Closed-Loop Electronic Referral From Primary Care Clinics to a State Tobacco Cessation Quitline: Effects Using Real-World Implementation Training.

INTRODUCTION: Patients who use tobacco are too rarely connected with tobacco use treatment during healthcare visits. Electronic health record enhancements may increase such referrals in primary care settings. This project used the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to assess the implementation of a healthcare system change carried out in an externally valid manner (executed by the healthcare system). METHODS: The healthcare system used their standard, computer-based training approach to implement the electronic health record and clinic workflow changes for electronic referral in 30 primary care clinics that previously used faxed quitline referral. Electronic health record data captured rates of assessment of readiness to quit and quitline referral 4 months before implementation and 8 months (May-December 2017) after implementation. Data, analyzed from October 2018 to June 2019, also reflected intervention reach, adoption, and maintenance. RESULTS: For reach and effectiveness, from before to after implementation for electronic referral, among adult patients who smoked, assessment of readiness to quit increased from 24.8% (2,126 of 8,569) to 93.2% (11,163 of 11,977), quitline referrals increased from 1.7% (143 of 8,569) to 11.3% (1,351 of 11,977), and 3.6% were connected with the quitline after implementation. For representativeness of reach, electronic referral rates were especially high for women, African Americans, and Medicaid patients. For adoption, 52.6% of staff who roomed at least 1 patient who smoked referred to the quitline. For maintenance, electronic referral rates fell by approximately 60% over 8 months but remained higher than pre-implementation rates. CONCLUSIONS: Real-world implementation of an electronic health record-based electronic referral system markedly increased readiness to quit assessment and quitline referral rates in primary care patients. Future research should focus on implementation methods that produce more consistent implementation and better maintenance of electronic referral.

Helping women veterans quit smoking: a qualitative analysis of successful and unsuccessful attempts.

BACKGROUND: Tobacco use is the number one cause of death and disability of women in the United States, and our women Veteran population is disproportionately affected. Despite revisions to the Veterans Affairs' approach to smoking cessation, women continue to smoke at equal or higher rates than men, are prescribed cessation medications less frequently, and are less likely to quit. In this qualitative pilot study, individual interviews with women Veterans revealed their experiences with smoking cessation attempts. METHODS: The lead author conducted semi-structured interviews with 14 women Veterans who were either current or former smokers. Participants gave a narrative account of recent quit smoking attempts. Inductive thematic analysis explored the underlying themes. RESULTS: Four main themes emerged as important: health and well-being, smoking as an addiction, optimism, and resilience. Health and well-being encompassed physical health, mental health, and financial stability. Women often felt that stability in these key areas made a successful attempt possible. Women with successful quit attempts were more likely to consider tobacco use as an addiction, as well as expressed optimism about their quit attempts. Women with successful quit attempts also demonstrated more resilience to lapses and relapses. CONCLUSIONS: Women Veterans' quit smoking attempts demonstrate four main themes: baseline health and wellbeing, acknowledging smoking as an addiction, the participant's optimism towards quitting, and resilience. Patterns were observed within themes with respect to whether the woman was currently quit or had experienced a prolonged quit attempt in the past. Further research is needed to help women Veterans quit smoking.

Tobacco, Alcohol, Drug Use, and Intimate Partner Violence Among MSM Living With HIV.

Men who have sex with men (MSM) and are living with HIV have reported high rates of intimate partner violence (IPV) and substance use. We examined relationships between accumulative IPV, incidents of IPV, and numbers of substances used. One hundred twenty Taiwanese MSM living with HIV completed a cross-sectional survey. Accumulative IPV was assessed by summing the number of 15 types of IPV experienced in the previous year; substance use was measured by any use of alcohol, tobacco, or other drugs during the previous week. In multivariate analysis, IPV was not associated with tobacco use but was positively associated with alcohol and other drug use and significantly associated with the probability of using multiple substances. MSM living with HIV who experienced greater IPV were more likely to use alcohol and other drugs and were more likely to use more than one substance. Health care providers screening for IPV should also screen for substance use.

