Declines in Pregnancies among U.S. Adolescents from 2007 to 2017: Behavioral Contributors to the Trend.

STUDY OBJECTIVES: Adolescent pregnancies and births in the United States have undergone dramatic declines in recent decades. We aimed to estimate the contribution of changes in 3 proximal behaviors to these declines among 14- to 18-year-olds for 2007-2017: 1) delays in age at first sexual intercourse, 2) declines in number of sexual partners, and 3) changes in contraceptive use, particularly uptake of long-acting reversible contraception (LARC). DESIGN: We adapted an existing iterative dynamic population model and parameterized it using 6 waves of the Centers for Disease Control and Prevention's Youth Risk Behavior Survey. We compared pregnancies from observed behavioral trends with counterfactual scenarios that assumed constant behaviors over the decade. We calculated outcomes by cause, year, and age. RESULTS: We found that changes in these behaviors could explain pregnancy reductions of 496,200, 78,500, and 40,700 over the decade, respectively, with total medical and societal cost savings of $9.71 billion, $1.54 billion, and $796 million. LARC adoption, particularly among 18-year-olds, could explain much of the improvement from contraception use. The 3 factors together did not fully explain observed birth declines; adding a 50% decline in sex acts per partner did. CONCLUSIONS: Delays in first sexual intercourse contributed the most to declining births over this decade, although all behaviors considered had major effects. Differences from earlier models could result from differences in years and ages covered. Evidence-based teen pregnancy prevention programs, including comprehensive sex education, youth-friendly reproductive health services, and parental and community support, can continue to address these drivers and reduce teen pregnancy.

Adenomas no funcionantes: análisis retrospectivo de 202 pacientes / Non-functional adenomas: retrospective analysis of 202 patients

RESUMEN Los pacientes con adenomas hipofisarios constituyen una población heterogénea y requieren un enfoque individualizado. El objetivo de nuestro trabajo fue analizar nuestra población con adenomas hipofisarios no funcionantes (ACNF) y evaluar factores pronóstico de crecimiento (como el Ki-67) que ayuden en la toma de decisiones. Se realizó un análisis retrospectivo de 202 pacientes, incluyendo evaluación basal, enfoque terapéutico y evolución tumoral en 2 grupos: pacientes con conducta expectante (n = 69) y pacientes con cirugía (n = 133). La serie tuvo 55% de pacientes mujeres y la edad media al diagnóstico fue de 49 años. Los motivos de consulta más frecuentes fueron incidentaloma hipofisario y alteraciones visuales. Radiológicamente, 83% fueron macroadenomas, 77% invasivos y 55% mostraron compromiso visual. Entre los adenomas invasores, el 53% tenían disfunción hipofisaria, siendo el hipogonadismo el hallazgo más frecuente. El tratamiento inicial fue la cirugía en el 65,8% realizándose por vía transnasal en el 79% de los casos. Las complicaciones más frecuentes fueron diabetes insípida transitoria e hiponatremia, con mayor incidencia de diabetes insípida permanente en la cirugía transcraneal. La inmunohistoquímica mostró gonatropinomas en el 43,4% de los casos y fue negativa en el 37,7%. Doce adenomas tuvieron índice de proliferación Ki-67 ≥3%. Luego de la cirugía 56,8% de los pacientes mejoraron el campo visual, 22,6% recuperó alguna función endocrina y 18,8% agregó un nuevo déficit. En pacientes no operados, se observó crecimiento tumoral en 5,6% de los adenomas Hardy 1-2 y en el 21% de los Hardy 3-4. Entre los adenomas operados, aquellos sin resto tumoral postoperatorio no presentaron recurrencia. De los tumores con remanente postoperatorio (78,6%) no irradiados, el 41,5% mostró recrecimiento lesional al seguimiento. Este porcentaje se eleva a 66,6% en aquellos con Ki-67 ≥3% y disminuye a 12% en los que recibieron radioterapia.

