Citations

Abstract Objective: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. Methods: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E 2 ) 50 μg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ 2 tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. Results: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E 2 , and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E 2 , and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO ( P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months ( P = 0.002 and 0.05) and t-E 2 being more effective than PBO at 48 months ( P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. Conclusions: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT‐OD‐15–102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.—Miller, L. R., Marks, C., Becker, J.B., Hurn, P.D., Chen, W.‐J., Woodruff, T., McCarthy, M.M., Sohrabji, F., Schiebinger, L., Wetherington, C.L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research. FASEB J. 31, 29–34 (2017) www.fasebj.org

Summary Objective Infantile spasms ( IS ) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first‐line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome. Methods The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ ACTH ] or oral corticosteroids), vigabatrin, or “other.” Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi‐square tests and multivariable logistic regression models. Results One hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040). Significance Greater than one third of children with IS will respond to a second medication. Choosing a standard medication ( ACTH , oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.

Objective: The Lung Injury Prediction Score identifies patients at risk for acute respiratory distress syndrome in the emergency department, but it has not been validated in non-emergency department hospitalized patients. We aimed to evaluate whether Lung Injury Prediction Score identifies non-emergency department hospitalized patients at risk of developing acute respiratory distress syndrome at the time of critical care contact. Design: Retrospective study. Setting: Five academic medical centers. Patients: Nine hundred consecutive patients (≥ 18 yr old) with at least one acute respiratory distress syndrome risk factor at the time of critical care contact. Interventions: None. Measurements and Main Results: Lung Injury Prediction Score was calculated using the worst values within the 12 hours before initial critical care contact. Patients with acute respiratory distress syndrome at the time of initial contact were excluded. Acute respiratory distress syndrome developed in 124 patients (13.7%) a median of 2 days (interquartile range, 2–3) after critical care contact. Hospital mortality was 22% and was significantly higher in acute respiratory distress syndrome than non-acute respiratory distress syndrome patients (48% vs 18%; p < 0.001). Increasing Lung Injury Prediction Score was significantly associated with development of acute respiratory distress syndrome (odds ratio, 1.31; 95% CI, 1.21–1.42) and the composite outcome of acute respiratory distress syndrome or death (odds ratio, 1.26; 95% CI, 1.18–1.34). A Lung Injury Prediction Score greater than or equal to 4 was associated with the development of acute respiratory distress syndrome (odds ratio, 4.17; 95% CI, 2.26–7.72), composite outcome of acute respiratory distress syndrome or death (odds ratio, 2.43; 95% CI, 1.68–3.49), and acute respiratory distress syndrome after accounting for the competing risk of death (hazard ratio, 3.71; 95% CI, 2.05–6.72). For acute respiratory distress syndrome development, the Lung Injury Prediction Score has an area under the receiver operating characteristic curve of 0.70 and a Lung Injury Prediction Score greater than or equal to 4 has 90% sensitivity (misses only 10% of acute respiratory distress syndrome cases), 31% specificity, 17% positive predictive value, and 95% negative predictive value. Conclusions: In a cohort of non-emergency department hospitalized patients, the Lung Injury Prediction Score and Lung Injury Prediction Score greater than or equal to 4 can identify patients at increased risk of acute respiratory distress syndrome and/or death at the time of critical care contact but it does not perform as well as in the original emergency department cohort.

OBJECTIVE Historically, performing neurosurgery with the patient in the sitting position offered advantages such as improved visualization and gravity-assisted retraction. However, this position fell out of favor at many centers due to the perceived risk of venous air embolism (VAE) and other position-related complications. Some neurosurgical centers continue to perform sitting-position cases in select patients, often using modern monitoring techniques that may improve procedural safety. Therefore, this paper reports the risks associated with neurosurgical procedures performed in the sitting position in a modern series. METHODS The authors reviewed the anesthesia records for instances of clinically significant VAE and other complications for all neurosurgical procedures performed in the sitting position between January 1, 2000, and October 8, 2013. In addition, a prospectively maintained morbidity and mortality log of these procedures was reviewed for instances of subdural or intracerebral hemorrhage, tension pneumocephalus, and quadriplegia. Both overall and specific complication rates were calculated in relation to the specific type of procedure. RESULTS In a series of 1792 procedures, the overall complication rate related to the sitting position was 1.45%, which included clinically significant VAE, tension pneumocephalus, and subdural hemorrhage. The rate of any detected VAE was 4.7%, but the rate of VAE requiring clinical intervention was 1.06%. The risk of clinically significant VAE was highest in patients undergoing suboccipital craniotomy/craniectomy with a rate of 2.7% and an odds ratio (OR) of 2.8 relative to deep brain stimulator cases (95% confidence interval [CI] 1.2–70, p = 0.04). Sitting cervical spine cases had a comparatively lower complication rate of 0.7% and an OR of 0.28 as compared with all cranial procedures (95% CI 0.12–0.67, p < 0.01). Sitting cervical cases were further subdivided into extradural and intradural procedures. The rate of complications in intradural cases was significantly higher (OR 7.3, 95% CI 1.4–39, p = 0.02) than for extradural cases. The risk of VAE in intradural spine procedures did not differ significantly from sitting suboccipital craniotomy/craniectomy cases (OR 0.69, 95% CI 0.09–5.4, p = 0.7). Two cases (0.1%) had to be aborted intraoperatively due to complications. There were no instances of intraoperative deaths, although there was a single death within 30 days of surgery. CONCLUSIONS In this large, modern series of cases performed in the sitting position, the complication rate was low. Suboccipital craniotomy/craniectomy was associated with the highest risk of complications. When appropriately used with modern anesthesia techniques, the sitting position provides a safe means of surgical access.

