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1.  Bayesian Models for Multiple Outcomes in Domains with Application to the Seychelles Child Development Study 
The Seychelles Child Development Study (SCDS) examines the effects of prenatal exposure to methylmercury on the functioning of the central nervous system. The SCDS data include 20 outcomes measured on 9-year old children that can be classified broadly in four outcome classes or “domains”: cognition, memory, motor, and social behavior. Previous analyses and scientific theory suggest that these outcomes may belong to more than one of these domains, rather than only a single domain as is frequently assumed for modeling. We present a framework for examining the effects of exposure and other covariates when the outcomes may each belong to more than one domain and where we also want to learn about the assignment of outcomes to domains.
Each domain is defined by a sentinel outcome which is preassigned to that domain only. All other outcomes can belong to multiple domains and are not preassigned. Our model allows exposure and covariate effects to differ across domains and across outcomes within domains, and includes random subject-specific effects which model correlations between outcomes within and across domains. We take a Bayesian MCMC approach. Results from the Seychelles study and from extensive simulations show that our model can effectively determine sparse domain assignment, and at the same time give increased power to detect overall, domain-specific and outcome-specific exposure and covariate effects relative to separate models for each endpoint. When fit to the Seychelles data, several outcomes were classified as partly belonging to domains other than their originally assigned domains. In retrospect, the new partial domain assignments are reasonable and, as we discuss, suggest important scientific insights about the nature of the outcomes. Checks of model misspecification were improved relative to a model that assumes each outcome is in a single domain.
PMCID: PMC3979566  PMID: 24729645
Bayesian variable selection; Latent variable model; Markov chain Monte Carlo; Methylmercury; Sparsity
2.  The Clinical Education Partnership Initiative: an innovative approach to global health education 
BMC Medical Education  2014;14:1043.
Despite evidence that international clinical electives can be educationally and professionally beneficial to both visiting and in-country trainees, these opportunities remain challenging for American residents to participate in abroad. Additionally, even when logistically possible, they are often poorly structured. The Universities of Washington (UW) and Nairobi (UoN) have enjoyed a long-standing research collaboration, which recently expanded into the UoN Medical Education Partnership Initiative (MEPI). Based on MEPI in Kenya, the Clinical Education Partnership Initiative (CEPI) is a new educational exchange program between UoN and UW. CEPI allows UW residents to partner with Kenyan trainees in clinical care and teaching activities at Naivasha District Hospital (NDH), one of UoN’s MEPI training sites in Kenya.
UW and UoN faculty collaborated to create a curriculum and structure for the program. A Chief Resident from the UW Department of Medicine coordinated the program at NDH. From August 2012 through April 2014, 32 UW participants from 5 medical specialties spent between 4 and 12 weeks working in NDH. In addition to clinical duties, all took part in formal and informal educational activities. Before and after their rotations, UW residents completed surveys evaluating clinical competencies and cross-cultural educational and research skills. Kenyan trainees also completed surveys after working with UW residents for three months.
UW trainees reported a significant increase in exposure to various tropical and other diseases, an increased sense of self-reliance, particularly in a resource-limited setting, and an improved understanding of how social and cultural factors can affect health. Kenyan trainees reported both an increase in clinical skills and confidence, and an appreciation for learning a different approach to patient care and professionalism.
After participating in CEPI, both Kenyan and US trainees noted improvement in their clinical knowledge and skills and a broader understanding of what it means to be clinicians. Through structured partnerships between institutions, educational exchange that benefits both parties is possible.
Electronic supplementary material
The online version of this article (doi:10.1186/s12909-014-0246-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4335420  PMID: 25547408
International; Clinical rotation; Medical education; Residents; Kenya
3.  Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins 
The Journal of Cell Biology  2014;205(6):847-862.
Intramembrane proteolytic cleavage by signal peptide peptidase is required for the turnover of some ER-resident, tail-anchored membrane proteins.
