Gallbladder and Biliary Disease in Pregnancy.

Diseases of the gallbladder and biliary tract are extremely common in developed nations. Because of the physiology of pregnancy, their incidence increases during gestation. This article represents a review of the existing literature on the entire spectrum of biliary disease. The physiology, clinical presentation, and diagnostic evaluation of a variety of conditions are reviewed. Historical and contemporary data regarding pregnancy implications and treatment options are discussed.

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

Revisiting the prehypertension debate: increasing evidence for treatment yet randomized clinical trials are lacking.

In 2009, Blood Pressure featured a debate about whether to treat patients with prehypertension (Kiely et al., Blood Press. 2009;18:300-303; McInnes GT, Blood Press. 2009;18:304-307). Our group supported pharmacotherapy for this condition at that time. Since then, additional evidence linking prehypertension with associated morbidities has emerged. These studies are detailed below and provide further evidence for the treatment of prehypertension.

Sleep behavior and chronotype before and throughout pregnancy.

STUDY OBJECTIVE: To compare sleep behavior before and during pregnancy. METHODS: In this prospective cohort study, healthy women were followed from pre-pregnancy until delivery. At pre-pregnancy and each trimester, participants completed validated questionnaires of chronotype and sleep quality and timing, including the Munich ChronoType Questionnaire, Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index. The primary outcomes were sleep period start and end times, sleep duration, sleep midpoint, and social jetlag, compared between pre-pregnancy and each trimester. Wrist actigraphy was used to measure the same outcomes in a subset of participants. RESULTS: Eighty-six women were included in analysis of questionnaires. Of these, 37 provided complete actigraphy data. Questionnaire and actigraphy data indicate that participants had less social jetlag during pregnancy than before pregnancy. Sleep period start times were earlier on both work and free days in the first and second trimesters than pre-pregnancy, and returned to pre-pregnancy times by the third trimester. Actigraphy data revealed that, compared to pre-pregnancy, participants had longer sleep periods in all trimesters on work days and in the first trimester on free days. Sleep surveys revealed that participants had poorer sleep quality in the first and third trimesters and more sleepiness in the first trimester than pre-pregnancy. CONCLUSION: The first trimester of pregnancy is characterized by earlier sleep period start time, longer sleep duration, and poorer sleep quality than pre-pregnancy. Sleep quality temporarily improves in the second trimester, and sleep period start time returns to pre-pregnancy time by the third trimester. STUDY RATIONALE: Multiple parameters of sleep have been studied in the context of pregnancy and pregnancy outcomes, but rarely in comparison to pre-pregnancy or longitudinally through pregnancy. STUDY IMPACT: Actigraphy and questionnaire data reveal sleep timing and quality change throughout pregnancy. These data on sleep changes in healthy pregnancy can be used as a baseline to identify sleep-related risk factors throughout pregnancy.

Antenatal corticosteroids in preterm small-for-gestational age infants: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to estimate the effect of antenatal corticosteroid administration on neonatal mortality and morbidity in preterm small-for-gestational age infants through a systematic review and meta-analysis. DATA SOURCES: A predefined, systematic search was conducted through Ovid MEDLINE, Embase, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trial Registry Platform, and ClinicalTrials.gov yielding 5324 articles from 1970 to 2019. STUDY ELIGIBILITY CRITERIA: Eligible studies compared neonatal morbidity and mortality among small-for-gestational age infants delivered preterm who received antenatal corticosteroids with those who did not. METHODS: The primary outcome was neonatal mortality. Secondary outcomes were respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage and periventricular leukomalacia, bronchopulmonary dysplasia or chronic lung disease of prematurity, or neonatal sepsis. We assessed heterogeneity by means of Higgins I2 statistic and Cochran's Q test and calculated pooled odds ratios with 95% confidence intervals using random effects models. RESULTS: A total of 16 observational cohort and case-control studies published from 1995 to 2018 met the selection criteria for the systematic review and included 8989 preterm small-for-gestational age infants. Antenatal corticosteroid administration was explicitly reported among 8376 small-for-gestational age infants; 4631 (55.3%) received antenatal corticosteroids and 3741 (44.7%) did not. Of note, 13 studies including 6387 preterm small-for-gestational age infants were then included in the meta-analysis. Neonatal mortality was significantly lower among infants who received antenatal corticosteroids than those who did not (12 studies: 12.8% vs 15.1%; pooled odds ratio, 0.63; 95% confidence interval, 0.46-0.86), with significant heterogeneity between studies (I2=55.1%; P=.011). There was no significant difference in respiratory distress syndrome (12 studies: odds ratio, 0.89; 95% confidence interval, 0.69-1.15), necrotizing enterocolitis (7 studies: odds ratio, 0.93; 95% confidence interval, 0.70-1.22), intraventricular hemorrhage and periventricular leukomalacia (10 studies: odds ratio, 0.82; 95% confidence interval, 0.56-1.20), bronchopulmonary dysplasia or chronic lung disease of prematurity (8 studies: odds ratio, 1.11; 95% confidence interval, 0.88-1.41), or neonatal sepsis (6 studies: odds ratio, 1.13; 95% confidence interval, 0.86-1.49). CONCLUSION: These data indicate that antenatal corticosteroid administration reduces neonatal mortality in small-for-gestational age infants delivered preterm, with no apparent effect on neonatal morbidity. This supports the use of antenatal corticosteroids to reduce neonatal mortality in pregnancies with small-for-gestational age infants at risk of preterm birth.