ABSTRACT Patients with pituitary adenomas are a heterogeneous population and require an individualized approach. The aim of our study was to analyze our population of patients with nonfunctioning pituitary adenomas (NFA) and to evaluate prognostic growth factors (such as Ki-67) that help in decision making. A retrospective analysis of 202 patients, including baseline assessment, therapeutic approach and tumor evolution was performed in 2 groups: expectant management (n = 69) and surgery (n = 133). The mean age at diagnosis was 49 years, 55% women. The most frequent reasons for consultation were pituitary incidentaloma and visual impairment. Eighty three percent were macroadenomas, 77% invasive, and 55% with visual impairment. Among the invasive adenomas, 53% had pituitary dysfunction, with hypogonadism being the most frequent finding. The initial treatment was surgery in 65.8%, 79% of them through transnasal approach. The most frequent complications were transient diabetes insipidus and hyponatremia, with a higher incidence of permanent diabetes insipidus in transcranial surgery. The immunohistochemistry showed: 43.4% gonadotropinomas, 37.7% negative. Twelve adenomas had proliferation index Ki-67 ≥3%. After surgery, 56.8% improved the visual fields, 22.6% recovered some endocrine function and 18.8% added a new deficit. In non-operated patients, tumor growth was observed in 5.6% of the Hardy 1-2 adenomas and 21% of the Hardy 3-4 adenomas. Among the operated adenomas, those without postoperative tumor residue did not present recurrence. In tumors with non-irradiated postoperative remnant (78.6%), 41.5% increased. This percentage rises to 66.6% in those with Ki-67 ≥3%, and decreases to 12% in those who received radiotherapy.

Peripheral and central nervous system inhibition of 11ß-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.

ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ≥2 mg daily maintained peripheral HSD-1 inhibition ≥88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ≥81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ≥2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly-6C(high) inflammatory monocytes in murine sepsis survivors.

BACKGROUND: More than 500,000 hospitalized patients survive severe sepsis annually in the USA. Recent epidemiological evidence, however, demonstrated that these survivors have significant morbidity and mortality, with 3-year fatality rates higher than 70%. To investigate the mechanisms underlying persistent functional impairment in sepsis survivors, here we developed a model to study severe sepsis survivors following cecal ligation and puncture (CLP). METHODS: Sepsis was induced in mice by CLP and survivors were followed for twelve weeks. Spleen and blood were collected and analyzed at different time points post-sepsis. RESULTS: We observed that sepsis survivors developed significant splenomegaly. Analysis of the splenic cellular compartments revealed a major expansion of the inflammatory CD11b+ Ly-6CHigh pool. Serum high-mobility group box 1 (HMGB1) levels in the sepsis surviving mice were significantly elevated for 4-6 weeks after post-sepsis, and administration of an anti-HMGB1 monoclonal antibody significantly attenuated splenomegaly as well as splenocyte priming. Administration of recombinant HMGB1 to naive mice induced similar splenomegaly, leukocytosis and splenocyte priming as observed in sepsis survivors. Interestingly analysis of circulating HMGB1 from sepsis survivors by mass spectroscopy demonstrated a stepwise increase of reduced form of HMGB1 (with known chemo-attractant properties) during the first 3 weeks, followed by disulphide form (with known inflammatory properties) 4-8 weeks after CLP. DISCUSSION: Our results indicate that prolonged elevation of HMGB1 is a necessary and sufficient mediator of splenomegaly and splenocyte expansion, as well as splenocyte inflammatory priming in murine severe sepsis survivors.

Association of dopamine-related genetic loci to dopamine D3 receptor antagonist ABT-925 clinical response.

ABT-925, a selective dopamine D3 receptor (DRD3) antagonist, was tested in schizophrenia. A DRD3 gene polymorphism results in an S9G amino-acid change that has been associated with lower risk of schizophrenia, higher affinity for dopamine and some antipsychotics, and differential response to some antipsychotics. The effect of S9G genotype on response to ABT-925 was examined. DNA samples (N=117) were collected in a proof-of-concept, double-blind, randomized, placebo-controlled study of ABT-925 (50 or 150 mg QD) in acute exacerbation of schizophrenia. A pre-specified analysis assessed impact of genotype (SS versus SG+GG) on change from baseline to final evaluation for the Positive and Negative Syndrome Scale (PANSS) total score using analysis of covariance with genotype, treatment and genotype-by-treatment interaction as factors, and baseline score as covariate. Significant genotype-by-treatment interaction (P=0.015) was observed for change from baseline to final evaluation for the PANSS total score. Within subgroup analyses showed significant improvement from placebo in the SG+GG group treated with ABT-925 150 mg. More favorable clinical outcomes were observed in patients treated with ABT-925 150 mg who carried the DRD3 G allele than in those who carried the DRD3 SS genotype.

CCR5, RANTES and SDF-1 polymorphisms and mother-to-child HIV-1 transmission.