The regulated turnover of endoplasmic reticulum (ER)–resident membrane proteins requires their extraction from the membrane lipid bilayer and subsequent proteasome-mediated degradation. Cleavage within the transmembrane domain provides an attractive mechanism to facilitate protein dislocation but has never been shown for endogenous substrates. To determine whether intramembrane proteolysis, specifically cleavage by the intramembrane-cleaving aspartyl protease signal peptide peptidase (SPP), is involved in this pathway, we generated an SPP-specific somatic cell knockout. In a stable isotope labeling by amino acids in cell culture–based proteomics screen, we identified HO-1 (heme oxygenase-1), the rate-limiting enzyme in the degradation of heme to biliverdin, as a novel SPP substrate. Intramembrane cleavage by catalytically active SPP provided the primary proteolytic step required for the extraction and subsequent proteasome-dependent degradation of HO-1, an ER-resident tail-anchored protein. SPP-mediated proteolysis was not limited to HO-1 but was required for the dislocation and degradation of additional tail-anchored ER-resident proteins. Our study identifies tail-anchored proteins as novel SPP substrates and a specific requirement for SPP-mediated intramembrane cleavage in protein turnover.
PMCID: PMC4068138  PMID: 24958774
4.  Echinoderm conundrums: Hox genes, heterochrony, and an excess of mouths 
EvoDevo  2014;5(1):46.
Two issues relating to the translocation of anterior Hox genes in echinoderms to the 5’ end of the Hox cluster are discussed: i) that developmental changes associated with fixation to the substratum have led to an acceleration of mesodermal development relative to that of ectoderm, resulting in a mismatch of anteroposterior registry between the two tissues and a larger role for mesoderm in patterning control, and ii) whether this helps explain the ability of some echinoderms to form separate mouths at different locations, one for the larva and one for the juvenile rudiment. Freeing the mesoderm from ectodermal influences may have encouraged morphogenetic innovation, paralleling the situation in tunicates, where an early genomic (or genomic and developmental) change has allowed the body to evolve in novel ways.
PMCID: PMC4297399  PMID: 25598963
Body plan; Echinoderms; Heterochrony; Hox genes; Hydrocoel
6.  Protected Areas in Tropical Africa: Assessing Threats and Conservation Activities 
PLoS ONE  2014;9(12):e114154.
Numerous protected areas (PAs) have been created in Africa to safeguard wildlife and other natural resources. However, significant threats from anthropogenic activities and decline of wildlife populations persist, while conservation efforts in most PAs are still minimal. We assessed the impact level of the most common threats to wildlife within PAs in tropical Africa and the relationship of conservation activities with threat impact level. We collated data on 98 PAs with tropical forest cover from 15 countries across West, Central and East Africa. For this, we assembled information about local threats as well as conservation activities from published and unpublished literature, and questionnaires sent to long-term field workers. We constructed general linear models to test the significance of specific conservation activities in relation to the threat impact level. Subsistence and commercial hunting were identified as the most common direct threats to wildlife and found to be most prevalent in West and Central Africa. Agriculture and logging represented the most common indirect threats, and were most prevalent in West Africa. We found that the long-term presence of conservation activities (such as law enforcement, research and tourism) was associated with lower threat impact levels. Our results highlight deficiencies in the management effectiveness of several PAs across tropical Africa, and conclude that PA management should invest more into conservation activities with long-term duration.
PMCID: PMC4254933  PMID: 25469888
7.  Model Averaging Procedure for Partially Linear Single-index Modelsa 
This paper is concerned with model selection and model averaging procedures for partially linear single-index models. The profile least squares procedure is employed to estimate regression coefficients for the full model and submodels. We show that the estimators for submodels are asymptotically normal. Based on the asymptotic distribution of the estimators, we derive the focused information criterion (FIC), formulate the frequentist model average (FMA) estimators and construct proper confidence intervals for FMA estimators and FIC estimator, a special case of FMA estimators. Monte Carlo studies are performed to demonstrate the superiority of the proposed method over the full model, and over models chosen by AIC or BIC in terms of coverage probability and mean squared error. Our approach is further applied to real data from a male fertility study to explore potential factors related to sperm concentration and estimate the relationship between sperm concentration and monobutyl phthalate.
PMCID: PMC4021728  PMID: 24839347
Profile least squares procedure; AIC; BIC; Focused information criterion (FIC); Frequentist model averaging (FMA)
8.  Prospective Evaluation of Hot Flashes during Pregnancy and Postpartum 
Fertility and sterility  2013;100(6):1667-1672.
To determine the prevalence, course, and risk factors for hot flashes during pregnancy and postpartum.
Study Design
Women (N=429) were assessed prospectively during pregnancy (weeks 20, 30, 36) and up to a year after delivery (weeks 2, 12, 26, 52). A clinical interview, physical measurements, and questionnaires were administered at each visit.