Abstract This article is part of the To the Point Series prepared by the Association of Professors of Gynecology and Obstetrics Undergraduate Medical Education Committee. Principles and education in patient safety have been well integrated into academic obstetrics and gynecology practices, although progress in safety profiles has been frustratingly slow. Medical students have not been included in the majority of these ambulatory practice or hospital-based initiatives. Both the Association of American Medical Colleges and Accreditation Council for Graduate Medical Education have recommended incorporating students into safe practices. The Accreditation Council for Graduate Medical Education milestone 1 for entering interns includes competencies in patient safety. We present data and initiatives in patient safety, which have been successfully used in undergraduate and graduate medical education. In addition, this article demonstrates how using student feedback to assess sentinel events can enhance safe practice and quality improvement programs. Resources and implementation tools will be discussed to provide a template for incorporation into educational programs and institutions. Medical student involvement in the culture of safety is necessary for the delivery of both high-quality education and high-quality patient care. It is essential to incorporate students into the ongoing development of patient safety curricula in obstetrics and gynecology.

Abstract The completion of The Cancer Genome Atlas (TCGA) project for colorectal cancer (CRC) has enabled a new, focused phase of sequencing tumor samples for which genome-wide genetic, epidemiological, clinical and lifestyle data have been collected. By combining somatic mutational profiles with these aforementioned data, we may identify and report effective prevention and treatment approaches for a broader population of individuals. The advent of targeted deep sequencing approaches using DNA obtained from formalin fixed paraffin embedded tissues has made possible the genetic characterization of the large numbers of patients needed to make such an effort relevant. As a first step, we describe a custom gene panel designed from large-scale studies for targeted deep sequencing, and its application to over 4,200 CR tumors, collected by the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). This study is designed to identify recurrent somatic mutations and copy number alterations (CNAs) for association testing with germline genetic and lifestyle and environmental risk factors for CRC, and thereby identify relevant approaches to impact cancer prevention. The targeted CRC panel includes 205 genes. Genes were primarily selected as significantly mutated genes identified from the Nurses’ Health Study and Health Professional's Follow-up Study (n = 700), and TCGA (n = 525). We also included 15 genes associated with high penetrance germline mutations and augmented the list to include genes in pathways of somatically altered genes, identified by literature review, from public databases and known to be associated with loss of heterozygosity. For these 205 genes, amplification primers were designed to include all coding regions of transcripts that are listed in the UCSC Genome Browser. For regions with CNAs, the TCGA dataset was analyzed to include regions with greater than or equal to 2 copy focal gains or losses that were found in more than 4 or 3 tumors, respectively. Candidate genes in regions with significant CNAs from the TCGA CRC publication (Nature 2012) were also included. For CNAs, 6 to 12 amplicons were designed for each of the 56 selected regions (32 gains and 24 losses). Additional target regions include: 1) 25 microsatellite loci previously used to identify defective DNA mismatch repair and 212 homoploymer repeats. These include microsatellite loci recommended by the NCI Consensus Panel for identifying MSI; 2) amelogenin (for gender); and 3) Fusobacterium to detect a putative CRC-associated pathogen in tumor biopsies. At the AACR annual meeting, we expect to present results for deep sequencing (∼1,000X) of the first 1,000 CR tumors, including any preliminarily identified pathways and subtypes that may provide the basis for association testing with germline genetic and lifestyle and environmental risk factors needed for inferring better approaches to prevention and treatment of CRC. Citation Format: Syed H. Zaidi, Catie Grasso, Jasmine Mu, Eve Shinbrot, Marios Giannakis, Charles Connolly, Ivan Borozan, Hermann Brenner, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Mengmeng Du, Vincent Ferretti, Amy French, Charles Fuchs, Steven Gallinger, Levi Garraway, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen Huyghe, Mathieu Lemire, Elaine Mardis, John McPherson, Polly Newcomb, Lincoln Stein, Wei Sun, Lee Timms, Quang Trinh, David Wheeler, Christina Yung, Niha Zubair, Shuji Ogino, Stephen Thibodeau, Ulrike Peters, Thomas Hudson. Linking the molecular profile of colorectal tumors to germline genetic and environmental risk factors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5221.