MetroWest Medical Center

CONTEXT: The association of obesity with development of type 2 diabetes may be partly mediated by altered secretion of adipokines by adipose tissue. Greater adiposity down-regulates secretion of adiponectin, an adipokine with anti-inflammatory and insulin-sensitizing properties. The strength and consistency of the relation between plasma adiponectin and risk of type 2 diabetes is unclear. OBJECTIVE: To systematically review prospective studies of the association of plasma adiponectin levels and risk of type 2 diabetes. DATA SOURCES: A systematic search of the MEDLINE, EMBASE, and Science Citation Index Expanded databases using adiponectin and diabetes and various synonyms and reference lists of retrieved articles up to April 10, 2009. STUDY SELECTION: We included prospective studies with plasma adiponectin levels as the exposure and incidence of type 2 diabetes as the outcome variable. DATA EXTRACTION: Two reviewers independently extracted data and assessed study quality. Generalized least-squares trend estimation was used to assess dose-response relationships. Pooled relative risks and 95% confidence intervals were calculated using random-effects models to incorporate between-study variation. RESULTS: Thirteen prospective studies with a total of 14 598 participants and 2623 incident cases of type 2 diabetes were included in the meta-analysis. Higher adiponectin levels were monotonically associated with a lower risk of type 2 diabetes. The relative risk of type 2 diabetes was 0.72 (95% confidence interval, 0.67-0.78) per 1-log microg/mL increment in adiponectin levels. This inverse association was consistently observed in whites, East Asians, Asian Indians, African Americans, and Native Americans and did not differ by adiponectin assay, method of diabetes ascertainment, duration of follow-up, or proportion of women. The estimated absolute risk difference (cases per 1000 person-years) per 1-log microg/mL increment in adiponectin levels was 3.9 for elderly Americans and 30.8 for Americans with impaired glucose tolerance. CONCLUSION: Higher adiponectin levels are associated with a lower risk of type 2 diabetes across diverse populations, consistent with a dose-response relationship.

The variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of membrane-bound catechol-O-methyltransferase (MB-COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB-COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60%; P=0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81%; P=0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB-COMT in schizophrenia and bipolar disorder patients compared with the controls (P=0.02) with an accompanying inverse correlation between MB-COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB-COMT hypomethylation in the patients. These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder.

BACKGROUND: Aspirin products are known to cause irritation and injury to the gastric mucosa. The belief that enteric-coated and buffered varieties are less likely to occasion major upper-gastrointestinal bleeding (UGIB) than plain aspirin was tested in data from a multicentre case-control study. METHODS: 550 incident cases of UGIB admitted to hospital with melaena or haematemesis and confirmed by endoscopy, and 1202 controls identified from population census lists, were interviewed about use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) during the 7 days before the onset of bleeding (cases) or interview (controls). Relative risks of UGIB for each type of aspirin used regularly (at least every other day) were calculated overall, and according to dose, by multiple logistic regression, with control for age, sex, marital status, date, education, cigarette smoking, alcohol use, and use of NSAIDs. FINDINGS: The relative risks of UGIB for plain, enteric-coated, and buffered aspirin at average daily doses of 325 mg or less were 2.6, 2.7, and 3.1, respectively. At doses greater than 325 mg, the relative risk was 5.8 for plain and 7.0 for buffered aspirin; there were insufficient data to evaluate enteric-coated aspirin at this dose level. There were no important differences in risk attributable to the three aspirin forms according to bleeding site (gastric vs duodenal), or when users of NSAIDs were excluded. INTERPRETATION: Use of low doses of enteric-coated or buffered aspirin carries a three-fold increase in the risk of major UGIB. The assumption that these formulations are less harmful than plain aspirin may be mistaken.

DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol-chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73% of the trials (16 of 22) in schizophrenic patients compared with 24% (5 of 21) of controls. Thus, the hypermethylation of the CpG islands flanking a CRE and SP1 binding site observed at a significantly higher level (t = -5.07, P = 0.001) may provide a mechanism for the decreased RELN expression, frequently observed in post-mortem brains of schizophrenic patients. We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR. Despite the small sample size, these studies indicate that promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELN gene hypoactivity in schizophrenia. Further studies with a larger sample set would be required to validate these preliminary observations.

Acute hepatitis A superimposed on chronic liver disease (CLD) has been associated with severe or fulminant hepatitis. An open, multicenter study was performed to compare the safety and immunogenicity of an inactivated hepatitis A vaccine in patients with CLD with that in healthy subjects. A secondary objective was to compare the safety of the hepatitis A vaccine with that of a commercial hepatitis B vaccine in subjects with chronic hepatitis C. A total of 475 subjects over the age of 18 years were enrolled into 1 of 5 groups according to history, serological data, and previous diagnosis. Patients in groups 1 (healthy adults), 2 (chronic hepatitis B), 3 (chronic hepatitis C), and 5 (other CLD not caused by viral hepatitis) were vaccinated with two doses of inactivated hepatitis A vaccine, 6 months apart. Patients in group 4 (chronic hepatitis C) received 3 doses of a recombinant hepatitis B vaccine, according to a 0-, 1-, and 6-month schedule. Local injection-site symptoms were the most common reactions reported following vaccination in all groups (35.5% of all doses), with the hepatitis B vaccine eliciting fewer injection-site symptoms than the hepatitis A vaccine (19.8% compared with 37.5%). Although a higher percentage of healthy subjects (93%) seroconverted after a single dose of the hepatitis A vaccine than did subjects with chronic hepatitis C (73.7%) or CLD of nonviral etiologies (83.1%), more than 94% of all vaccinees were seropositive for anti-HAV after the complete vaccination course. At each time point, a lower geometric mean concentration of anti-HAV was observed for each group of CLD patients compared with the healthy control subjects. In conclusion, hepatitis A vaccine was well tolerated and induced a satisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.

OBJECTIVES: The American Academy of Pediatrics (AAP) believes that health education, through office-based counseling, can contribute to childhood injury prevention. This report presents the results of a critical review of the scientific literature on the effectiveness of primary care-based counseling to prevent childhood unintentional injury. METHODS: A panel selected from the AAP Committee and the AAP Section on Injury and Poison Prevention searched the English-language scientific literature for all articles about childhood unintentional injury prevention counseling. A standardized format was developed to record data on each study. Two members of the panel independently reviewed each article. Articles that were original reports and in which unintentional injury prevention counseling took place in a primary care setting were included. Articles were encoded and analyzed by computer and then grouped by quality of evidence using the US Preventive Services Task Force (USPSTF) method of categorizing results of medical care evaluation. Articles were rated by strength of study design in order to compare studies within each USPSTF group. RESULTS: Twenty articles met the criteria for inclusion. Of these, 18 showed positive effects of injury prevention counseling including five randomized/controlled, 10 non-randomized/controlled, two multiple time series, and one descriptive study. In 15 of the positive studies, physicians performed the counseling. Positive outcomes as measured by increased knowledge, improved behavior, or decreased injury occurrence were reported for both motor vehicle and non-motor vehicle injuries. CONCLUSIONS: The literature review supports the recommendation of the AAP to include injury prevention counseling as part of routine health supervision. This recommendation has implications for health care reimbursement and care content.