Thirty-five percent of women reported hot flashes during pregnancy and 29% reported hot flashes after delivery. In multivariable binomial mixed effects models, women who were younger (per year: OR(95%CI): 0.94(0.88–0.99)), had a higher pre-pregnancy body mass index (BMI; per unit increase: OR(95%CI): 1.05(1.01–1.10)), and had less than a college education (OR(95%CI): 2.58(1.19–5.60); vs. college) were more likely to report hot flashes during pregnancy. Higher depressive symptoms were associated with hot flashes during pregnancy (per unit increase: OR(95%CI): 1.08(1.04–1.13)) and after birth (OR(95%CI): 1.19(1.14–1.25), multivariable models).
Hot flashes, typically considered a menopausal symptom, were reported by over a third of women during pregnancy and/or postpartum. Predictors of hot flashes during this reproductive transition, including depressive symptoms, low education, and higher BMI are similar to those experienced during menopause. Future work should investigate the role of hormonal and affective factors in hot flashes during pregnancy and postpartum.
PMCID: PMC4167790  PMID: 24035604
Hot flashes; pregnancy; postpartum; night sweats; vasomotor symptoms
9.  Selective Internal Radiation Therapy (SIRT) with yttrium-90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first-line treatment of non-resectable liver metastases from colorectal cancer: the SIRFLOX study 
BMC Cancer  2014;14(1):897.
In colorectal cancer (CRC), unresectable liver metastases are linked to poor prognosis. Systemic chemotherapy with regimens such as FOLFOX (combination of infusional 5-fluorouracil, leucovorin and oxaliplatin) is the standard first-line treatment. The SIRFLOX trial was designed to assess the efficacy and safety of combining FOLFOX-based chemotherapy with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, North Sydney, Australia).
SIRFLOX is a randomised, multicentre trial of mFOLFOX6 chemotherapy ± SIRT as first-line treatment of patients with liver-only or liver-predominant metastatic CRC (mCRC). The trial aims to recruit adult chemotherapy-naïve patients with proven liver metastases with or without limited extra-hepatic disease, a life expectancy of ≥3 months and a WHO performance status of 0–1. Patients will be randomised to receive either mFOLFOX6 or SIRT + mFOLFOX6 (with a reduced dose of oxaliplatin in cycles 1–3 following SIRT). Patients in both arms can receive bevacizumab at investigator discretion. Protocol chemotherapy will continue until there is unacceptable toxicity, evidence of tumour progression, complete surgical resection or ablation of cancerous lesions, or the patient requests an end to treatment. The primary endpoint of the SIRFLOX trial is progression-free survival (PFS). Secondary endpoints include: PFS in the liver; tumour response rate (liver and any site); site of tumour progression; health-related quality of life; toxicity and safety; liver resection rate; and overall survival. Assuming an increase in the median PFS from 9.4 months to 12.5 months with the addition of SIRT to mFOLFOX6, recruiting ≥450 patients will be sufficient for 80% power and 95% confidence.
The SIRFLOX trial will establish the potential role of SIRT + standard systemic chemotherapy in the first-line management of mCRC with non-resectable liver metastases.
Trial registration
SIRFLOX identifier: NCT00724503. Registered 25 July 2008.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-897) contains supplementary material, which is available to authorized users.
PMCID: PMC4289171  PMID: 25487708
Metastatic colorectal cancer; Liver metastases; Systemic chemotherapy; SIR-Spheres® microspheres; Selective Internal Radiation Therapy (SIRT)
10.  Personal exposures to traffic-related particle pollution among children with asthma in the South Bronx, NY 
Personal exposures to fine Particulate Matter air pollution (PM2.5), and to its traffic-related fraction, were investigated in a group of urban children with asthma. The relationships of personal and outdoor school-site measurements of PM2.5 and elemental carbon (EC) were characterized for a total of forty fifth-grade children. These students, from four South Bronx, NY schools, each carried air pollution monitoring equipment with them 24 hours per day for approximately one month. Daily EC concentrations were estimated using locally calibrated reflectance of the PM2.5 samples. Personal EC was more closely related to outdoor school-site EC (median subject-specific r = 0.64) than was personal PM with school-site PM2.5 (median subject specific r = 0.33). Regression models also showed a stronger, more robust association of school-site with personal measurements for EC than for PM2.5. High traffic pollution exposure was found to coincide with the weekday early morning rush hour, with higher personal exposures for subjects living closer to a highway (< 500 ft). A significant linear relationship of home distance from a highway with personal EC pollution exposure was also found (up to 1000 ft.). This supports the assumptions by previous epidemiological studies using distance from a highway as an index of traffic PM exposure. These results are also consistent with the assumption that traffic, and especially diesel vehicles, are a significant contributor to personal PM exposure levels of children living in urban areas such as the South Bronx, NY.