Triple Smoking Cessation Therapy with Varenicline, Nicotine Patch and Nicotine Lozenge: A Pilot Study to Assess Tolerability, Satisfaction, and End-of-Treatment Quit Rates.

INTRODUCTION: The majority of attempts to stop smoking end in failure. One way to improve success may be to explore different combinations of existing cessation medications. AIMS: This observational study examined "triple therapy" (varenicline + nicotine patch + nicotine lozenge) in 36 smokers trying to quit. METHODS: A 12-week, observational study exploring tolerability, via adverse events (AEs) elicited at each of 9 phone assessments. Secondary outcomes included satisfaction rates, medication changes, and self-reported quit rates at week 12. RESULTS: 35 of 36 participants reported at least one AE. Insomnia (75%), abnormal dreams (72%) and nausea (64%) were most common. Most were mild to moderate. No deaths, hospitalizations, cardiovascular events, or suicidality were reported. Six participants (17%) decreased the dose of at least one medication, 5 (14%) decreased the dose then discontinued at least one medication, and 13 (36%) discontinued at least one medication without trying a lesser dose. Participants were highly satisfied with their medications, and 58% reported quitting at 12 weeks, with 38% reporting prolonged abstinence. CONCLUSION: Despite high rates of AEs and medication changes, high rates of satisfaction and self-reported quitting, with no serious AEs, were observed with triple therapy. Additional data on tolerability and efficacy are needed. TRIAL REGISTRATION: clinicaltrials.gov number NCT02681510.

Identifying Differences in Rates of Invitation to Participate in Tobacco Treatment in Primary Care.

INTRODUCTION: The progress achieved in reducing tobacco use has not been consistent across groups of smokers, and health systems are inconsistently implementing best practice guidelines. Guideline implementation could be associated with improved treatment invitation rates. AIMS: To evaluate differences in tobacco treatment invitation rates based on patient characteristics in primary care clinics implementing best practice guidelines. METHODS: A secondary analysis of patients presenting to 11 primary care clinics from 2 Wisconsin health systems from June 2010 to February 2013. The main outcome was whether patients received an invitation to participate in tobacco treatment. Invitation rates were examined by sex, age group (≤ 24 years, 25-44, 45-64, ≥ 64), race (white, black, other), insurance status (private, Medicare, Medicaid, none), and visit diagnosis ("high-risk" [cardiovascular and pulmonary disease, malignancy, pregnancy] vs "low-risk" [all other ICD-9 categories]). Moderation effects of health systems also were examined. RESULTS: Of the 95,471 patients seen, 84,668 (89%) were screened for smoking. Among the 15,193 smokers, 10,242 (67%) were invited to participate. Invited patients were older, white or black, and carried low-risk diagnoses. Invitation rates and patient-level differences varied between the health systems. CONCLUSIONS: Variable treatment invitation rates and health system differences remain evident in the primary care setting employing robust clinical practice guideline recommendations.

Offering smoking treatment to primary care patients in two Wisconsin healthcare systems: Who chooses smoking reduction versus cessation?

Smokers unwilling to make a quit attempt can still benefit from smoking intervention. However, it is unclear what proportion of smokers will enter such a Motivation phase intervention, and whether such an intervention attracts different types of smokers than does abstinence oriented treatment. We conducted a study from June 2010 to October 2013 based on a chronic care model of tobacco treatment among study eligible primary care patients (N=1579; 58% women, 89% White) presenting for regular health care visits in southern Wisconsin, U.S. Medical assistants, prompted via the electronic health record (EHR), invited smokers (n=10,242) to learn more about treatment options to help them either reduce their smoking or quit. Of those invited to learn more who were then reached by study staff, 10.2% (n=1046) reported interest in reduction treatment and 24% (n=2465) reported interest in cessation treatment. Patients who selected and ultimately entered reduction (n=492) versus cessation (n=1087) were more likely to report: older age; a history of anxiety; lower motivation to quit; lower primary dependence motives; more close friends or family who smoke; and a greater interval since their last quit attempt. Results suggest that Motivation phase treatment aimed at smoking reduction may increase the proportion and range of smokers inducted into tobacco treatment.

