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Background: Emerging multidrug-resistant organisms (MDROs), such as carbapenem-resistant Enterobacterales (CRE), can spread rapidly in a region. Facilities that care for high-acuity patients with longer stays may have a disproportionate impact on this spread., Objective: We assessed the impact of implementing preventive interventions, directed at a subset of facilities, on regional prevalence., Methods: We developed a deterministic compartmental model, parametrized using CRE and patient transfer data. The model included the community and healthcare facilities within a US state. Individuals may be either susceptible or infectious with CRE. Individuals determined to be infectious through admission screening, periodic prevalence surveys (PPSs), or interfacility communication were placed in a state of lower transmissibility if enhanced infection prevention and control (IPC) practices were in place at a facility., Results: Intervention bundles that included PPS and enhanced IPC practices at ventilator-capable skilled nursing facilities (vSNFs) and long-term acute-care hospitals (LTACHs) had the greatest impact on regional prevalence. The benefits of including targeted admission screening in acute-care hospitals, LTACHs, and vSNFs, and improved interfacility communication were more modest. Daily transmissions in each facility type were reduced following the implementation of interventions primarily focused at LTACHs and vSNFs., Conclusions: Our model suggests that interventions that include screening to limit unrecognized MDRO introduction to, or dispersal from, LTACHs and vSNFs slow regional spread. Interventions that pair detection and enhanced IPC practices within LTACHs and vSNFs may substantially reduce the regional burden.

Objective: The McGill Thyroid Nodule Score (MTNS) is a preoperative tool used to predict the risk for well-differentiated thyroid cancer in adults. It was developed by a multidisciplinary team using established evidence-based risk factors for thyroid cancer. The modified McGill Thyroid Nodule Score (mMTNS) was developed to predict malignancy risk in children. A pilot study suggested the mMTNS was able to assess malignancy risk in children with indeterminate cytology on fine needle aspiration (FNA). This study seeks to validate these findings., Methods: Retrospective chart review identified subjects who underwent FNA biopsy and subsequent resection. Each patient was assigned a score to compare to final pathology. Statistical analysis was performed with SPSS. All tests were 2-tailed and statistical significance defined p < 0.05. Logistic regression used to determine predictive values of scores., Results: 46 patients ≤21 years of age underwent resection of a thyroid nodule. Female predominance of 85% (n = 39). 78% (n = 36) of patients had palpable nodule. 65% (n = 30) found to have benign pathology and 35% (n = 16) found to have malignancy. Malignant nodules associated with greater mean mMTNS compared to benign [13.63 vs 7.23]. An mMTNS greater >12 had sensitivity of 86.7%, specificity of 90.3%, positive predictive value of 81.3%, and negative predictive value of 93.3%., Conclusion: Our data suggests the mMTNS continues to be a useful adjunct in predicting malignancy risk of pediatric thyroid nodules. An mMTNS >12 has a high risk for malignancy, which can aid in counseling and clinical decision making, particularly when there is indeterminate cytology on FNA., Level of Evidence: IV., Competing Interests: Conflicts of interest The authors have no competing interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Culture-independent diagnostic testing (CIDT) provides rapid results to clinicians and is quickly displacing traditional detection methods. Increased CIDT use and sensitivity likely result in higher case detection but might also obscure infection trends. Severe illness outcomes, such as hospitalization and death, are likely less affected by changes in testing practices and can be used as indicators of the expected case incidence trend had testing methods not changed., Methods: Using US Foodborne Diseases Active Surveillance Network data during 1996-2019 and mixed effects quasi-Poisson regression, we estimated the expected yearly incidence for nine enteric pathogens., Results: Removing the effect of CIDT use, CIDT panel testing and culture-confirmation of CIDT testing, the modelled incidence in all but three pathogens (Salmonella, Shigella, STEC O157) was significantly lower than the observed and the upward trend in Campylobacter was reversed from an observed 2.8% yearly increase to a modelled -2.8% yearly decrease (95% credible interval: -4.0, -1.4)., Conclusions: Severe outcomes may be useful indicators in evaluating trends in surveillance systems that have undergone a marked change., (Published by Oxford University Press on behalf of the International Epidemiological Association 2023.)

Our ability to forecast epidemics far into the future is constrained by the many complexities of disease systems. Realistic longer-term projections may, however, be possible under well-defined scenarios that specify the future state of critical epidemic drivers. Since December 2020, the U.S. COVID-19 Scenario Modeling Hub (SMH) has convened multiple modeling teams to make months ahead projections of SARS-CoV-2 burden, totaling nearly 1.8 million national and state-level projections. Here, we find SMH performance varied widely as a function of both scenario validity and model calibration. We show scenarios remained close to reality for 22 weeks on average before the arrival of unanticipated SARS-CoV-2 variants invalidated key assumptions. An ensemble of participating models that preserved variation between models (using the linear opinion pool method) was consistently more reliable than any single model in periods of valid scenario assumptions, while projection interval coverage was near target levels. SMH projections were used to guide pandemic response, illustrating the value of collaborative hubs for longer-term scenario projections., (© 2023. The Author(s).)