PMCID: PMC4240219  PMID: 19865073
11.  The General Surgery Chief Resident Operative Experience 
JAMA surgery  2013;148(9):841-847.
The chief resident (CR) year is a pivotal experience in surgical training. Changes in case volume and diversity may impact the educational quality of this important year.
To evaluate changes in operative experience for general surgery CRs.
Review of Accreditation Council for Graduate Medical Education case logs from 1989–1990 through 2011–2012 divided into 5 periods. Graduates in period 3 were the last to train with unrestricted work hours; those in period 4 were part of a transition period and trained under both systems; and those in period 5 trained fully under the 80-hour work week. Diversity of cases was assessed based on Accreditation Council for Graduate Medical Education defined categories.
Total cases and defined categories were evaluated for changes over time.
The average total CR case numbers have fallen (271 in period 1 vs 242 in period 5, P < .001). Total CR cases dropped to their lowest following implementation of the 80-hour work week (236 cases), but rebounded in period 5. The percentage of residents’ 5-year operative experience performed as CRs has decreased (30% in period 1 vs 25.6% in period 5, P < .001). Regarding case mix: thoracic, trauma, and vascular cases declined steadily, while alimentary and intra-abdominal operations increased. Recent graduates averaged 80 alimentary and 78 intra-abdominal procedures during their CR years. Compared with period 1, in which these 2 categories represented 47.1% of CR experience, in period 5, they represented 65.2% (P < .001). Endocrine experience has been relatively unchanged.
Total CR cases declined especially acutely following implementation of the 80-hour work week but have since rebounded. Chief resident cases contribute less to overall experience, although this proportion stabilized before the 80-hour work week. Case mix has narrowed, with significant increases in alimentary and intra-abdominal cases. Broad-based general surgery training may be jeopardized by reduced case diversity. Chief resident cases are crucial in surgical training and educators should consider these findings as surgical training evolves.
PMCID: PMC4237586  PMID: 23864049
12.  ACGME case logs: Surgery resident experience in operative trauma for two decades 
Surgery resident education is based on experiential training, which is influenced by changes in clinical management strategies, technical and technologic advances, and administrative regulations. Trauma care has been exposed to each of these factors, prompting concerns about resident experience in operative trauma. The current study analyzed the reported volume of operative trauma for the last two decades; to our knowledge, this is the first evaluation of nationwide trends during such an extended time line.
The Accreditation Council for Graduate Medical Education (ACGME) database of operative logs was queried from academic year (AY) 1989–1990 to 2009–2010 to identify shifts in trauma operative experience. Annual case log data for each cohort of graduating surgery residents were combined into approximately 5-year blocks, designated Period I (AY1989–1990 to AY1993–1994), Period II (AY1994–1995 to AY1998–1999), Period III (AY1999–2000 to AY2002–2003), and Period IV (AY2003–2004 to AY2009–2010). The latter two periods were delineated by the year in which duty hour restrictions were implemented.
Overall general surgery caseload increased from Period I to Period II (p < 0.001), remained stable from Period II to Period III, and decreased from Period III to Period IV (p < 0.001). However, for ACGME-designated trauma cases, there were significant declines from Period I to Period II (75.5 vs. 54.5 cases, p < 0.001) and Period II to Period III (54.5 vs. 39.3 cases, p < 0.001) but no difference between Period III and Period IV (39.3 vs. 39.4 cases). Graduating residents in Period I performed, on average, 31 intra-abdominal trauma operations, including approximately five spleen and four liver operations. Residents in Period IV performed 17 intra-abdominal trauma operations, including three spleen and approximately two liver operations.
Recent general surgery trainees perform fewer trauma operations than previous trainees. The majority of this decline occurred before implementation of work-hour restrictions. Although these changes reflect concurrent changes in management of trauma, surgical educators must meet the challenge of training residents in procedures less frequently performed.