Identifying Opportunities to Improve Smoking Cessation Among Women Veterans at a Veterans Hospital.

While women Veterans have a higher prevalence of smoking than civilian women, little is known about their quitting behavior. Via a chart review, we characterized referral and enrollment patterns in tobacco cessation services (TCS), and quit attempts among 366 women Veteran smokers at a Midwestern Veterans Hospital. Cases receiving referrals to TCS (n = 183) were matched 1:1 to controls who did not (n = 183), by year of referral. Variables included age, marital status, urbanicity, smoking status, comorbidities, pregnancy, packs per day, number of prior smoking cessation medications, provider gender, provider type, and clinical location of referral placement. Of women Veteran smokers, 24% were referred to TCS, and tended to be older, heavier smokers, with more comorbidities, more prior cessation medication prescriptions, and more likely seen by a resident or attending physician. Only 54% of referred women enrolled, and these women were older, had more medical comorbidities and prior cessation medication prescriptions than nonenrolled women. Primary care providers were more likely to have patients enroll versus inpatient providers. Only 8% of enrolled women achieved abstinence at 6 months. Quit attempts were associated with the number of cessation medication prescriptions for enrolled women, and lighter smoking histories for nonenrolled women.

Neopterin predicts cardiac dysfunction following cardiac surgery.

OBJECTIVES: Oxidative stress following ischaemia and reperfusion, as well as inflammation, are thought to be important for the development of cardiac dysfunction after cardiac surgery. Our main objective was to investigate whether the inflammatory biomarkers C-reactive protein (CRP), lactoferrin, neopterin and the terminal complement complex (TCC) were associated with cardiac dysfunction after cardiac surgery. Another objective was to assess whether the biomarkers could improve prediction of postoperative cardiac dysfunction compared with clinical variables only. METHODS: Blood samples and clinical data from 1018 consecutive patients undergoing cardiac surgery from 1 April 2008 to 19 April 2010 at St. Olavs University Hospital, Trondheim, Norway, were collected prospectively. The end-point was postoperative cardiac dysfunction, defined as the need for more than one inotropic agent or an intra-aortic balloon pump occurring after the operation and until the patient was discharged from the department. CRP, lactoferrin, neopterin and TCC were analysed in plasma, and we used logistic regression to evaluate the association of the biomarkers with postoperative cardiac dysfunction. We adjusted for the following clinical variables previously associated with postoperative cardiac dysfunction: urgent operation, operation type, previous cardiac surgery, chronic heart failure, pulmonary hypertension, previous myocardial infarction and haemoglobin. The likelihood ratio test, the integrated discrimination improvement and receiver operating characteristic (ROC) curves were used to assess whether the biomarkers could improve prediction of postoperative cardiac dysfunction compared with clinical variables alone. RESULTS: Neopterin was the only biomarker significantly associated with postoperative cardiac dysfunction (odds ratio 2.73, 95% confidence interval 1.65-4.51) after adjustment for clinical variables. Neopterin improved risk prediction of cardiac dysfunction following heart surgery compared with clinical variables alone according to the likelihood ratio test (P < 0.0001) and the integrated discrimination improvement (P = 0.02), particularly for patients with intermediate risks. CONCLUSIONS: Neopterin was associated with cardiac dysfunction following cardiac surgery, and improved the accuracy of risk prediction of postoperative cardiac dysfunction. At present, we do not suggest that neopterin should be measured routinely before heart surgery, but our findings support the hypothesis of the role of oxidative stress and inflammation in development of cardiac dysfunction following heart surgery.

Defining and predicting short-term alcohol use changes during a smoking cessation attempt.

