULT), or no (NO) glucocorticoids. Multiple gestations and infants with chromosomal abnormalities or not receiving a full course of antenatal dexamethasone were excluded from the study. The incidences of the following outcomes were examined: respiratory distress syndrome (RDS), Grades III or IV intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis, and in-hospital death. Means were compared with analysis of variance and outcome variable frequencies with chi-square test., Results: A total of 147 infants were included in the analysis. There were no differences in the gestational age or growth parameters among the groups. As anticipated, infants exposed to antenatal glucocorticoids had a significantly lower incidence of morbidities (BPD, NEC, and IVH) than the unexposed infants. There were no differences in the incidence of RDS, IVH, BPD, NEC, ROP, PDA, sepsis, or death between the SIN and MULT groups., Conclusion: A single course of antenatal glucocorticoid therapy is associated with improved neonatal outcomes in infants less than 30 weeks' gestation. Multiple courses were not shown to confer additional benefits, but further investigation is required to definitively address the need for weekly treatment.

Objective: Human and ovine fetuses demonstrate an enhanced rate of spontaneous and angiotensin II-stimulated swallowing. Angiotensin II and nitric oxide synthase have been localized to thirst centers in the brain. This study was performed to determine whether central nitric oxide contributes to the regulation of angiotensin II-induced fetal swallowing., Study Design: Six pregnant ewes with near-term singleton fetuses were chronically prepared with fetal vascular and lateral ventricle catheters and electrocorticogram and esophageal electromyogram electrodes. After a 2-hour control period, fetuses were administered serial lateral ventricle injections (1 mL) of angiotensin II (3.2 microg; time, 2 hours) and N omega-nitro-L -arginine methyl ester (3 mg; time, 3 hours) and a repeat angiotensin II injection (3.2 microg; time, 5 hours). All fetuses received an additional control study of lateral ventricle injections of artificial cerebrospinal fluid on a previous day., Results: Angiotensin II injection significantly increased mean +/- SEM fetal swallowing (0.9 +/- 0.1 to 2.7 +/- 0.4 swallows/min). N omega-nitro-L -arginine methyl ester significantly decreased fetal swallowing to below the basal rate (0.4 +/- 0.1 swallows/min), and swallowing did not increase with the second angiotensin II dose (in the presence of nitric oxide blockade)., Conclusions: These results demonstrate that inhibition of central nitric oxide suppresses fetal swallowing behavior in response to central angiotensin II. We speculate that tonic nitric oxide facilitates angiotensin II swallowing stimulation by maintenance of glutamate activation of hypothalamic N -methyl-D -aspartate receptors.