Epidemiologic study, level III; therapeutic study, level IV.
PMCID: PMC4237587  PMID: 23188243
Surgical residents; trauma; ACGME; resident work-hour restrictions; education
13.  Accreditation Council for Graduate Medical Education Case Log: General Surgery Resident Thoracic Surgery Experience 
The Annals of thoracic surgery  2014;98(2):459-465.
General surgery resident training has changed dramatically over the past 2 decades, with likely impact on specialty exposure. We sought to assess trends in general surgery resident exposure to thoracic surgery using the Accreditation Council for Graduate Medical Education (ACGME) case logs over time.
The ACGME case logs for graduating general surgery residents were reviewed from academic year (AY) 1989–1990 to 2011–2012 for defined thoracic surgery cases. Data were divided into 5 eras of training for comparison: I, AY89 to 93; II, AY93 to 98; III, AY98 to 03; IV, AY03 to 08; V, AY08 to 12. We analyzed quantity and types of cases per time period. Student t tests compared averages among the time periods with significance at a p values less than 0.05.
A total of 21,803,843 general surgery cases were reviewed over the 23-year period. Residents averaged 33.6 thoracic cases each in period I and 39.7 in period V. Thoracic cases accounted for nearly 4% of total cases performed annually (period I 3.7% [134,550 of 3,598,574]; period V 4.1% [167,957 of 4,077,939]). For the 3 most frequently performed procedures there was a statistically significant increase in thoracoscopic approach from period II to period V.
General surgery trainees today have the same volume of thoracic surgery exposure as their counterparts over the last 2 decades. This maintenance in caseload has occurred in spite of work-hour restrictions. However, general surgery graduates have a different thoracic surgery skill set at the end of their training, due to the predominance of minimally invasive techniques. Thoracic surgery educators should take into account these differences when training future cardiothoracic surgeons.
PMCID: PMC4237588  PMID: 24968766
14.  The ACGME case log: General surgery resident experience in pediatric surgery 
Journal of pediatric surgery  2013;48(8):1643-1649.
General surgery (GS) residents in ACGME programs log cases performed during their residency. We reviewed designated pediatric surgery (PS) cases to assess for changes in performed cases over time.
The ACGME case logs for graduating GS residents were reviewed from academic year (AY) 1989–1990 to 2010–2011 for designated pediatric cases. Overall and designated PS cases were analyzed. Data were combined into five blocks: Period I (AY1989–90 to AY1993–94), Period II (AY1994–95 to AY1998–99), Period III (AY1999–00 to AY2002–03), Period IV (AY2003–04 to AY2006–07), and Period V (AY2007–08 to AY2010–11). Periods IV and V were delineated by implementation of duty hour restrictions. Student t-tests compared averages among the time periods with significance at P < .05.
Overall GS case load remained relatively stable. Of total cases, PS cases accounted for 5.4% in Period I and 3.7% in Period V. Designated pediatric cases declined for each period from an average of 47.7 in Period I to 33.8 in Period V. These changes are due to a decline in hernia repairs, which account for half of cases. All other cases contributed only minimally to the pediatric cases. The only laparoscopic cases in the database were anti-reflux procedures, which increased over time.
GS residents perform a diminishing number of designated PS cases. This decline occurred before the onset of work-hour restrictions. These changes have implications on the capabilities of the current graduating workforce. However, the case log does not reflect all cases trainees may be exposed to, so revision of this list is recommended.
PMCID: PMC4235999  PMID: 23932601
General surgery; Resident; Education; Pediatric surgery; Case log
15.  Dll4 Blockade Potentiates the Anti-Tumor Effects of VEGF Inhibition in Renal Cell Carcinoma Patient-Derived Xenografts 
PLoS ONE  2014;9(11):e112371.
The Notch ligand Delta-like 4 (Dll4) is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF) and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC).
Methods and Results
Severe combined immunodeficiency (SCID) mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI) examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36–62%) that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38–54%) and ziv-aflibercept (46%). Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72–80% growth inhibition), including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.
Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.
PMCID: PMC4231048  PMID: 25393540
16.  Sexual violence in the lives of first-year university women in Canada: no improvements in the 21st century 
BMC Women's Health  2014;14(1):135.