Vermetid worm-snails are sessile and irregularly coiled marine mollusks common in warmer nearshore and coral reef environments that are subject to high predation pressures by fish. Often cryptic, some have evolved sturdy shells or long columellar muscles allowing quick withdrawal into better protected parts of the shell tube, and most have variously developed opercula that protect and seal the shell aperture trapdoor-like. Members of Thylacodes (previously: Serpulorbis ) lack such opercular protection. Its species often show polychromatic head-foot coloration, and some have aposematic coloration likely directed at fish predators. A new polychromatic species, Thylacodes bermudensis n. sp., is described from Bermuda and compared morphologically and by DNA barcode markers to the likewise polychromatic western Atlantic species T. decussatus (Gmelin, 1791). Operculum loss, previously assumed to be an autapomorphy of Thylacodes , is shown to have occurred convergently in a second clade of the family, for which a new genus Cayo n. gen. and four new western Atlantic species are introduced: C. margarita n. sp. (type species; with type locality in the Florida Keys), C. galbinus n. sp., C. refulgens n. sp., and C. brunneimaculatus n. sp. (the last three with type locality in the Belizean reef) (all new taxa authored by Bieler, Collins, Golding & Rawlings). Cayo n. gen. differs from Thylacodes in morphology (e.g., a protoconch that is wider than tall), behavior (including deep shell entrenchment into the substratum), reproductive biology (fewer egg capsules and eggs per female; an obliquely attached egg capsule stalk), and in some species, a luminous, "neon-like", head-foot coloration. Comparative investigation of the eusperm and parasperm ultrastructure also revealed differences, with a laterally flattened eusperm acrosome observed in two species of Cayo n. gen. and a spiral keel on the eusperm nucleus in one, the latter feature currently unique within the family. A molecular phylogenetic analysis based on mitochondrial and nuclear rRNA gene sequences (12SrRNA, trnV, 16SrRNA, 28SrRNA) strongly supports the independent evolution of the two non-operculate lineages of vermetids. Thylacodes forms a sister grouping to a clade comprising Petaloconchus , Eualetes , and Cupolaconcha, whereas Cayo n. gen is strongly allied with the small-operculate species Vermetus triquetrus and V. bieleri . COI barcode markers provide support for the species-level status of the new taxa. Aspects of predator avoidance/deterrence are discussed for these non-operculate vermetids, which appear to involve warning coloration, aggressive behavior when approached by fish, and deployment of mucous feeding nets that have been shown, for one vermetid in a prior study, to contain bioactive metabolites avoided by fish. As such, non-operculate vermetids show characteristics similar to nudibranch slugs for which the evolution of warning coloration and chemical defenses has been explored previously., Competing Interests: Rüdiger Bieler, Petra Sierwald and Timothy Collins are Academic Editors for PeerJ., (©2023 Bieler et al.)

Beginning in December 2020, the COVID-19 Scenario Modeling Hub has provided quantitative scenario-based projections for cases, hospitalizations, and deaths, aggregated across up to nine modeling groups. Projections spanned multiple months into the future and provided timely information on potential impacts of epidemiological uncertainties and interventions. Projections results were shared with the public, public health partners, and the Centers for Disease Control COVID-19 Response Team. The projections provided insights on situational awareness and informed decision-making to mitigate COVID-19 disease burden (e.g., vaccination strategies). By aggregating projections from multiple modeling teams, the Scenario Modeling Hub provided rapidly synthesized information in times of great uncertainty and conveyed possible trajectories in the presence of emerging variants. Here we detail several use cases of these projections in public health practice and communication, including assessments of whether modeling results directly or indirectly informed public health communication or guidance. These include multiple examples where comparisons of projected COVID-19 disease outcomes under different vaccination scenarios were used to inform Advisory Committee for Immunization Practices recommendations. We also describe challenges and lessons learned during this highly beneficial collaboration., Competing Interests: Declaration of Competing Interest The authors report no financial/personal interests or beliefs that could affect their objectivity., (Published by Elsevier B.V.)

Background: Campylobacter is the most common cause of bacterial diarrhea in the United States; resistance to macrolides and fluoroquinolones limits treatment options. We examined the epidemiology of US Campylobacter infections and changes in resistance over time., Methods: The Foodborne Diseases Active Surveillance Network receives information on laboratory-confirmed Campylobacter cases from 10 US sites, and the National Antimicrobial Resistance Monitoring System receives a subset of isolates from these cases for antimicrobial susceptibility testing. We estimated trends in incidence of Campylobacter infection, adjusting for sex, age, and surveillance changes attributable to culture-independent diagnostic tests. We compared percentages of isolates resistant to erythromycin or ciprofloxacin during 2005-2016 with 2017-2018 and used multivariable logistic regression to examine the association of international travel with resistance., Results: Adjusted Campylobacter incidence remained stable or decreased for all groups analyzed since 2012. Among 2449 linked records in 2017-2018, the median patient age was 40.2 years (interquartile range, 21.6-57.8 years), 54.8% of patients were male, 17.2% were hospitalized, and 0.2% died. The percentage of resistant infections increased from 24.5% in 2005-2016 to 29.7% in 2017-2018 for ciprofloxacin ( P < .001) and from 2.6% to 3.3% for erythromycin ( P = .04). Persons with recent international travel had higher odds than nontravelers of having isolates resistant to ciprofloxacin (adjusted odds ratio [aOR] varied from 1.7 to 10.6 by race/ethnicity) and erythromycin (aOR = 1.7; 95% confidence interval, 1.3-2.1)., Conclusions: Campylobacter incidence has remained stable or decreased, whereas resistance to antimicrobials recommended for treatment has increased. Recent international travel increased the risk of resistance., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Reconstructing the incidence of SARS-CoV-2 infection is central to understanding the state of the pandemic. Seroprevalence studies are often used to assess cumulative infections as they can identify asymptomatic infection. Since July 2020, commercial laboratories have conducted nationwide serosurveys for the U.S. CDC. They employed three assays, with different sensitivities and specificities, potentially introducing biases in seroprevalence estimates. Using models, we show that accounting for assays explains some of the observed state-to-state variation in seroprevalence, and when integrating case and death surveillance data, we show that when using the Abbott assay, estimates of proportions infected can differ substantially from seroprevalence estimates. We also found that states with higher proportions infected (before or after vaccination) had lower vaccination coverages, a pattern corroborated using a separate dataset. Finally, to understand vaccination rates relative to the increase in cases, we estimated the proportions of the population that received a vaccine prior to infection., (© 2023. The Author(s).)