Supporting Veterans in Massachusetts: An Assessment of Needs, Well-Being, and Available Resources.

Massachusetts is home to approximately 380,000 of the nation's more than 21 million veterans, but there has been little research on the resources available to this population at the state level. There are numerous resources available to veterans and other military-affiliated groups in Massachusetts, but there are still pockets of unmet need in the areas of education, employment, health care, housing, financial, and legal services-particularly for newer veterans and current National Guard/reserve members. Although Massachusetts veterans fare better overall than their peers in other states, they lag behind other Massachusetts residents in terms of health and financial status. Massachusetts veterans and National Guard/reserve members who need support and services face such barriers as a lack of knowledge about how to access services, a lack of awareness about eligibility, and geographic distance from service providers. As the veteran population changes both nationally and in Massachusetts, it will be important for public- and private-sector providers serving Massachusetts veterans and service members to continue addressing unmet needs while ensuring that resources are responsive to shifts in these populations. A better understanding of the unique needs of Massachusetts veterans can help inform investments in initiatives that target these populations and guide efforts to remedy barriers to accessing available support services and other resources.

Current and Projected Characteristics and Unique Health Care Needs of the Patient Population Served by the Department of Veterans Affairs.

The Veterans Access, Choice, and Accountability Act of 2014 addressed the need for access to timely, high-quality health care for veterans. Section 201 of the legislation called for an independent assessment of various aspects of veterans' health care. The RAND Corporation was tasked with an assessment of the current and projected demographics and health care needs of patients served by the Department of Veterans Affairs (VA). The number of U.S. veterans will continue to decline over the next decade, and the demographic mix and geographic locations of these veterans will change. While the number of veterans using VA health care has increased over time, demand will level off in the coming years. Veterans have more favorable economic circumstances than non-veterans, but they are also older and more likely to be diagnosed with many health conditions. Not all veterans are eligible for or use VA health care. Whether and to what extent an eligible veteran uses VA health care depends on a number of factors, including access to other sources of health care. Veterans who rely on VA health care are older and less healthy than veterans who do not, and the prevalence of costly conditions in this population is projected to increase. Potential changes to VA policy and the context for VA health care, including effects of the Affordable Care Act, could affect demand. Analysis of a range of data sources provided insight into how the veteran population is likely to change in the next decade.

Effect of Bupropion SR on the Quality of Life of Elderly Depressed Patients With Comorbid Medical Disorders.

BACKGROUND: There is a need for additional studies of the quality of life (QOL) of elderly depressed subjects with medical comorbidity. METHOD: We conducted an 8-week, open trial of bupropion sustained release (SR) in 18 elderly (60-81 years) subjects with DSM-IV major depressive disorder and one or more serious medical illnesses (e.g., congestive heart failure, type 1 diabetes mellitus, irritable bowel syndrome) with a week-12 follow-up interview. The intent-to-treat method with the last observation carried forward was used to analyze depression and QOL measures. Dosing was initiated at 100 mg once daily and increased at weekly intervals to a maximum of 150 mg twice daily as clinically indicated. RESULTS: Bupropion SR treatment was associated with reductions in Clinical Global Impressions-Severity of Illness scale (p <.0001) score and in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score (p <.0001). QOL as measured by the Medical Outcomes Study Short Form-36 (SF-36) also tended to improve with treatment. The SF-36 "mental health" (p <.01) and "social functioning" (p <.0006) domains improved significantly by week 4. "Vitality" (p <.03) improved significantly by week 12. On the HAM-D, statistically significant improvement was noted on "depressed mood" (p <.0001), "feelings of guilt" (p <.01), "work and activities" (p <.001), "hypochondriasis" (p <.02), and "insomnia" (p <.01) at week 8. The mean dose of bupropion SR at endpoint was 222 mg/day, and the drug was relatively well tolerated. Two subjects dropped out owing to adverse events and 2 owing to other reasons. No drug-drug interactions occurred. CONCLUSION: These data suggest that bupropion SR is well tolerated and may improve depression, insomnia, somatic symptoms, work functioning, and certain quality-of-life measures in elderly depressed subjects with medical disorders. A randomized, placebo-controlled study is warranted to confirm these promising findings.

Propofol and the risk of delirium: exploring the anticholinergic properties of propofol.

Delirium is a common pathologic event in both medical and surgical patients. It is essential to note that patients who develop delirium have worse long term outcomes. The etiology and pathogenesis of delirium are extremely complex and not entirely understood. Certain medications classes are implicated in delirium. For example, medications targeting muscarinic acetylcholine receptors are well known to be associated with delirium and altered mentation. Propofol is a medication commonly used in anesthesiology practice and sedation in intubated patients. In vitro studies provided evidence that propofol actively interacts with muscarinic acetylcholine receptors. Additionally, some, but not all clinical studies demonstrated that propofol led to delirium. Therefore, future prospective studies investigating the use of propofol and delirium occurrence are of paramount importance. These studies should adjust for such common confounders as patients' demographics and age, comorbid conditions, use of other medications, type of surgery, baseline cognitive status, etc. Another important task would be to research the susceptibility for propofol-related delirium. By studying these critical questions, we will gain additional insights into the complex etiology and pathobiology of delirium in addition to a better understanding of the pharmacology of propofol.