Summarizes the frequency, type, and context of sexual assault in a large sample of first-year university women at three Canadian universities.
As part of a randomized controlled trial assessing the efficacy of a sexual assault resistance education program, baseline data were collected from women between ages of 17 and 24 using computerized surveys. Participants’ experience with sexual victimization since the age of 14 years was assessed using the Sexual Experiences Survey--Short Form Victimization (SES-SFV).
Among 899 first-year university women (mean age = 18.5 years), 58.7% (95% CI: 55.4%, 62.0%) had experienced one or more forms of victimization since the age of 14 years, 35.0% (95% CI: 31.9%, 38.3%) had experienced at least one completed or attempted rape, and 23.5% (95% CI: 20.7%, 26.4%) had been raped. Among the 211 rape victims, 46.4% (95% CI: 39.7%, 53.2%) had experienced more than one type of assault (oral, vaginal, anal) in a single incident or across multiple incidents. More than three-quarters (79.6%; 95% CI: 74.2%, 85.1%) of the rapes occurred while women were incapacitated by alcohol or drugs. One-third (33.3%) of women had previous self-defence training, but few (4.0%) had previous sexual assault education.
Findings from the first large Canadian study of university women since the 1990s indicate that a large proportion of women arrive on campuses with histories of sexual victimization, and they are generally unprepared for the perpetrators they may face during their academic years. There is an urgent need for effective rape prevention programs on university campuses.
Trial registration NCT01338428. Registered 13 April 2011.
PMCID: PMC4228092  PMID: 25410412
Sexual assault; Sexual coercion; Rape; Sexual violence; University women; Female university students
17.  Let's Talk!, A South African Worksite-Based HIV Prevention Parenting Program 
South African adolescents have high HIV risk, yet few prevention interventions are effective. Parents play a pivotal role in youths’ healthy sexual development and may be at-risk themselves. We tested whether Let’s Talk!, a worksite-based parenting program, improves parent-child communication about HIV and sexual health, and parent condom use self-efficacy and behavior.
We culturally adapted Let’s Talk! in two languages, drawing on formative research and community stakeholder input. We then conducted a small randomized test at a large public worksite in Cape Town. The intervention consisted of five weekly two-hour group sessions for parents of youth aged 11–15. Sixty-six parents [64% female] and their 64 adolescents [41% female] completed surveys before and 1–2 weeks post-intervention; surveys assessed comfort with talking about sex, communication about 16 HIV- and sex-related topics, and parents’ condom use self-efficacy and behavior. Thirty-four Black-African (Xhosa-language) and 32 Coloured (mixed-race; Afrikaans-language) parent-child dyads participated. Parents were randomized to intervention (n=34) and control (n=32) groups; randomization was stratified by language.
Multivariate regressions indicated that the intervention significantly increased parents’ comfort with talking to their adolescent about sex, b(SE)=0.98(0.39), p=0.02, and the number of sex- and HIV-related topics discussed with their adolescent, b(SE)=3.26(1.12), p=0.005. Compared to control parents, intervention parents were more likely to discuss new sex- and HIV-related topics not discussed before the intervention, b(SE)=2.85(0.80), p<.001. The intervention significantly increased parents’ self-efficacy for condom use, b(SE)=0.60(0.21), p=0.007.
Let’s Talk! holds promise for improving parent-child communication, a critical first step in preventing HIV among youth.
PMCID: PMC3707983  PMID: 23566563
South Africa; HIV; adolescents; parents; communication
18.  Epidemiology of severe influenza outcomes among adult patients with obesity in Detroit, Michigan, 2011 
Influenza and other respiratory viruses  2013;7(6):10.1111/irv.12115.
We conducted a retrospective cohort study to evaluate the impact of obesity on influenza disease severity. Individuals with obesity were more likely to have lower pulmonary disease manifestations (OR=1.97 (95% C.I. 1.05, 3.69) p=0.03) and to be admitted to an inpatient ward (OR=2.93 (95% C.I. 1.50, 5.71) p=0.002) when compared to non-obese individuals. Among admitted individuals, persons with obesity were more likely to require a lengthy hospital stay (OR=3.86 (95% C.I. 1.03, 14.42) p=0.045). Five of the six deaths in study subjects occurred in persons with obesity.