INTRODUCTION: Alcohol and nicotine are commonly used substances in the U.S., with significant impacts on health. Using both substances concurrently impacts quit attempts. While studies have sought to examine changes in alcohol use co-occurring with tobacco cessation, results have not been consistent. Understanding these changes has clinical implications. The objective of this study is to identify changes in alcohol consumption that occur following tobacco cessation, as well as predictors of alcohol use patterns following a smoking cessation attempt. METHODS: A secondary analysis of a randomized, placebo-controlled trial evaluating the efficacy of five tobacco cessation pharmacotherapies. Participants (N=1301) reported their smoking and alcohol consumption daily for two weeks prior to, and two weeks after, the target quit date (TQD). RESULTS: Generally, alcohol use decreased post-TQD. Smokers who reported less pre-quit alcohol use, as well as smokers who were female, non-white, and had a history of alcohol dependence tended to use less alcohol post-quit. Pre- and post-quit alcohol use were more strongly related among men and among those without a history of alcohol dependence. CONCLUSIONS: For most smokers alcohol use decreased following smoking cessation. These results suggest that the expectation should be of decreased alcohol use post cessation. However, attention may be warranted for those who drink higher amounts of alcohol pre-cessation because they may be more likely to drink more in the post-quit period which may influence smoking cessation success.

Prediction of bleeding after cardiac surgery: comparison of model performances: a prospective observational study.

OBJECTIVES: Primary aims were to (1) perform external validation of the Papworth Bleeding Risk Score, and (2) compare the usefulness of the Dyke et al universal definition of perioperative bleeding with that used in the Papworth Bleeding Risk Score. A secondary aim was to use a locally developed logistic prediction model for severe postoperative bleeding to investigate whether prediction could be improved with inclusion of the variable "surgeon" or selected intraoperative variables. DESIGN: Single-center prospective observational study. SETTING: University hospital. PARTICIPANTS: 7,030 adults undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Papworth Bleeding Risk Score could identify the group of patients with low risk of postoperative bleeding, with negative predictive value of 0.98, when applying the Papworth Score on this population. The positive predictive value was low; only 15% of the patients who were rated high risk actually suffered from increased postoperative bleeding when using the Papworth Score on this population. Using the universal definition of perioperative bleeding proposed by Dyke et al, 28% of patients in the Papworth high-risk group exceeded the threshold of excessive bleeding in this population. The local models showed low ability for discrimination (area under the receiver operating characteristics curve<0.75). Addition of the factor "surgeon" or selected intraoperative variables did not substantially improve the models. CONCLUSION: Prediction of risk for excessive bleeding after cardiac surgery was not possible using clinical variables only, independent of endpoint definition and inclusion of the variable "surgeon" or of selected intraoperative variables. These findings may be due to incomplete understanding of the causative factors underlying excessive bleeding.

Battling tobacco use at home: an analysis of smoke-free home rules among U.S. veterans from 2001 to 2011.

OBJECTIVES: We examined national trends in smoke-free home rules among U.S. veterans and nonveterans. METHODS: We used data from the 2001-2002 and 2010-2011 Tobacco Use Supplement to the Current Population Survey to estimate and compare the existence of smoke-free home rules among veterans and nonveterans for each survey period. RESULTS: The prevalence of a complete smoke-free home rule among veterans increased from 64.0% to 79.7% between 2001 and 2011 (P < .01) but was consistently lower than were rates estimated for nonveterans (67.6% and 84.4%, respectively). Disparities between the 2 groups increased significantly over time (P < .05). CONCLUSIONS: Despite the general increase in the adoption of smoke-free home rules, veterans lag behind the rest of the U.S. population. Interventions promoting the adoption of complete smoke-free home rules are necessary to protect veterans and their families and to reduce disparities.

Undifferentiated carcinoma of pancreas: a rare entity with aggressive behavior and possible genetic link.