Fine-tuning of neuronal connections during development is regulated through environmental interactions. Some fine-tuning occurs through changes in gene expression and/or epigenetic gene-specific DNA methylation states. DNA methylation occurs by transfer of a methyl group from S-adenosyl methionine to cytosine residues in the dinucleotide sequence CpG. Although CpG sequences spread throughout the genome are usually heavily methylated, those occurring in CpG islands in the promoter regions of genes are less methylated. In most cases, the extent of DNA methylation correlates with the extent of gene inactivation. Other known epigenetic mechanisms include histone deacetylation and chromatin remodeling, RNA inhibition, RNA modification, and DNA rearrangement. Exposure memory expressed as epigenetic DNA modifications allows genomic plasticity and short-term adaptation of each generation to their environment. Environmental factors that affect DNA methylation include diet, proteins, drugs, and hormones. Induced methylation changes may produce altered gene response upon subsequent hormonal stimulation. The gene-specific DNA methylation state may be preserved upon transmission through mitosis and meiosis. An increasing amount of data implicates a role for DNA methylation in multi-factorial psychiatric disorders. For example, L-methionine treatment can exacerbate psychosis; while valproate, a drug producing hypomethylated DNA, reduces such symptoms. Hypermethylation of the promoter region of the RELN gene correlates with reduced gene expression. This gene's protein Reelin, which is necessary for neuronal migration and synaptogenesis, is reduced in schizophrenia and bipolar disorder, suggesting hypermethylation of the promoter region in these disorders. Some evidence implicates methylation of the promoter regions of the DRD2 and HTR2A genes in schizophrenia and mood disorders as well. DNA methylation usually increases with age, although hypomethylation of the promoter region of the amyloid A4 precursor gene during aging may play a role in Alzheimer's disease. More studies are needed to define the role of methylomics and other epigenetic phenomena in the nervous system.

Objective: To estimate the cost-effectiveness of interferon-α2B for the treatment of patients with chronic hepatitis B infection who are positive for hepatitis B e antigen (HBeAg). Design: Meta-analysis of nine randomized, controlled trials and cost-effectiveness analysis, projecting the clinical and economic outcomes expected from changes in serologic markers of hepatitis B viral replication. Data Sources: MEDLINE search, expert panel opinion, hospital cost data, and adjusted physician charges. Patients: 552 patients with confirmed chronic hepatitis B infection who were positive for HBeAg. Intervention: Interferon-α2b. Measurements: Lifetime incidence of cirrhosis and hepatocellular carcinoma; life expectancy; quality-adjusted life expectancy; and costs and marginal cost-effectiveness ratios from a societal perspective. Results: Interferon-α2b increases the likelihood of becoming negative for HBeAg from 9.1% to 45.6% (difference, 36.5%; 95% CI, 23.7% to 49.2%) and of becoming negative for hepatitis B surface antigen from 1.7% to 7.7% (difference, 6.0%; CI, 2.8% to 9.3%) in the first year. For a 35-year-old person with chronic hepatitis B who is HBeAg positive, our analysis suggests that interferon-α2b will increase life expectancy by 3.1 years or 3.4 quality-adjusted life-years and will decrease projected lifetime costs, even if future savings are discounted; thus, interferon-α2b is the dominant strategy. Even with the model biased strongly in favor of standard care, the marginal cost-effectiveness ratio of interferon did not exceed $12 000 per life-year gained. Conclusions: Interferon-α2b should prolong life and lower costs for patients with chronic hepatitis B who are HBeAg positive.

BACKGROUND: The reported risk of hypomagnesemia in patients with proton pump inhibitor (PPI) use is conflicting. The objective of this meta-analysis was to assess the association between the use of PPIs and the risk of hypomagnesemia. METHODS: A literature search of observational studies was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception through September 2014. Studies that reported odd ratios or hazard ratios comparing the risk of hypomagnesemia in patients with PPI use were included. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Nine observational studies (three cohort studies, five cross-sectional studies and a case-control study) with a total of 109,798 patients were identified and included in the data analysis. The pooled RR of hypomagnesemia in patients with PPI use was 1.43 (95% CI, 1.08-1.88). The association between the use of PPIs and hypomagnesemia remained significant after the sensitivity analysis including only studies with high quality score (Newcastle-Ottawa scale score ≥ 8) with a pooled RR of 1.63 (95% CI, 1.14-2.23). CONCLUSIONS: Our study demonstrates a statistically significant increased risk of hypomagnesemia in patients with PPI use. The finding of this meta-analysis of observational studies suggests that PPI use is associated with hypomagnesemia and may impact clinical management of patients who are taking PPIs and at risk for hypomagnesemia related cardiovascular events.