PMCID: PMC3749256  PMID: 23594280
Influenza; Human; Obesity; Body Mass Index
19.  Prenatal Organochlorine and Methylmercury Exposure and Memory and Learning in School-Age Children in Communities Near the New Bedford Harbor Superfund Site, Massachusetts 
Environmental Health Perspectives  2014;122(11):1253-1259.
Background: Polychlorinated biphenyls (PCBs), organochlorine pesticides, and methylmercury (MeHg) are environmentally persistent with adverse effects on neurodevelopment. However, especially among populations with commonly experienced low levels of exposure, research on neurodevelopmental effects of these toxicants has produced conflicting results.
Objectives: We assessed the association of low-level prenatal exposure to these contaminants with memory and learning.
Methods: We studied 393 children, born between 1993 and 1998 to mothers residing near a PCB-contaminated harbor in New Bedford, Massachusetts. Cord serum PCB, DDE (dichlorodiphenyldichloroethylene), and maternal peripartum hair mercury (Hg) levels were measured to estimate prenatal exposure. Memory and learning were assessed at 8 years of age (range, 7–11 years) using the Wide Range Assessment of Memory and Learning (WRAML), age-standardized to a mean ± SD of 100 ± 15. Associations with each WRAML index—Visual Memory, Verbal Memory, and Learning—were examined with multivariable linear regression, controlling for potential confounders.
Results: Although cord serum PCB levels were low (sum of four PCBs: mean, 0.3 ng/g serum; range, 0.01–4.4), hair Hg levels were typical of the U.S. fish-eating population (mean, 0.6 μg/g; range, 0.3–5.1). In multivariable models, each microgram per gram increase in hair Hg was associated with, on average, decrements of –2.8 on Visual Memory (95% CI: –5.0, –0.6, p = 0.01), –2.2 on Learning (95% CI: –4.6, 0.2, p = 0.08), and –1.7 on Verbal Memory (95% CI: –3.9, 0.6, p = 0.14). There were no significant adverse associations of PCBs or DDE with WRAML indices.
Conclusions: These results support an adverse relationship between low-level prenatal MeHg exposure and childhood memory and learning, particularly visual memory.
Citation: Orenstein ST, Thurston SW, Bellinger DC, Schwartz JD, Amarasiriwardena CJ, Altshul LM, Korrick SA. 2014. Prenatal organochlorine and methylmercury exposure and memory and learning in school-age children in communities near the New Bedford Harbor Superfund Site, Massachusetts. Environ Health Perspect 122:1253–1259;
PMCID: PMC4216164  PMID: 25062363
20.  Improvement in the Diagnosis of Appendicitis 
Advances in surgery  2013;47:299-328.
PMCID: PMC4214266  PMID: 24298858
Appendicitis; Diagnosis; Advanced imaging; Negative appendectomy
21.  Enteral Contrast in the Computed Tomography Diagnosis of Appendicitis 
Annals of surgery  2014;260(2):311-316.
Our goal was to perform a comparative effectiveness study of intravenous (IV)-only versus IV + enteral contrast in computed tomographic (CT) scans performed for patients undergoing appendectomy across a diverse group of hospitals.
Small randomized trials from tertiary centers suggest that enteral contrast does not improve diagnostic performance of CT for suspected appendicitis, but generalizability has not been demonstrated. Eliminating enteral contrast may improve efficiency, patient comfort, and safety.
We analyzed data for adult patients who underwent nonelective appendectomy at 56 hospitals over a 2-year period. Data were obtained directly from patient charts by trained abstractors. Multivariate logistic regression was utilized to adjust for potential confounding. The main outcome measure was concordance between final radiology interpretation and final pathology report.
A total of 9047 adults underwent appendectomy and 8089 (89.4%) underwent CT, 54.1% of these with IV contrast only and 28.5% with IV + enteral contrast. Pathology findings correlated with radiographic findings in 90.0% of patients who received IV + enteral contrast and 90.4% of patients scanned with IV contrast alone. Hospitals were categorized as rural or urban and by their teaching status. Regardless of hospital type, there was no difference in concordance between IV-only and IV + enteral contrast. After adjusting for age, sex, comorbid conditions, weight, hospital type, and perforation, odds ratio of concordance for IV + enteral contrast versus IV contrast alone was 0.95 (95% CI: 0.72–1.25).
Enteral contrast does not improve CT evaluation of appendicitis in patients undergoing appendectomy. These broadly generalizable results from a diverse group of hospitals suggest that enteral contrast can be eliminated in CT scans for suspected appendicitis.