UNLABELLED: An aggressive undifferentiated carcinoma of pancreas is a rare tumor, especially with a strong personal and family history of malignant melanoma. Limited literature review and few case reports described a genetic association between distinct types of pancreatic cancer and malignant melanoma. CASE REPORT: We present an uncommon case of an aggressive undifferentiated carcinoma of the pancreas in a 50-year-old Caucasian female. Initially, she presented with intermittent epigastric postprandial pain and mild nausea. A computed tomography scan of the abdomen showed a 5 cm heterogenous pancreatic tail mass, which on biopsy was found to be a poorly differentiated non-small cell carcinoma. Past medical history included malignant melanoma, with extensive family history of pancreatic cancer and malignant melanoma. However, not genetically confirmed, a hereditary pancreatic linkage was highly suspected. A week later, repeat computed tomography demonstrated tremendous enlargement of the pancreatic tail mass. Within a few weeks, the patient developed aggressive metastasis in various organ systems, followed by multiple surgeries. An emergent first round of chemotherapy was started, followed by an intensive care unit stay, and she eventually died. CONCLUSION: Our case exposes the aggressive behavior of undifferentiated carcinoma of pancreas, along with possible hereditary link between pancreatic cancer and malignant melanoma.

How can we best predict acute kidney injury following cardiac surgery?: a prospective observational study.

BACKGROUND: Several models for predicting acute kidney injury following cardiac surgery have been published, and various end-point definitions have been used. OBJECTIVES: Our aim was to investigate how acute kidney injury following cardiac surgery could be most accurately predicted. DESIGN: Single-centre prospective observational study. SETTING: St Olav's University Hospital, Trondheim, Norway, from 2000 to 2007. PATIENTS: All 5029 adult patients undergoing cardiac surgery were considered eligible for participation. Patients who required preoperative dialysis and patients with missing information on preoperative or maximum postoperative serum creatinine concentration were excluded (n=51). A total of 4978 patients were entered into the statistical analyses. MAIN OUTCOME MEASURES: Logistic regression with bootstrapping methods was applied for model development and validation, together with the area under the receiver operating characteristic curve and Hosmer-Lemeshow test. We tested different end-points, exchanged serum creatinine concentration with creatinine clearance or estimated glomerular filtration rate and added intraoperative variables. The main end-point was at least 50% increase in serum creatinine concentration, an increase in concentration by at least 26.4 µmol l(-1) (0.3 mg dl(-1)) or a new requirement for dialysis after surgery. RESULTS: The final model consisted of 11 preoperative predictors of acute kidney injury: age, BMI, lipid-lowering treatment, hypertension, peripheral vascular disease, chronic pulmonary disease, haemoglobin concentration, serum creatinine concentration, previous cardiac surgery, emergency operation and operation type. The area under the receiver operating characteristic curve was 0.819 (95% confidence interval 0.801 to 0.837), and the Hosmer-Lemeshow test P value was 0.17. Exchanging serum creatinine concentration with glomerular filtration rate or creatinine clearance slightly reduced model discrimination and the addition of intraoperative variables improved discrimination somewhat. Slight end-point definition changes had little impact. CONCLUSION: The risk of acute kidney injury can be accurately predicted using preoperative variables. Serum creatinine concentration was more accurate than estimated glomerular filtration rate or creatinine clearance. Intraoperative variables slightly improved the model, but did not seem to outweigh the advantages of a preoperative model.

Relations of alcohol consumption with smoking cessation milestones and tobacco dependence.

OBJECTIVE: Alcohol consumption is associated with smoking cessation failure in both community and clinical research. However, little is known about the relation between alcohol consumption and smoking cessation milestones (i.e., achieving initial abstinence, avoiding lapses and relapse). Our objective in this research was to examine the relations between pretreatment alcohol consumption patterns (non/infrequent drinker, moderate drinker, binge drinker) and smoking cessation milestones and tobacco dependence. METHOD: Data were collected from 1,504 smokers (58.2% women; 83.9% White; mean age = 44.67 years, SD = 11.08) making an aided smoking cessation attempt as part of a clinical trial. Alcohol consumption pattern was determined with the Composite International Diagnostic Interview. Tobacco dependence was assessed with the Wisconsin Inventory of Smoking Dependence Motives (WISDM). RESULTS: Alcohol consumption pattern was significantly associated with initial cessation and lapse, and these findings remained after controlling for the effects of treatment, race, gender, and cigarettes per day. Relative to moderate drinkers, both non/infrequent drinkers and binge drinkers were less likely to achieve initial cessation (p < .05), and binge drinkers were more likely to lapse (p < .01). When drinking categories were compared on tobacco dependence indices, results showed that relative to moderate drinkers, non/infrequent drinkers scored higher on several WISDM Primary Dependence Motives subscales (Tolerance, Loss of Control, and Automaticity) and binge drinkers scored higher on WISDM Secondary Dependence Motives subscales (Cue Exposure and Social-Environmental Goads). CONCLUSIONS: Non/infrequent drinkers' smoking cessation difficulties may be particularly related to core features of tobacco dependence, whereas binge drinkers' difficulties may be related to environmental and social influences.