Abstract Thyroid disorders have emerged as one of the most common immune-related adverse events associated with anti–PD-1 monotherapy or combination anti–PD-1 and anti–CTLA-4 therapy. This study characterizes and compares the evolution of monotherapy and combination therapy-related thyroid disorders. We analyzed the dynamic evolution of thyroid disorders in 45 patients who developed thyroid disorders following treatment with either anti–PD-1 monotherapy or anti–PD-1 and anti–CTLA-4 combination therapy. The patients presented with thyrotoxicosis or hypothyroidism as the initial presentation of their thyroid disorder. Thyrotoxicosis as the initial presentation occurred in the majority of patients (93% and 56% of the patients receiving combination therapy and monotherapy, respectively). The onset pattern of the thyroid disorder was significantly different between the two groups (P = 0.01). Subsequently, 76% and 90% of the patients with thyrotoxicosis evolved to develop hypothyroidism in the combination and monotherapy groups, respectively. In the combination therapy and monotherapy groups, the median times to onset of thyrotoxicosis and hypothyroidism after first treatment were 21 and 63 days, and 31 and 68 days, respectively. The median time for transition from thyrotoxicosis to hypothyroidism was 42 days in both groups. Our study demonstrates that most thyroid disorders induced by either anti–PD-1 or combination anti–PD-1 and anti–CTLA-4 therapy are thyroiditis. The time to onset of thyrotoxicosis after treatment initiation and evolution of thyrotoxicosis to hypothyroidism was short, emphasizing the importance of close monitoring of thyroid function in these patients. Cancer Immunol Res; 5(12); 1133–40. ©2017 AACR.

Do healthy work environments (HWEs) facilitate new graduate transition into professional practice in hospitals? Are such environments related to a decrease in Environmental Reality Shock? Experienced nurses in 17 Magnet hospitals completed the Essentials of Magnetism II(©) (EOMII(©)) instrument that measures health of unit work environments. New graduates (N = 468) were then tracked with modified versions of the EOMII(©) from immediate post hire to 4, 8, and 12 months post hire to ascertain degree of Environmental Reality Shock. New graduate nurses have extremely high anticipations of unit work environments that would enable delivery of quality patient care. HWE is the most-significant variable in Environmental Reality Shock, number of related Issues and Concerns, and perceptions of quality of patient care. Suggestions of how to improve quality of unit work environments are offered.

The rupture of vulnerable atherosclerotic plaque accounts for the majority of clinically significant acute cardiovascular events. Because stability of these culprit lesions is directly related to chemical and morphological composition, Raman spectroscopy may be a useful technique for their study. Recent developments in optical fiber probe technology have allowed for the real-time in vivo Raman spectroscopic characterization of human atherosclerotic plaque demonstrated in this work. We spectroscopically examine 74 sites during carotid endarterectomy and femoral artery bypass surgeries. Of these, 34 are surgically biopsied and examined histologically. Excellent signal-to-noise ratio spectra are obtained in only 1 s and fit with an established model, demonstrating accurate tissue characterization. We also report the first evidence that Raman spectroscopy has the potential to identify vulnerable plaque, achieving a sensitivity and specificity of 79 and 85%, respectively. These initial findings indicate that Raman spectroscopy has the potential to be a clinically relevant diagnostic tool for studying cardiovascular disease.