Summary Among 288 HIV-1-infected, breastfeeding women who received zidovudine prophylaxis and were followed with their infants in Nairobi, we found no associations between maternal genetic polymorphisms in CCR5 (59029G/A, 59353T/C, 59356T/C, 59402G/A), RANTES (-403G/A) and SDF-1 (3'801G/A) and mother-to-child HIV-1 transmission; plasma, cervical and breastmilk viral loads; or breastmilk chemokine concentrations.

HIV testing men in the antenatal setting: understanding male non-disclosure.

Prevention of infant HIV is a powerful incentive for maternal HIV diagnosis and an opportunity to increase male HIV testing and disclosure of HIV status within couples. We examined male HIV disclosure in couples who attended a Nairobi antenatal clinic (ANC), had individual HIV testing, and were counselled to disclose to their partner. At two-week follow-up, men and women independently reported HIV disclosure. Of 2104 women, 1993 requested partner attendance; 313 male partners came, of whom 183 chose individual HIV testing. Of 106 couples who followed up, 93% of both partners reported disclosure by women versus 71% by men (P < 0.0001); 27% of men reported disclosure while their female partner reported not knowing partner HIV status. In these couples, male ANC HIV testing did not result in shared knowledge of HIV status. Couple counselling models that incorporate disclosure may yield greater HIV prevention benefits than offering individual partner HIV testing services at ANC.

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression.

The HTR1A -1019C>G genotype was associated with major depression in the Utah population. Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with the HTR1A -1019G allele revealed a linkage peak on chromosome 10 (maximum HLOD=4.4). Sequencing of all known genes in the linkage region revealed disease-segregating single-nucleotide polymorphisms (SNPs) in LHPP. LHPP SNPs were also associated with major depression in both Utah and Ashkenazi populations. Consistent with the linkage evidence, LHPP associations depended on HTR1A genotype. Lhpp or a product of a collinear brain-specific transcript, therefore, may interact with Htr1a in the pathogenesis of major depression.

OPTN policy regarding prioritization of patients with hepatopulmonary syndrome: does it provide equitable organ allocation?

United Network for Organ Transplantation (UNOS) policy 3.6.4.5.1 provides exception points to patients diagnosed with hepatopulmonary syndrome (HPS) to compensate for their reported increased mortality risk. We compared pre- and posttransplant and overall outcomes in 255 patients receiving exception points under this policy (HPS policy patients) with 32 358 nonexception control patients listed in the model for end-stage liver disease (MELD) era to determine whether the intent of the policy is being met. Overall, 92.5% of HPS policy patients versus 45.5% of controls had been transplanted, 5.1% versus 31.2% remained on waiting list and 1.5% versus 14.1% had died while awaiting transplant (p < 0.0001 for each comparison). Relative risk (RR) of death for HPS policy patients compared to controls was 0.158 (confidence interval [CI]: 0.059-0.420, p = 0.0002) pretransplant, and 0.827 (CI: 0.587-1.170, p = 0.28) posttransplant. Overall (combined waitlist and posttransplant) RR of death was 0.514 (CI: 0.374-0.707, p = 0.00004) compared with controls. After adjustment for laboratory MELD, overall RR was 0.807 (CI: 0.587-1.110, p = 0.19), indicating that HPS policy patients' mortality risk would be similar to that of controls had they been listed with their laboratory MELD score. HPS policy patients have a significant pretransplant survival advantage over standard liver transplant candidates because of the exception points awarded, and have similar posttransplant survival. Better criteria for diagnosing and grading of HPS are required.

Association of CYP3A5 polymorphisms with hypertension and antihypertensive response to verapamil.

In the CYP3A5 gene, the A>G (*3) and G>A (*6) polymorphisms result in severely decreased expression of CYP3A5 enzyme relative to a normal functional allele (*1). We sought to determine if the CYP3A5 genetic polymorphisms were associated with level of blood pressure (BP), risk of hypertension (HTN), and the antihypertensive response to verapamil. A total of 676 normotensive and hypertensive participants (mean age 49+/-8.2 years) from the Hypertension Genes study and 722 patients (mean age 66+/-9 years) from the International Verapamil/Trandolapril Study Genetic Substudy (INVEST-GENES) were genotyped for CYP3A5 to test for associations with BP, HTN, and in the latter cohort, antihypertensive response to verapamil. CYP3A5 haplotypes were determined using PHASE 2, with any allele containing either (*3) or (*6) designated as non functional. In the HTN genes population, there were no significant differences based on the number of functional CYP3A5 alleles, in systolic blood pressure (SBP) or diastolic blood pressure (DBP) among the normotensive whites or blacks (all P> or =0.70) or in allele frequency between normotensives and hypertensives. In INVEST-GENES, when controlled for baseline BP, race, age, and gender, untreated BP in carriers versus non carriers of a CYP3A5 functional allele was 158.2+/-13.7 and 154.8+/-13.7 (P=0.061), respectively. CYP3A5 functional allele status was marginally associated with the SBP response to verapamil in blacks (P=0.075) and Hispanics (P=0.056), but not in whites (P=0.40), with the effect being largely driven by higher SBP in the carriers of two functional alleles. There was no association with DBP response and CYP3A5 allele status. CYP3A5 genotype does not contribute importantly to BP or risk of HTN, but may influence response to calcium channel blockers in populations in which carrier status of two functional alleles is common.