Preoperative and intraoperative prediction of risk of cardiac dysfunction following open heart surgery.

CONTEXT: Cardiac dysfunction following open heart surgery is a major determinant of subsequent morbidity and mortality. OBJECTIVES: To develop a specific risk prediction model for postoperative cardiac dysfunction based on preoperative variables, to investigate whether prediction could be improved by inclusion of selected intraoperative variables and to compare our model with five previously published risk scores. DESIGN: Single-centre prospectively collected data. SETTING: Tertiary care centre, Middle Norway. PATIENTS: Four thousand nine hundred and eighty-nine patients (all eligible) undergoing open cardiac surgery from 2000 to 2007. MAIN OUTCOME MEASURES: Logistic regression models for postoperative cardiac dysfunction: predictive accuracy/calibration, discrimination as shown by area under the receiver operating characteristics curve, internal validity as indicated by bootstrapping, comparison of goodness-of-fit with predictions based on alternative risk scores. RESULTS: The preoperative model included chronic cardiac insufficiency, previous myocardial infarction, previous cardiac operation, pulmonary hypertension, renal dysfunction, low haemoglobin concentration, urgent operation and operation type other than isolated coronary artery bypass surgery. The area under the curve was 0.838 [95% confidence interval (CI) 0.812-0.864]. Risk prediction was accurate apart from a slight overestimation in the 2% of highest risk patients. Inclusion of a few intraoperative variables (inotropic or vasoconstrictor drugs, plasma or red cell transfusion) improved the model slightly, increasing the area under the curve to 0.875 (95% CI 0.854-0.896) or 0.890 (95% CI 0.863-0.902) for two equivalent models. On the basis of estimated shrinkage factors of 0.94, 0.97 and 0.98, respectively, the models should behave with 6% or less error in future datasets. Our preoperative model was significantly better than the previously published risk scores (P < 0.0002 for comparison of area under the curves). CONCLUSION: The preoperative model including variables obtained easily in routine clinical work performed well and was improved only slightly by inclusion of intraoperative variables. Performance was better than those of the five previously published risk scores.

Salmonella Typhimurium invasion of HEp-2 epithelial cells in vitro is increased by N-acylhomoserine lactone quorum sensing signals.

BACKGROUND: In Gram-negative bacteria, the most commonly studied quorum sensing signals are the N-acylhomoserine lactones (AHLs). In Salmonella, AHLs are recognized by SdiA, which is believed to be a sensor of AHLs produced by other bacteria, since Salmonella does not produce AHLs itself. It has been speculated that AHLs produced by the gastrointestinal flora may influence the regulation of virulence traits in Salmonella. The aim of the present work was to study the effect of AHLs on epithelial cell invasion by Salmonella in vitro. METHODS: Invasion by Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium) strain and its isogenc sdiA mutant was studied using a conventional gentamycin invasion assay with HEp-2 cells at 37°C. Gene expression was studied using a semi-quantitative PCR. RESULTS: The S. Typhimurium strain, but not its isogenic sdiA mutant, displayed increased in vitro invasion after addition of both N-hexanoyl-DL-homoserine lactone (C6-AHL) and N-octanoyl-DL-homoserine lactone (C8-AHL). Increased expression of two of the genes in the SdiA regulon (rck and srgE) was observed in the wild type strain, but not in the sdiA mutant. CONCLUSIONS: The results from the present study show that S. Typhimurium can respond to two different AHL quorum sensing signals (C6-AHL and C8-AHL) with increased cell invasion at 37°C in vitro, and that this response most likely is sdiA mediated. These results indicate that if AHLs are present in the intestinal environment, they may increase the invasiveness of Salmonella.