OBJECTIVE: To determine whether patellofemoral (PF), tibiofemoral (TF), and combined patterns of knee osteoarthritis (OA) differ in their strengths of associations with any of the known risk factors for knee OA, and especially to evaluate whether body mass index (BMI) correlates with all 3 patterns, or only with tibiofemoral disease, as previously suggested. METHODS: We obtained anteroposterior and lateral knee radiographs on 608 participants at the 22nd biennial examination of the Framingham cohort study (1992-3). The presence or absence of OA in the TF and PF compartments of each knee was scored, and subjects were classified on the basis of the pattern of compartmental involvement in their 2 knees. The strength of association of age, sex, BMI, chondrocalcinosis, and knee injury was computed for PF, TF, and combined pattern of knee OA using multiple logistic regression. RESULTS: The mean age and BMI of the sample were 80.7 yrs (SD 5.0) and 25.4.kg-2 (SD 3.7), respectively. PF, TF, and combined patterns of knee OA were present in 5.3, 23.0 and 19.7%, respectively. Elevated BMI was a risk factor for all 3 patterns of disease (adjusted OR for highest vs lowest tertile of BMI 3.7, 1.9, and 7.0 for PF, TF, and combined pattern, respectively). Risk factor profiles were broadly similar for TF and PF OA, with the possible exception of knee injury in men (adjusted OR = 2.0 for PF, 3.7 for TF OA). Risk factors were generally more strongly associated with the combined pattern of OA. CONCLUSION: Obesity is an important risk factor for PF, TF, and combined patterns of knee OA. The relationships of these patterns with the risk factors investigated here appear similar and are strongest for the combined pattern.

BACKGROUND: Age-related cataract is a major cause of visual impairment in the elderly. Oxidative stress has been implicated in its formation and progression. Antioxidant vitamin supplementation has been investigated in this context. OBJECTIVES: To assess the effectiveness of antioxidant vitamin supplementation in preventing and slowing the progression of age-related cataract. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 2), MEDLINE (January 1950 to March 2012), EMBASE (January 1980 to March 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to March 2012), Open Grey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 2 March 2012. We also checked the reference lists of included studies and ongoing trials and contacted investigators to identify eligible randomized trials. SELECTION CRITERIA: We included only randomized controlled trials in which supplementation with one or more antioxidant vitamins (beta-carotene, vitamin C and vitamin E) in any form, dosage or combination for at least one year was compared to another antioxidant vitamin or to placebo. DATA COLLECTION AND ANALYSIS: Two authors extracted data and assessed trial quality independently. We pooled results for the primary outcomes, i.e., incidence of cataract and incidence of cataract extraction. We did not pool results of the secondary outcomes - progression of cataract and loss of visual acuity, because of differences in definitions of outcomes and data presentation. We pooled results by type of cataract when data were available. We did not perform a sensitivity analysis. MAIN RESULTS: Nine trials involving 117,272 individuals of age 35 years or older are included in this review. The trials were conducted in Australia, Finland, India, Italy, the United Kingdom and the United States, with duration of follow-up ranging from 2.1 to 12 years. The doses of antioxidant vitamins were higher than the recommended daily allowance. There was no evidence of effect of antioxidant vitamin supplementation in reducing the risk of cataract, cataract extraction, progression of cataract or in slowing the loss of visual acuity. In the pooled analyses, there was no evidence of effect of beta-carotene supplementation in reducing the risk of cataract (two trials) (relative risk (RR) 0.99, 95% confidence interval (CI) 0.91 to 1.08; n = 57,703) or in reducing the risk of cataract extraction (three trials) (RR 1.00, 95% CI 0.91 to 1.10; n = 86,836) or of vitamin E supplementation in reducing the risk of cataract (three trials) (RR 0.97, 95% CI 0.91 to 1.04; n = 50,059) or of cataract extraction (five trials) (RR 0.98, 95% CI 0.91 to 1.05; n = 83,956). The proportion of participants developing hypercarotenodermia (yellowing of skin) while on beta-carotene ranged from 7.4% to 15.8%. AUTHORS' CONCLUSIONS: There is no evidence from RCTs that supplementation with antioxidant vitamins (beta-carotene, vitamin C or vitamin E) prevents or slows the progression of age-related cataract. We do not recommend any further studies to examine the role of antioxidant vitamins beta-carotene, vitamin C and vitamin E in preventing or slowing the progression of age-related cataract. Costs and adverse effects should be weighed carefully with unproven benefits before recommending their intake above recommended daily allowances.