Variants in Apaf-1 segregating with major depression promote apoptosome function.

APAF1, encoding the protein apoptosis protease activating factor 1 (Apaf-1), has recently been established as a chromosome 12 gene conferring predisposition to major depression in humans. The molecular phenotypes of Apaf-1 variants were determined by in vitro reconstruction of the apoptosome complex in which Apaf-1 activates caspase 9 and thus initiates a cascade of proteolytic events leading to apoptotic destruction of the cell. Cellular phenotypes were measured using a yeast heterologous expression assay in which human Apaf-1 and other proteins necessary to constitute a functional apoptotic pathway were overexpressed. Apaf-1 variants encoded by APAF1 alleles that segregate with major depression in families linked to chromosome 12 shared a common gain-of-function phenotype in both assay systems. In contrast, other Apaf-1 variants showed neutral or loss-of-function phenotypes. The depression-associated alleles thus have a common phenotype that is distinct from that of non-associated variants. This result suggests an etiologic role for enhanced apoptosis in major depression.

Periacetabular osteotomy in patients with Down's syndrome.

We treated eight dysplastic acetabula in six skeletally mature patients with Down's syndrome by a modified Bernese periacetabular osteotomy. The mean age at the time of surgery was 16.5 years (12.8 to 28.5). Mean length of follow-up was five years (2 to 10.4).Pre-operatively the mean (Tonnis) acetabular angle was 28 degrees, the centre-edge angle was -9 degrees, and the extrusion index was 60%; post-operatively they were 3 degrees, 37 degrees, and 17%, respectively. Two patients with post-operative (Tonnis) acetabular angles > 10 degrees developed subluxation post-operatively and required secondary varus derotation femoral osteotomies. Another patient developed a late labral tear which was treated arthroscopically. All eight hips remain clinically stable, and are either asymptomatic or symptomatically improved. These results suggest that the modified Bernese periacetabular osteotomy can be used successfully in the treatment of acetabular dysplasia in patients with Down's syndrome.

Effect of treatment on quality of life among men with clinically localized prostate cancer.

BACKGROUND: Quality-of-life outcomes are an important consideration for patients evaluating therapeutic options for localized prostate cancer. OBJECTIVES: The objective of this study was to describe the effect of treatment choice on change in health-related quality of life (HRQOL) among men with clinically localized prostate cancer. RESEARCH DESIGN: This was a prospective observational study. SUBJECTS: The study subjects were 122 men with clinically localized adenocarcinoma of the prostate. Forty-two subjects (34%) underwent radical prostatectomy, 51 (42%) underwent radiation therapy, and 29 (24%) were followed with expectant management. MEASURES: The University of California at Los Angeles Prostate Cancer Quality of Life Inde- and the Medical Outcomes Study Short Form-36 were administered before and 3 and 12 months after initial treatment. The study used an analysis of covariance model adjusted for baseline differences in clinical and demographic factors. RESULTS: Men who underwent radical prostatectomy experienced significant declines in urinary and sexual function and bother that persisted at 12 months after treatment. Men treated with radiation therapy experienced smaller but significant declines in sexual function and a decline in social function. Expectant management patients did not have a significant change in disease-targeted or generic HRQOL domains. Differential rates of change in urinary and sexual function between treatment groups persisted after adjustment for differences in pretreatment clinical and demographic factors. CONCLUSIONS: Men undergoing radical prostatectomy have substantial declines in urinary and sexual function, and men undergoing radiotherapy have declines in sexual function. Men undergoing expectant management have no change in disease-specific or general HRQOL in the first year after treatment.

Randomised clinical trial of two bypass operations for unresectable cancer of the pancreatic head.