Background: The COVID-19 Scenario Modeling Hub convened nine modeling teams to project the impact of expanding SARS-CoV-2 vaccination to children aged 5-11 years on COVID-19 burden and resilience against variant strains., Methods: Teams contributed state- and national-level weekly projections of cases, hospitalizations, and deaths in the United States from September 12, 2021 to March 12, 2022. Four scenarios covered all combinations of 1) vaccination (or not) of children aged 5-11 years (starting November 1, 2021), and 2) emergence (or not) of a variant more transmissible than the Delta variant (emerging November 15, 2021). Individual team projections were linearly pooled. The effect of childhood vaccination on overall and age-specific outcomes was estimated using meta-analyses., Findings: Assuming that a new variant would not emerge, all-age COVID-19 outcomes were projected to decrease nationally through mid-March 2022. In this setting, vaccination of children 5-11 years old was associated with reductions in projections for all-age cumulative cases (7.2%, mean incidence ratio [IR] 0.928, 95% confidence interval [CI] 0.880-0.977), hospitalizations (8.7%, mean IR 0.913, 95% CI 0.834-0.992), and deaths (9.2%, mean IR 0.908, 95% CI 0.797-1.020) compared with scenarios without childhood vaccination. Vaccine benefits increased for scenarios including a hypothesized more transmissible variant, assuming similar vaccine effectiveness. Projected relative reductions in cumulative outcomes were larger for children than for the entire population. State-level variation was observed., Interpretation: Given the scenario assumptions (defined before the emergence of Omicron), expanding vaccination to children 5-11 years old would provide measurable direct benefits, as well as indirect benefits to the all-age U.S. population, including resilience to more transmissible variants., Funding: Various (see acknowledgments)., Competing Interests: JL has served as an expert witness on cases where the likely length of the pandemic was of issue. MCR reports stock ownership in Becton Dickinson & Co., which manufactures medical equipment used in COVID-19 testing, vaccination, and treatment. JS and Columbia University disclose partial ownership of SK Analytics. JS discloses consulting for BNI. There are no other competing interests to declare.

In Spring 2021, the highly transmissible SARS-CoV-2 Delta variant began to cause increases in cases, hospitalizations, and deaths in parts of the United States. At the time, with slowed vaccination uptake, this novel variant was expected to increase the risk of pandemic resurgence in the US in summer and fall 2021. As part of the COVID-19 Scenario Modeling Hub, an ensemble of nine mechanistic models produced 6-month scenario projections for July-December 2021 for the United States. These projections estimated substantial resurgences of COVID-19 across the US resulting from the more transmissible Delta variant, projected to occur across most of the US, coinciding with school and business reopening. The scenarios revealed that reaching higher vaccine coverage in July-December 2021 reduced the size and duration of the projected resurgence substantially, with the expected impacts was largely concentrated in a subset of states with lower vaccination coverage. Despite accurate projection of COVID-19 surges occurring and timing, the magnitude was substantially underestimated 2021 by the models compared with the of the reported cases, hospitalizations, and deaths occurring during July-December, highlighting the continued challenges to predict the evolving COVID-19 pandemic. Vaccination uptake remains critical to limiting transmission and disease, particularly in states with lower vaccination coverage. Higher vaccination goals at the onset of the surge of the new variant were estimated to avert over 1.5 million cases and 21,000 deaths, although may have had even greater impacts, considering the underestimated resurgence magnitude from the model., Competing Interests: ST, CS, MQ, LM, RB, KS, EH, LC, JL, JK, HH, MK, KT, SW, LS, KR, JL, JD, JK, EL, JP, AH, DK, MC, JD, KM, XX, AP, AV, AS, PP, SV, AA, BL, BK, JO, MO, GH, BH, JC, AV, MM, SH, PB, DM, SC, RP, DJ, JT, MG, TY, SP, JH, RS, MB, MJ, CV No competing interests declared, JL has served as an expert witness on cases where the likely length of the pandemic was of issue, JS and Columbia University disclose partial ownership of SK Analytics. Discloses consulting for BNI, MR reports stock ownership in Becton Dickinson & Co, which manufactures medical equipment used in COVID testing, vaccination, and treatment

As of March 2021, three COVID-19 vaccines had been authorized by the U.S. Food and Drug Administration (FDA) for use in the United States. Each has substantial efficacy in preventing COVID-19. However, as efficacy from trials was <100% for all three vaccines, disease in vaccinated people is expected to occur. We created a spreadsheet-based tool to estimate the number of symptomatic COVID-19 cases among vaccinated people (vaccine breakthrough infections) based on published vaccine efficacy (VE) data, percent of the population that has been fully vaccinated, and average number of COVID-19 cases reported per day. We estimate that approximately 199,000 symptomatic vaccine breakthrough infections (95% CI: ~183,000-214,000 cases) occurred in the United States during January-July 2021 among >156 million fully vaccinated people. With high SARS-CoV-2 transmission and increasing numbers of people vaccinated in the United States, vaccine breakthrough infections will continue to accumulate. Understanding expectations regarding number of vaccine breakthrough infections enables accurate public health messaging to help ensure that the occurrence of such cases does not negatively affect vaccine perceptions, confidence, and uptake., Competing Interests: The authors have declared that no competing interests exist.