PMCID: PMC4208938  PMID: 24598250
appendicitis; comparative effectiveness; Computed tomography; diagnosis; enteral contrast; oral contrast
23.  Traumatic near amputation secondary to hippopotamus attack: lessons for surgeons 
The Journal of surgical research  2013;188(1):58-63.
A 34-y-old man presented to Naivasha District Hospital (NDH) in Naivasha Town, Kenya, with near-complete below-knee amputation and hemorrhage after a hippopotamus attack. Residents from the University of Washington (UW), Departments of Surgery, Anesthesia, and Medicine, were rotating at NDH with the Clinical Education Partnership Initiative, a joint venture of UW and University of Nairobi. These providers met the patient in the operating theater. The leg was mangled with severely traumatized soft tissues and tibia–fibula fractures. The visiting UW Surgery resident (R3) and an NDH medical officer (second-year house officer) performed emergency below-knee completion amputation—the first time either had performed this operation. The three major vessel groups were identified and ligated. Sufficient gastrocnemius and soleus were preserved for future stump construction. The wound was washed out, packed with betadine-soaked gauze, and wrapped in an elasticized bandage. Broad-spectrum antibiotics were initiated. Unfortunately, the patient suffered infection and was revised above the knee. After a prolonged course, the patient recovered well and was discharged home. NDH house officers and UW trainees collaborated successfully in an emergency and conducted the postoperative care of a patient with a serious and challenging injury. Their experience highlights the importance of preparedness, command of surgical basics, humility, learning from mistakes, the expertise of others, a digitally connected surgical community, and the role of surgery in global health. These lessons will be increasingly pertinent as surgical training programs create opportunities for their residents to work in developing countries; many of these lessons are equally applicable to surgical practice in the developed world.
PMCID: PMC4209841  PMID: 24411302
Surgical education; Global health; Traumatic amputation; Surgical training; Preparedness
24.  Documentation Quality of Inpatient Code Status Discussions 
Accurate documentation of inpatient code status discussions (CSDs) is important because of frequent patient care handoffs.
To examine the quality of inpatient CSD documentation and compare documentation quality across physician services.
This was a retrospective study of patients hospitalized between January 1 and June 30, 2011 with a new or canceled do-not-resuscitate (DNR) order at least 24 hours after hospital admission. We developed a chart abstraction tool to assess the documentation of five quality elements: 1) who the DNR discussion was held with, 2) patient goals/values, 3) prognosis, 4) treatment options and resuscitation outcomes, and 5) health care power of attorney (HCPOA).
We identified 379 patients, of whom 235 (62%) had a note documenting a CSD. After excluding patients lacking a note from their primary service, 227 remained for analysis. Sixty-three percent of notes contained documentation of who the discussion was held with. Patient goals/values were documented in 43%, discussion of prognosis in 14%, treatment options and resuscitation outcomes in 40%, and HCPOA in 29%. Hospitalists were more likely than residents to document who the discussion was held with (P < 0.001) and patient goals/values (P < 0.001), whereas internal medicine residents were more likely to document HCPOA (P = 0.04). The mean number of elements documented for hospitalists was 2.40, followed by internal medicine residents at 2.07, and noninternal medicine trainees at 1.30 (P < 0.001).
Documentation quality of inpatient CSDs was poor. Our findings highlight the need to improve the quality of resident and attending CSD documentation.
PMCID: PMC4177509  PMID: 24681110
Documentation; advance care planning; resuscitation; DNR orders
25.  Latent Factor Regression Models for Grouped Outcomes 
Biometrics  2013;69(3):785-794.
We consider regression models for multiple correlated outcomes, where the outcomes are nested in domains. We show that random effect models for this nested situation fit into a standard factor model framework, which leads us to view the modeling options as a spectrum between parsimonious random effect multiple outcomes models and more general continuous latent factor models. We introduce a set of identifiable models along this spectrum that extend an existing random effect model for multiple outcomes nested in domains. We characterize the tradeoffs between parsimony and flexibility in this set of models, applying them to both simulated data and data relating sexually dimorphic traits in male infants to explanatory variables. Supplementary material is available in an online appendix.
PMCID: PMC4171058  PMID: 23845121
epidemiology; factor analysis; multiple outcomes; regression

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