The number of systematic review and meta-analyses on plantar fasciitis is expanding. The purpose of this review was to provide a comprehensive summary of reviews on the topic pertaining to plantar fasciitis, identify any conflicting and inconsistent results, and propose future research direction. A qualitative review of all systematic reviews and meta-analyses related to plantar fasciitis up to February 2021 was performed using PubMed, Embase, Web of Science, and the Cochrane Database. A total of 1052 articles were initially identified and 96 met the inclusion criteria. Included articles were summarized and divided into the following topics: epidemiology, diagnosis, and treatment. While the majority of reviews had high level of heterogeneity and included a small number of studies, there was general consensus on certain topics, such as BMI as a risk factor for plantar fasciitis and extracorporeal shockwave therapy as an effective mode of therapy. A qualitative summary of systematic reviews and meta-analyses published on plantar fasciitis provides a single source of updated information for clinicians. Evidence on topics such as the epidemiology, exercise therapy, or cost-effectiveness of treatment options for plantar fasciitis are lacking and warrant future research.

INTRODUCTION: Preterm birth is a major contributor to neonatal morbidity and mortality and its rate has been increasing over the past two decades. Antidepressant medication use during pregnancy has also been rising, with rates up to 7.5% in the US. The objective was to systematically review the literature to determine the strength of the available evidence relating to a possible association between antidepressant use during pregnancy and preterm birth. METHODS: We conducted a computerized search in PUBMED, MEDLINE and PsycINFO through September 2012, supplemented with a manual search of reference lists, to identify original published research on preterm birth rates in women taking antidepressants during pregnancy. Data were independently extracted by two reviewers, and absolute and relative risks abstracted or calculated. Our a priori design was to group studies by level of confounding adjustment and by timing of antidepressant use during pregnancy; we used random-effects models to calculate summary measures of effect. RESULTS: Forty-one studies met inclusion criteria. Pooled adjusted odds ratios (95% CI) were 1.53 (1.40-1.66) for antidepressant use at any time and 1.96 (1.62-2.38) for 3rd trimester use. Controlling for a diagnosis of depression did not eliminate the effect. There was no increased risk [1.16 (0.92-1.45)] in studies that identified patients based on 1st trimester exposure. Sensitivity analyses demonstrated unmeasured confounding would have to be strong to account for the observed association. DISCUSSION: Published evidence is consistent with an increased risk of preterm birth in women taking antidepressants during the 2nd and 3rd trimesters, although the possibility of residual confounding cannot be completely ruled out.

OBJECTIVE: Major upper gastrointestinal bleeding (UGIB) is the most important adverse effect of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Alcoholic beverages also precipitate UGIB. This analysis was conducted to evaluate whether the deleterious effects of NSAIDs are further increased among drinkers. METHODS: An interview-based, case-control study was conducted in the U.S. and Sweden; 1224 patients hospitalized with acute major UGIB due to newly occurring peptic ulcer or gastritis were compared to 2945 neighbor controls. RESULTS: Compared with those who drank less than one drink/wk, the relative risk of acute UGIB increased with increasing alcohol consumption, rising to 2.8 among those who drank > or = 21 drinks/wk. Among current drinkers, the relative risk of acute UGIB due to the use of aspirin was raised at all levels of alcohol consumption; the estimate for aspirin taken at least every other day (regular use) at doses of > 325 mg among all current drinkers combined was 7.0; for regular use at lower doses, the corresponding estimate was 2.8, and for any occasional use, it was 2.4. All estimates were statistically significant. Data for ibuprofen were more limited, but the relative risk estimates did not appear to vary consistently with level of alcohol consumption. For regular use (all doses combined), the estimate among all drinkers combined was significantly elevated, at 2.7; occasional ibuprofen use was not associated with UGIB (1.2). There were insufficient data to evaluate other NSAIDs according to alcohol consumption. CONCLUSIONS: The findings suggest that acute UGIB is similarly associated with the use of the two most common nonprescription NSAIDs, aspirin and ibuprofen, at all levels of alcohol consumption. As heavy alcohol intake independently increases the risk, the incidence of UGIB is highest among persons who are both heavy drinkers and users of aspirin or ibuprofen.