After a period of rapidly declining U.S. COVID-19 incidence during January-March 2021, increases occurred in several jurisdictions (1,2) despite the rapid rollout of a large-scale vaccination program. This increase coincided with the spread of more transmissible variants of SARS-CoV-2, the virus that causes COVID-19, including B.1.1.7 (1,3) and relaxation of COVID-19 prevention strategies such as those for businesses, large-scale gatherings, and educational activities. To provide long-term projections of potential trends in COVID-19 cases, hospitalizations, and deaths, COVID-19 Scenario Modeling Hub teams used a multiple-model approach comprising six models to assess the potential course of COVID-19 in the United States across four scenarios with different vaccination coverage rates and effectiveness estimates and strength and implementation of nonpharmaceutical interventions (NPIs) (public health policies, such as physical distancing and masking) over a 6-month period (April-September 2021) using data available through March 27, 2021 (4). Among the four scenarios, an accelerated decline in NPI adherence (which encapsulates NPI mandates and population behavior) was shown to undermine vaccination-related gains over the subsequent 2-3 months and, in combination with increased transmissibility of new variants, could lead to surges in cases, hospitalizations, and deaths. A sharp decline in cases was projected by July 2021, with a faster decline in the high-vaccination scenarios. High vaccination rates and compliance with public health prevention measures are essential to control the COVID-19 pandemic and to prevent surges in hospitalizations and deaths in the coming months., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Katriona Shea reports receipt of two National Science Foundation (NSF) COVID-19 RAPID awards, and a Huck Institutes of the Life Sciences Coronavirus Research Seed Grant. Rebecca Borchering reports funding from an NSF COVID-19 RAPID award. Katharine Tallaksen, Kaitlin Rainwater-Lovett, Laura Asher, Luke C. Mullany, Molly E. Gallagher, Matt Kinsey, Richard F. Obrecht, and Lauren Shin report funding from the U.S. Department of Health and Human Services (HHS), Office of the Assistant Secretary for Preparedness and Response to the Johns Hopkins Applied Physics Laboratory. Matteo Chinazzi reports grants from the National Institutes of Health (NIH), the Council of State and Territorial Epidemiologists (CSTE), and Metabiota to Northeastern University. Ana Pastore y Piontti reports funding from Metabiota, Inc. to Northeastern University and royalties from Springer Publishing. Joseph Lemaitre reports funding from the Swiss National Science Foundation, State of California, HHS, and the Department of Homeland Security (DHS). Kyra H. Grantz reports support from the California Department of Public Health, Johns Hopkins Bloomberg School of Public Health, NIH, and travel support from the World Health Organization (WHO). Elizabeth Lee and Claire Smith report support from the California Department of Public Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Health System, HHS, and DHS, and computing resources from Amazon Web Services, Johns Hopkins University Modeling and Policy Hub, and the Office of the Dean at the Johns Hopkins Bloomberg School of Public Health. Justin Lessler reports support from DHHS, DHS, California Institute of Technology, NIH, honorarium from the American Association for Cancer Research, personal fees for expert testimony from Paul, Weiss, Rifkind, Wharton & Garrison, LLP. Lindsay Keegan reports support from the State of California, and NIH, a University of Utah Immunology, Inflammation, and Infectious Disease Seed Grant, and a scholarship from the University of Washington Summer Institute in Statistics and Modeling of Infectious Diseases. Lucie Contamin, John Levander, Jessica Salerno, and Willem Gijsbert van Panhuis report a National Institute of General Medical Sciences grant. Ajitesh Srivastava reports a grant from the National Science Foundation. Michael C. Runge reports stock ownership in Becton Dickinson & Co., which manufactures medical equipment used in COVID testing, vaccination, and treatment. Alessandro Vespignani reports grants from NIH, NSF, WHO, CSTE, Metabiota Inc., Templeton Foundation, Scientific Interchange Foundation, Bill & Melinda Gates Foundation; royalties from Cambridge University Press, World Scientific, Springer Publishing, and Il Saggiatore; consulting fees from Human Technopole Foundation, Institute for Scientific Interchange Foundation, honorarium for lecture module at University of Washington; Scientific Advisory Board member of the Institute for Scientific Interchange Foundation, Italy, Supervisory Board member of the Human Technopole Foundation, Italy; and gifts to Northeastern University from the McGovern Foundation, the Chleck Foundation, the Sternberg Family, J. Pallotta, and Google Cloud research credits for COVID-19 from Google. Akhil Sai Peddireddy, Pyrros A. Telionis, Anil Vullikanti, Jiangzhuo Chen, Benjamin Hurt, Brian D. Klahn, Bryan Lewis, James Schlitt, Joseph Outten, Lijing Wang, Madhav Marathe, Patrick Corbett, Przemyslaw Porebski, and Srinivasan Venkatramanan report institutional support from the National Science Foundation, Expeditions, NIH, the U.S. Department of Defense, Virginia Department of Health, Virginia Department of Emergency Management, University of Virginia (internal seed grants), and Accuweather. No other potential conflicts of interest were disclosed.

Emerging epidemics are challenging to track. Only a subset of cases is recognized and reported, as seen with the Zika virus (ZIKV) epidemic where large proportions of infection were asymptomatic. However, multiple imperfect indicators of infection provide an opportunity to estimate the underlying incidence of infection. We developed a modeling approach that integrates a generic Time-series Susceptible-Infected-Recovered epidemic model with assumptions about reporting biases in a Bayesian framework and applied it to the 2016 Zika epidemic in Puerto Rico using three indicators: suspected arboviral cases, suspected Zika-associated Guillain-Barré Syndrome cases, and blood bank data. Using this combination of surveillance data, we estimated the peak of the epidemic occurred during the week of August 15, 2016 (the 33rd week of year), and 120 to 140 (50% credible interval [CrI], 95% CrI: 97 to 170) weekly infections per 10,000 population occurred at the peak. By the end of 2016, we estimated that approximately 890,000 (95% CrI: 660,000 to 1,100,000) individuals were infected in 2016 (26%, 95% CrI: 19% to 33%, of the population infected). Utilizing multiple indicators offers the opportunity for real-time and retrospective situational awareness to support epidemic preparedness and response., Competing Interests: The authors have declared that no competing interests exist.

Background: Reports of higher rates of medical errors in the month of July have generated concern regarding major surgery at academic institutions early in the yearly promotion cycle. This study was designed to evaluate perioperative outcomes in patients undergoing pancreaticoduodenectomy (PD) at different times of the year., Materials and Methods: Outcomes were retrospectively evaluated for patients treated in July versus the rest of the year and in the first quarter (July-September) versus the remaining quarters. The primary outcome was operative morbidity as measured by Clavien-Dindo grade, a classification system of surgical complications. Secondary outcomes included mortality, operative blood loss, pancreatic fistula formation, delayed gastric emptying, intraabdominal abscess, anastomotic leak, reoperation, and other variables of interest., Results: From January 2003 to September 2015, 472 patients underwent PD by a single academic surgeon. Overall, 77.1% of PDs were performed for malignancy. The number of patients did not significantly vary by month or by quarter. The incidence of major morbidity (Clavien-Dindo grade ≥ III) in patients who had a PD was 12.2% in July and 17.5% in all other months (P = 0.79). The rate of pancreatic fistula, intraabdominal abscess, reoperation, readmission, and mortality did not differ significantly by month or by quarter (P > 0.05 for all)., Conclusions: The current study does not find any correlation between time of year and operative morbidity or mortality, suggesting that PD can be safely performed irrespective of timing.