OBJECTIVE: To compare two different types of prophylactic gastric bypass in patients with cancer of the pancreatic head who were not suitable for curative resection. DESIGN: Prospective study. SETTING: University hospital, Turkey. SUBJECTS: 44 patients with unresectable cancer of the pancreatic head without duodenal obstruction who presented between May 1995 and June 2000 who were randomised into 2 groups. INTERVENTIONS: 22 patients had an antecolic, isoperistaltic gastrojejunostomy, jejunojejunostomy, and hepaticojejunostomy after cholecystectomy. The remaining 22 had a hepaticojejunostomy and antecolic, antiperistaltic gastrojejunostomy procedure after cholecystectomy. MAIN OUTCOME MEASURES: Mortality, morbidity, postoperative course, and survival. RESULTS: There were no significant differences between the groups in the incidence of postoperative complications, time until restoration of oral diet, relaparotomy rate, late upper gastrointestinal bleeding, mortality, duration of hospital stay, and survival. The isoperistaltic operation took significantly longer than the antiperistaltic operation (p < 0.001) and there was less delayed gastric emptying in the antiperistaltic group but not significantly so. Both operations caused a significant lengthening in the postoperative gastric emptying time (p = 0.04 and p = 0.01, respectively). CONCLUSION: Both procedures are suitable for patients with unresectable carcinoma of the pancreatic head without impending duodenal obstruction. There was a trend towards better clinical results with the isoperistaltic procedure.

Impact of obesity on health-related quality of life in patients with chronic illness.

OBJECTIVE: To determine the association between overweight and obesity and health-related quality of life (HRQOL) in patients with chronic conditions typical of those seen in general medical practice, after accounting for the effects of depression and medical comorbidities. DESIGN: Cross-sectional analysis of data from the Medical Outcomes Study. SETTING: Offices of physicians practicing family medicine, internal medicine, endocrinology, cardiology, and psychiatry in three U.S. cities. PATIENTS: We surveyed 2,931 patients with chronic medical and psychiatric conditions. The patients completed a self-administered questionnaire at enrollment and had complete data on height and weight. MEASUREMENTS AND MAIN RESULTS: Body mass index (BMI), chronic medical conditions, and depression were obtained by structured interview. Health-related quality of life was measured by the SF-36 Health Survey. Patients who were overweight (BMI 25.0-29.9 kg/m2), patients with class I obesity (BMI 30.0-34.9 kg/m2), and patients with class II-III obesity (BMI > or = 35 kg/m2) had significantly lower adjusted physical function scores (by 3.4, 7.8, and 13.8 points, respectively) compared with nonoverweight patients. Patients with class I and class II-III obesity also had significantly lower adjusted general health perceptions scores (by 2.8 and 4.4 points, respectively) and lower adjusted vitality scores (by 4.0 and 7.1 points, respectively), compared with nonoverweight patients. No significant differences between nonoverweight, overweight, and obese patients were observed for the mental health scale. Women with elevated BMI had significantly lower HRQOL scores compared with the scores of obese men in several domains. Additionally, blacks with elevated BMI had significantly lower scores than whites in several domains of HRQOL. CONCLUSIONS: Overweight and obesity have the largest association with physical function measures. Recent national standards, which have lowered the threshold for defining overweight, identify patients who are more likely to have clinically significant reductions in HRQOL and functional impairment.

Palliative decompression of obstructive hilar malignancies utilizing an extrahilar biliary approach.

Hilar cancers carry a dismal prognosis. Palliation of obstructive jaundice in patients with hilar cancer can be achieved by either surgical or nonsurgical means. Selection of the appropriate palliative measures is a challenging problem. Segmental bilioenteric anastomosis procedures were performed on 19 patients with hilar cancer. Seventeen of the bypasses were done to the segment III duct, known as the ligamentum teres approach, and two bypasses were to the segment V duct. Five patients, who had already been stented percutaneously or endoscopically, were operated on after the stents were clogged and a duodenal obstruction ensued. There were two postoperative deaths (10.5%) and four postoperative complications (21%). All of the 17 surviving patients experienced improvement in the level of jaundice postoperatively and the levels of serum total and direct bilirubin decreased by 78.9% and 84.2%, respectively. Two patients developed late cholangitis before death and were treated by external biliary drainage; one developed duodenal obstruction and was treated by gastrointestinal anastomosis. The mean length of hospital stay was 15.2 days. Mean survival was 8.2 months and the mean period of well-being was 7.8 months. Median survival was 7 months and median period of well being was 7 months. Three patients are still alive at 8, 8, and 24 months. These data suggest that the ligamentum teres approach offers effective palliation for patients with unresectable hilar cancer.