Everolimus, a proliferation signal inhibitor in the mammalian target of rapamycin (mTOR) drug class, has many clinical applications, including in organ transplantation, oncology, and cardiology. It currently has United States Food and Drug Administration (FDA) approval for prophylaxis against rejection in de novo renal transplant recipients, treatment of renal cell carcinoma, and use as a drug-eluting stent. To review the pharmacology, pharmacokinetics, efficacy, and safety of everolimus, we performed a search of the MEDLINE database (January 1997-April 2010) for all English-language articles of in vitro and in vivo studies that evaluated everolimus, as well as abstracts from recent scientific meetings and the manufacturer. In transplantation, everolimus demonstrates immunosuppressive properties and has been used to prevent acute rejection in cardiac, liver, lung, and renal transplant recipients. It appears that this agent may be potent enough to allow for the minimization or removal of calcineurin inhibitors in the long-term management of renal transplant recipients. In oncology, everolimus has been proven effective for the management of treatment-resistant renal cell carcinoma. In cardiology, everolimus is available as a drug-coated stent and is used in percutaneous coronary interventions for prevention of restenosis. In transplant recipients and patients with renal cell carcinoma, everolimus appears to have an extensive adverse-event profile. The pharmacologic properties of everolimus differentiate this agent from other drugs used in these clinical areas, and its pharmacokinetic properties differentiate it from sirolimus.

Several targeted therapies have shown efficacy in patients with advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJC), including anti-angiogenic agents and immune checkpoint inhibitors. Ramucirumab, an anti-VEGFR2 antibody, has shown efficacy in GC, but the benefits are limited, in part due to MET-mediated resistance. Other VEGF targeted agents like VEGF tyrosine kinase inhibitors (TKIs) with broad multi-kinase inhibitory spectrum like regorafenib and cabozantinib have also shown modest single agent activity in early phase trials. For immune checkpoint inhibitors, pembrolizumab (anti-PD-1) monotherapy confers survival advantage as 3rd line therapy for the PD-L1 expressing GC and GEJC population and has been approved for use in this setting. Extensive tumor microenvironment immune modulatory effects from antiangiogenic agents have been demonstrated from preclinical data which support the clinical study rationale of dual blockade of VEGF and immune checkpoint. In addition, FDA has approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in hepatocellular carcinoma and renal cell carcinoma. Promising clinical activity has been demonstrated in patients with refractory GC/GEJC when treated with dual blockade combination with antiangiogenic agents and immune checkpoint inhibitors like PD-1/PD-L1 inhibitors in several phase I/II trials. This review highlights the trials investigating these novel combinations as well as their preclinical rationale.

AIM: To describe extent to which experienced nurses in Magnet hospitals confirm healthy work environments (HWE). BACKGROUND: Differentiating differences in HWE allows managers to focus attention where changes may be needed to improve nurse and patient outcomes. METHOD: The sample was 12,233 experienced nurses from 717 clinical units in 34 Magnet hospitals. Based on Essentials of Magnetism II unit level scores, units were grouped as very healthy work environments (VHWE), HWE or work environments needing improvement. RESULTS: VHWE or HWE was confirmed by nurses on 82% of 540 clinical units. The most significant correlates of HWE units occur within individual hospitals. More nurses prepared at the Bachelor of Science in Nursing level or above work on VHWE or HWE units and score higher on seven essential work processes. Nurses' ratings of quality of patient care directly correlate to quality of work environment. CONCLUSIONS: Clinical units in 34 Magnet hospitals were markedly skewed toward excellence. Visionary leadership, empowerment and collaboration have an impact on development and maintenance of HWE. IMPLICATIONS FOR NURSING MANAGEMENT: Implementation of structures that promote interdisciplinary and intradisciplinary collaboration and decision-making positively affect development of HWE. Gap analysis of the steps/components of the eight work processes/relationships essential to HWE may enable achievement of HWEs on all hospital clinical units.