Background: Hepatitis A is a vaccine-preventable viral disease transmitted by the fecal-oral route. During 2016-2018, the County of San Diego investigated an outbreak of hepatitis A infections primarily among people experiencing homelessness (PEH) to identify risk factors and support control measures. At the time of the outbreak, homelessness was not recognized as an independent risk factor for the disease., Methods: We tested the association between homelessness and infection with hepatitis A virus (HAV) using a test-negative study design comparing patients with laboratory-confirmed hepatitis A with control subjects who tested negative for HAV infection. We assessed risk factors for severe hepatitis A disease outcomes, including hospitalization and death, using multivariable logistic regression. We measured the frequency of indications for hepatitis A vaccination according to Advisory Committee on Immunization Practices (ACIP) guidelines., Results: Among 589 outbreak-associated cases reported, 291 (49%) occurred among PEH. Compared with those who were not homeless, PEH had 3.3 (95% confidence interval [CI], 1.5-7.9) times higher odds of HAV infection, 2.5 (95% CI, 1.7-3.9) times higher odds of hospitalization, and 3.9 (95% CI, 1.1-16.9) times higher odds of death associated with hepatitis A. Among PEH, 212 (73%) patients recorded other ACIP indications for hepatitis A vaccination., Conclusions: PEH were at higher risk of infection with HAV and of severe hepatitis A disease outcomes compared with those not experiencing homelessness. Approximately one-fourth of PEH had no other ACIP indication for hepatitis A vaccination. These findings support the recent ACIP recommendation to add homelessness as an indication for hepatitis A vaccination., (Published by Oxford University Press for the Infectious Diseases Society of America 2019.)

Purpose: In high-income countries the presentation and treatment of intussusception is relatively rapid, and most cases are correctable with radiographically-guided reduction. In low-income countries, many delays affect outcomes and surgical intervention is required. This study characterizes the burden and outcome of pediatric intussusception in Uganda., Methods: Prospective case series of intussusception cases from May 2015 to July 2016 at a tertiary referral hospital in Uganda., Results: Forty patients were included in the study. Male to female ratio was 3:2. Average duration of symptoms before presentation was 4.5 days. Median duration of symptoms in referred patients was 4 days and 2 days in non-referred patients (P value 0.0009). All 40 patients underwent surgical treatment: 25% had resection and enterostomy, 15% had resection and primary anastomosis, 2.5% had resection, primary anastomosis and enterostomy and 57.5% underwent manual reduction. Mortality was 32% and febrile patients on admission were 20 times more likely to die (P value 0.040)., Conclusion: Intussusception carries a high operative and mortality rate in Uganda. Referred patients presented later than non-referred patients to health facilities. Fever on examination at admission was positively associated with mortality. This disease remains a target for quality metrics in global pediatric surgery., Type of Study: Diagnostic study., Level of Evidence: III., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Most nontyphoidal Salmonella (NTS) illnesses in the United States are thought to be foodborne. However, transmission routes likely vary among the different serotypes. We developed a relative ranking of NTS serotypes according to the strength of their association with foodborne transmission. We used Laboratory-based Enteric Disease Surveillance data to estimate the proportion of infections for each Salmonella serotype reported from 1998 to 2015 and Foodborne Disease Outbreak Surveillance System data to calculate the proportion of foodborne outbreak-associated Salmonella illnesses caused by each serotype. We calculated the ratios of these proportions to create a foodborne relatedness (FBR) measure for each serotype. Of the top 20 serotypes, Saintpaul (2.14), Heidelberg (1.61), and Berta (1.48) had the highest FBR measures; Mississippi (0.01), Bareilly (0.13), and Paratyphi B variant L(+) tartrate(+) (0.20) had the lowest. The FBRs for the three most prevalent serotypes were 1.22 for Enteritidis, 0.77 for Typhimurium, and 1.16 for Newport. This method provides a quantitative approach to estimating the relative differences in the likelihood that an illness caused by a particular serotype was transmitted by food, which may aid in tailoring strategies to prevent Salmonella illnesses and guide future research into serotype-specific source attribution.

Listeria monocytogenes is a foodborne pathogen that disproportionally affects pregnant females, older adults, and immunocompromised individuals. Using U.S. Foodborne Diseases Active Surveillance Network (FoodNet) surveillance data, we examined listeriosis incidence rates and rate ratios (RRs) by age, sex, race/ethnicity, and pregnancy status across three periods from 2008 to 2016, as recent incidence trends in U.S. subgroups had not been evaluated. The invasive listeriosis annual incidence rate per 100,000 for 2008-2016 was 0.28 cases among the general population (excluding pregnant females), and 3.73 cases among pregnant females. For adults ≥70 years, the annual incidence rate per 100,000 was 1.33 cases. No significant change in estimated listeriosis incidence was found over the 2008-2016 period, except for a small, but significantly lower pregnancy-associated rate in 2011-2013 when compared with 2008-2010. Among the nonpregnancy-associated cases, RRs increased with age from 0.43 (95% confidence interval: 0.25-0.73) for 0- to 14-year olds to 44.9 (33.5-60.0) for ≥85-year olds, compared with 15- to 44-year olds. Males had an incidence of 1.28 (1.12-1.45) times that of females. Compared with non-Hispanic whites, the incidence was 1.57 (1.18-1.20) times higher among non-Hispanic Asians, 1.49 (1.22-1.83) among non-Hispanic blacks, and 1.73 (1.15-2.62) among Hispanics. Among females of childbearing age, non-Hispanic Asian females had 2.72 (1.51-4.89) and Hispanic females 3.13 (2.12-4.89) times higher incidence than non-Hispanic whites. We observed a higher percentage of deaths among older patient groups compared with 15- to 44-year olds. This study is the first characterizing higher RRs for listeriosis in the United States among non-Hispanic blacks and Asians compared with non-Hispanic whites. This information for public health risk managers may spur further research to understand if differences in listeriosis rates relate to differences in consumption patterns of foods with higher contamination levels, food handling practices, comorbidities, immunodeficiencies, health care access, or other factors.