PCOS--what matters in early pregnancy?--data from a cross-sectional, multicenter study.

OBJECTIVE: To describe patient characteristics according to different diagnostic criteria in early pregnancy, in women with polycystic ovary syndrome (PCOS). DESIGN: Descriptive, cross-sectional study of 257 women with PCOS in the first trimester of pregnancy. SETTING: Data from a multicenter trial at the time of inclusion. POPULATION: 257 PCOS women with singleton pregnancies. METHODS: Investigator-administrated questionnaires were filled out. Clinical examination was performed by the investigators. Fasting blood samples were collected. MAIN OUTCOME MEASURES: Biometric data, androgens, glucose and insulin levels. RESULTS: Women who met the National Institutes of Health (NIH) criteria for PCOS had higher body mass index (BMI), testosterone, dehydroepiandrostenedione, free testosterone index (FTI) and insulin levels compared with those who only met the Rotterdam consensus criteria. Adjusted for age and BMI, only testosterone and FTI were higher in those who met the NIH criteria. BMI was a strong, independent predictor of both systolic and diastolic blood pressure in early PCOS pregnancy, while both FTI and fasting insulin were independent predictors of systolic blood pressure. Twenty-two (9%) of the participants had gestational diabetes mellitus in the first trimester of pregnancy. CONCLUSIONS: In the first trimester, PCOS women diagnosed according to NIH criteria were more metabolically and endocrinologically abnormal compared with those who only met the Rotterdam consensus criteria. BMI and FTI were independent predictive factors for blood pressure. There was a high prevalence of gestational diabetes mellitus in early PCOS pregnancies.

Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study.

CONTEXT: Metformin is widely prescribed to pregnant women with polycystic ovary syndrome (PCOS) in an attempt to reduce pregnancy complications. Metformin is not approved for this indication, and evidence for this practice is lacking. OBJECTIVES: Our objective was to test the hypothesis that metformin, from first trimester to delivery, reduces pregnancy complications in women with PCOS. DESIGN AND SETTING: We conducted a randomized, placebo-controlled, double-blind, multicenter study at 11 secondary care centers. PARTICIPANTS: The participants were 257 women with PCOS, in the first trimester of pregnancy, aged 18-42 yr. INTERVENTION: We randomly assigned 274 singleton pregnancies (in 257 women) to receive metformin or placebo, from first trimester to delivery. MAIN OUTCOME MEASURES: The prevalence of preeclampsia, gestational diabetes mellitus, preterm delivery, and a composite of these three outcomes is reported. RESULTS: Preeclampsia prevalence was 7.4% in the metformin group and 3.7% in the placebo group (3.7%; 95% CI, -1.7-9.2) (P=0.18). Preterm delivery prevalence was 3.7% in the metformin group and 8.2% in the placebo group (-4.4%; 95%, CI, -10.1-1.2) (P=0.12). Gestational diabetes mellitus prevalence was 17.6% in the metformin group and 16.9% in the placebo group (0.8%; 95% CI, -8.6-10.2) (P=0.87). The composite primary endpoint prevalence was 25.9 and 24.4%, respectively (1.5%; 95% CI, -8.9-11.3) (P=0.78). Women in the metformin group gained less weight during pregnancy compared with those in the placebo group. There was no difference in fetal birth weight between the groups. CONCLUSIONS: Metformin treatment from first trimester to delivery did not reduce pregnancy complications in PCOS.

A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma.

PURPOSE: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination. PATIENTS AND METHODS: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib. RESULTS: Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months. CONCLUSION: The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.