Objective: Medical students' abilities to predict postoperative complications and death are unknown. We hypothesize that medical students will lack confidence in determining surgical risk and will significantly overestimate surgical risk for post-operative morbidities and mortality., Design: Participants were invited to participate in an electronic, anonymous survey to assess their ability to predict surgical risk. The survey presented 7 complex clinical scenarios representative of a diverse general surgery practice. Participants were asked to assess the likelihood of different morbidities and mortality on a 0-100% scale, and predictions were compared to the ACS NSQIP risk calculator., Setting: Yale School of Medicine, New Haven, Connecticut; Tertiary medical center PARTICIPANTS: Third year medical students on their surgery clerkship as well as general surgery residents were invited to participate., Results: Most students were not confident about predicting postoperative complications (83.3%) or mortality (70.8%). Most students did not feel that the surgery clerkship adequately prepared them to assess surgical risk (69.6%). When compared to surgical residents for most presented cases (57% of cases), students and residents similarly overestimated postoperative morbidities and mortality. Estimates varied significantly, with wide 95% confidence intervals. Only 17% of NSQIP predicted estimates fell within the 95% confidence intervals., Conclusions: Medical students overestimate morbidity and mortality following surgery in complex patients. Additionally, they lack confidence in their ability to predict surgical complications. A formal curriculum for risk prediction is needed for medical students., (Published by Elsevier Inc.)

Importance: Reliance on prescription opioids for postprocedural analgesia has contributed to the opioid epidemic. With the implementation of electronic medical record (EMR) systems, there has been increasing use of computerized order entry systems for medication prescriptions, which is now more common than handwritten prescriptions. The EMR can autopopulate a default number of pills prescribed, and 1 potential method to alter prescriber behavior is to change the default number presented via the EMR system., Objective: To investigate the association of lowering the default number of pills presented when prescribing opioids in an EMR system with the amount of opioid prescribed after procedures., Design, Setting, and Participants: A prepost intervention study was conducted to compare postprocedural prescribing patterns during the 3 months before the default change (February 18 to May 17, 2017) with the 3 months after the default change (May 18 to August 18, 2017). The setting was a multihospital health care system that uses Epic EMR (Hyperspace 2015 IU2; Epic Systems Corporation). Participants were all patients in the study period undergoing 1 of the 10 most common operations and discharged by postoperative day 1., Intervention: The default number of opioid pills autopopulated in the EMR when prescribing discharge analgesia was lowered from 30 to 12., Main Outcomes and Measures: Linear regression estimating the change in the median number of opioid pills and the total dose of opioid prescribed was performed. Opioid doses were converted into morphine milligram equivalents (MME) for comparison. The frequency of patients requiring analgesic prescription refills was also evaluated., Results: There were 1447 procedures (mean [SD] age, 54.4 [17.3] years; 66.9% female) before the default change and 1463 procedures (mean [SD] age, 54.5 [16.4] years; 67.0% female) after the default change. After the default change, the median number of opioid pills prescribed decreased from 30 (interquartile range, 15-30) to 20 (interquartile range, 12-30) per prescription (P < .001). The percentage of prescriptions written for 30 pills decreased from 39.7% (554 of 1397) before the default change to 12.9% (183 of 1420) after the default change (P < .001), and the percentage of prescriptions written for 12 pills increased from 2.1% (29 of 1397) before the default change to 24.6% (349 of 1420) after the default change (P < .001). Regression analysis demonstrated a decrease of 5.22 (95% CI, -6.12 to -4.32) opioid pills per prescription after the default change, for a total decrease of 34.41 (95% CI, -41.36 to -27.47) MME per prescription. There was no statistical difference in opioid refill rates (3.0% [4 of 135] before the default change vs 1.5% [2 of 135] after the default change, P = .41)., Conclusions and Relevance: Lowering the default number of opioid pills prescribed in an EMR system is a simple, effective, cheap, and potentially scalable intervention to change prescriber behavior and decrease the amount of opioid medication prescribed after procedures.

Objectives: Among surgical educators, duty-hour restrictions led to concern regarding the adequacy of operative experience during residency, especially for junior residents. The American Board of Surgery recently instituted guidelines mandating "a minimum of 250 operations by the end of the PGY-2 year". A series of programmatic and institutional changes were implemented at our institution to augment the junior resident operative experience and to exceed compliance with this mandate., Methods: Operative data from Accreditation Council for Graduate Medical Education case logs for categorical and nondesignated preliminary interns from our large academic surgical residency were identified for 5 consecutive academic years, 2011 until 2016. American Board of Surgery In-Training Examination (ABSITE) scores were collected anonymously. The program systematically instituted the following changes: night float minimization, identification of new surgical opportunities, augmenting use of midlevel care providers, identification of rotations with suboptimal operative experiences, maximizing rotations with involvement of junior residents in the operating room, and systematic review of junior case logs., Results: After implementation, average total cases for residents completing postgraduate year (PGY)-2 increased from 176 to 330 (p < 0.001). Specifically, there was an 18% increase for interns (p = 0.059) and a 118% increase for PGY-2 residents (p < 0.001). There were statistically significant increases in skin and soft tissue cases, vascular cases, endoscopy, and complex laparoscopic cases. Average case volumes for senior residents did not change. Night float time was significantly decreased (5.7 vs 3.4 wk; p = 0.04). ABSITE scores were not significantly changed during this time., Conclusions: Before implementation of these interventions, our program would have had 0% compliance with the 250 junior resident case rule. Within 12 months of implementation, total case volumes for residents completing PGY-2 increased by 88%-exceeding minimum standards. Overall, 100% programmatic compliance was achieved. Our program's experience exemplifies how mandates from the American Board of Surgery can lead to programmatic changes that improve the experience of surgical house officers., (Copyright © 2017 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Drawing on published work from the Asia Pacific Observatory on Health Systems and Policies, this paper presents a framework for undertaking comparative studies on the health systems of countries. Organized under seven types of research approaches, such as national case-studies using a common format, this framework is illustrated using studies of low- and middle-income countries published by the Asia Pacific Observatory. Such studies are important contributions, since much of the health systems research literature comes from high-income countries. No one research approach, however, can adequately analyse a health system, let alone produce a nuanced comparison of different countries. Multiple comparative studies offer a better understanding, as a health system is a complex entity to describe and analyse. Appreciation of context and culture is crucial: what works in one country may not do so in another. Further, a single research method, such as performance indicators, or a study of a particular health system function or component, produces only a partial picture. Applying a comparative framework of several study approaches helps to inform and explain progress against health system targets, to identify differences among countries, and to assess policies and programmes. Multi-method comparative research produces policy-relevant learning that can assist countries to achieve Sustainable Development Goal 3: ensure healthy lives and promoting well-being for all at all ages by 2030., Competing Interests: None declared

Objective: Opioid abuse has become an epidemic in the United States, causing nearly 50,000 deaths a year. Postoperative pain is an unavoidable consequence of most surgery, and surgeons must balance the need for sufficient analgesia with the risks of overprescribing. Prescribing narcotics is often the responsibility of surgical residents, yet little is known about their opioid-prescribing habits, influences, and training experience., Design: Anonymous online survey that assessed the amounts of postoperative opioid prescribed by residents, including type of analgesia, dosage, and number of pills, for a series of common general surgery procedures. Additional questions investigated influences on opioid prescription, use of nonnarcotic analgesia, degree of engagement in patient education on opioids, and degree of training received on analgesia and opioid prescription., Setting: Accreditation Council for Graduate Medical Education accredited general surgery program at a university-based tertiary hospital., Participants: Categorical and preliminary general surgery residents of all postgraduate years., Results: The percentage of residents prescribing opioids postprocedure ranged from 75.5% for incision and drainage to 100% for open hernia repair. Residents report prescribing 166.3 morphine milligram equivalents of opioid for a laparoscopic cholecystectomy, yet believe patients will only need an average of 113.9 morphine milligram equivalents. The most commonly reported influences on opioid-prescribing habits include attending preference (95.2%), concern for patient satisfaction (59.5%), and fear of potential opioid abuse (59.5%). Only 35.8% of residents routinely perform a narcotic risk assessment before prescribing and 6.2% instruct patients how to properly dispose of excess opioids. More than 90% of residents have not had formal training in best practices of pain management or opioid prescription., Conclusion and Relevance: Surgical trainees are relying almost exclusively on opioids for postoperative analgesia, often in excessive amounts. Residents are heavily influenced by their superiors, but are not receiving formal opioid-prescribing education, pointing to a great need for increased resident education on postoperative pain and opioid management to help change prescribing habits., (Copyright © 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Multiple institutions have developed international electives and sustainable global surgery initiatives to facilitate clinical, research, and outreach opportunities with hospitals in resource-poor areas. Despite increasing interest among programs, many institutions have not successfully reached potential involvement., Objective: This study evaluates the experiences of Yale residents and faculty, measures interest in the development of an international surgical elective, and enumerates barriers to developing or participating in these opportunities. This was performed to develop a formalized elective and assess interest and capacity for surgical global health initiatives, as a seemingly increasing number of trainee applicants and residents were expressing interest in working in resource-poor settings., Methods: Electronic survey of Yale Surgery residents and faculty analyzed using SPSS and Graphpad Prism., Results: Among residents, previous global experience correlates with current interest in international opportunities, with 100% remaining interested, and 78% of those without prior experience also expressing interest (p = 0.018). Barriers to pursuing these activities included the use of vacation time, funding, scheduling, family obligations, and concern for personal safety. Among faculty, 28% of respondents have been involved internationally, and most (86%) expressed interest in additional opportunities and all were willing to take residents. Barriers to faculty participation included funding, relative value unit target reduction, protected time, and the desire for institutional support for such activities., Conclusions: A substantial proportion of residents and faculty have experience in global health and motivation to pursue additional opportunities. The main barriers to participation are not a lack of interest, but rather needs for funding support, protected time, and institutional recognition of academic contributions. These findings are being used to develop a global surgery elective and establish long-term partnerships with international colleagues., (Copyright © 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Use of drain remains frequent following pancreaticoduodenectomy (PD) due to concern for postoperative pancreatic fistula (POPF) and anastomotic leak development. Despite controversy, a recent randomized trial suggested omitting drainage would result in a large increase in operative mortality. This study sought to comprehensively examine the effects of forgoing drainage in the large cohort of patients undergoing PD. A prospective cohort study of two consecutive groups undergoing PD was constructed. The initial group had operative drains placed in cases subjectively concerning for POPF development; the second cohort did not undergo operative drainage. Outcomes including POPF incidence, need for reintervention, and overall morbidity were examined. A total of 106 patients were evaluated in two consecutive cohorts of 53; in the first group, 30 per cent had operative drains placed; 22.6 per cent developed POPF versus 7.5 per cent of patients in the no drainage group (P = 0.06). Despite this, no significant difference in major morbidity (Clavien ≥3, 20.8% versus 17.0%) or need for procedural reintervention (18.9% versus 15.1%) was observed. A subsequent validation cohort of 237 additional patients where drains were used only in exceptional circumstances was examined. Operative drains were placed in only 3 per cent of patients (n = 7) and 90-day mortality was 1.3 per cent (n = 3). Incidence of POPF was 8.0 per cent and the overall major complication rate was 14.8 per cent. Given such findings, it appears that drainage after PD can be avoided resulting in acceptable operative morbidity and mortality in most cases.

Background: Dysregulated WNT signaling dominates adrenocortical malignancies. This study investigates whether silencing of the WNT negative regulator DKK3 (Dickkopf-related protein 3), an implicated adrenocortical differentiation marker and an established tumor suppressor in multiple cancers, allows dedifferentiation of the adrenal cortex., Methods: We analyzed the expression and regulation of DKK3 in human adrenocortical carcinoma (ACC) by qRT-PCR, immunofluorescence, promoter methylation assay, and copy number analysis. We also conducted functional studies on ACC cell lines, NCI-H295R and SW-13, using siRNAs and enforced DKK3 expression to test DKK3's role in blocking dedifferentiation of adrenal cortex., Results: While robust expression was observed in normal adrenal cortex, DKK3 was down-regulated in the majority (>75%) of adrenocortical carcinomas (ACC) tested. Both genetic (gene copy loss) and epigenetic (promoter methylation) events were found to play significant roles in DKK3 down-regulation in ACCs. While NCI-H295R cells harboring β-catenin activating mutations failed to respond to DKK3 silencing, SW-13 cells showed increased motility and reduced clonal growth. Conversely, exogenously added DKK3 also increased motility of SW-13 cells without influencing their growth. Enforced over-expression of DKK3 in SW-13 cells resulted in slower cell growth by an extension of G1 phase, promoted survival of microcolonies, and resulted in significant impairment of migratory and invasive behaviors, largely attributable to modified cell adhesions and adhesion kinetics. DKK3-over-expressing cells also showed increased expression of Forkhead Box Protein O1 (FOXO1) transcription factor, RNAi silencing of which partially restored the migratory proficiency of cells without interfering with their viability., Conclusions: DKK3 suppression observed in ACCs and the effects of manipulation of DKK3 expression in ACC cell lines suggest a FOXO1-mediated differentiation-promoting role for DKK3 in the adrenal cortex, silencing of which may allow adrenocortical dedifferentiation and malignancy.

In 2014, an acute respiratory illness outbreak affected unaccompanied children from Central America entering the United States; 9% of 774 surveyed children were colonized with Streptococcus pneumoniae serotype 5. In our 2015 follow-up survey of 475 children, serotype 5 was not detected, and an interim recommendation to administer 13-valent pneumococcal conjugate vaccine to all unaccompanied children was discontinued.

The systematics of the molluscan class Bivalvia are explored using a 5-gene Sanger-based approach including the largest taxon sampling to date, encompassing 219 ingroup species spanning 93 (or 82%) of the 113 currently accepted bivalve families. This study was designed to populate the bivalve Tree of Life at the family level and to place many genera into a clear phylogenetic context, but also pointing to several major clades where taxonomic work is sorely needed. Despite not recovering monophyly of Bivalvia or Protobranchia-as in most previous Sanger-based approaches to bivalve phylogeny-our study provides increased resolution in many higher-level clades, and supports the monophyly of Autobranchia, Pteriomorphia, Heteroconchia, Palaeoheterodonta, Heterodonta, Archiheterodonta, Euheterodonta, Anomalodesmata, Imparidentia, and Neoheterodontei, in addition to many other lower clades. However, deep nodes within some of these clades, especially Pteriomorphia and Imparidentia, could not be resolved with confidence. In addition, many families are not supported, and several are supported as non-monophyletic, including Malletiidae, Nuculanidae, Yoldiidae, Malleidae, Pteriidae, Arcidae, Propeamussiidae, Iridinidae, Carditidae, Myochamidae, Lyonsiidae, Pandoridae, Montacutidae, Galeommatidae, Tellinidae, Semelidae, Psammobiidae, Donacidae, Mactridae, and Cyrenidae; Veneridae is paraphyletic with respect to Chamidae, although this result appears to be an artifact. The denser sampling however allowed testing specific placement of species, showing, for example, that the unusual Australian Plebidonax deltoides is not a member of Donacidae and instead nests within Psammobiidae, suggesting that major revision of Tellinoidea may be required. We also showed that Cleidothaerus is sister group to the cementing member of Myochamidae, suggesting that Cleidothaeridae may not be a valid family and that cementation in Cleidothaerus and Myochama may have had a single origin. These results highlight the need for an integrative approach including as many genera as possible, and that the monophyly and relationships of many families require detailed reassessment. NGS approaches may be able to resolve the most recalcitrant nodes in the near future., (Copyright © 2016 Elsevier Inc. All rights reserved.)

During December 2015-January 2016, the American Samoa Department of Health (ASDoH) detected through surveillance an increase in the number of cases of acute febrile rash illness. Concurrently, a case of laboratory-confirmed Zika virus infection, a mosquito-borne flavivirus infection documented to cause microcephaly and other severe brain defects in some infants born to women infected during pregnancy (1,2) was reported in a traveler returning to New Zealand from American Samoa. In the absence of local laboratory capacity to test for Zika virus, ASDoH initiated arboviral disease control measures, including public education and vector source reduction campaigns. On February 1, CDC staff members were deployed to American Samoa to assist ASDoH with testing and surveillance efforts.

Incidental appendectomy is the removal of the vermiform appendix accompanying another operation, without evidence of acute appendicitis. It is generally performed to eliminate the risk of future appendicitis. The risks and benefits of incidental appendectomy during various operations in children have been debated for over a century, but need to be revisited in light of innovations in medical practice, including minimally invasive surgery, improved imaging techniques, and use of the appendix as a tubular conduit for reconstruction. A detailed review was undertaken of the techniques, pathology, risks of appendectomy, utility of the appendix, and incidental appendectomy in the treatment of specific pediatric medical conditions. A comprehensive literature search was performed, and retrieved results were reviewed for relevance to the topic. The decision to perform a pediatric incidental appendectomy relies on informed consideration of the individual patient's co-morbid conditions, the indication for the initial operation, the future utility of the appendix, and the risk of future appendiceal pathology. The discussion includes a variety of situations and comorbid conditions that may influence a surgeon's decision to perform incidental appendectomy.

Background: Overexpression of Solute carrier family 12 member 7 (SLC12A7) promotes tumor aggressiveness in various cancers. Previous studies have identified the 5p15.33 region, containing the SLC12A7 locus, as being amplified frequently in adrenocortical carcinoma (ACC). Copy number amplifications (CNAs) may alter gene expression levels and occur frequently in ACC; however, SLC12A7 gene amplifications or expression levels have not been studied in ACC., Methods: Fifty-five cases of clinically well-characterized ACCs were recruited for this study. Whole-exome sequencing was used to predict CNAs in 19 samples. CNA analysis was performed on an expanded cohort of 26 samples with the use of TaqMan Copy Number Assays. SLC12A7 mRNA expression was analyzed in 32 samples with real-time quantitative polymerase chain reaction and protein expression was assessed by immunohistochemistry. SLC12A7 CNAs and expression patterns were evaluated for correlation with patient and tumor characteristics., Results: Whole-exome sequencing and TaqMan Copy Number Assays demonstrated SLC12A7 amplifications in 68.4% and 65.4% of ACCs tested, respectively. Furthermore, SLC12A7 copy gains were associated with increased gene expression (P < .05) and non-functional tumors (P < .05). SLC12A7 gene expression levels were increased in ACCs compared with normal adrenal tissue (P < .05)., Conclusion: SLC12A7 gene amplification and overexpression occurs frequently in ACCs and may represent a novel molecular event associated with ACC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: Aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia are important causes of secondary hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1 have been described in APAs., Objective: To characterize clinical-pathological features in APAs and unilateral adrenal hyperplasia, and correlate them with genotypes., Design: Retrospective study., Subjects and Measurements: Clinical and pathological characteristics of 90 APAs and seven diffusely or focally hyperplastic adrenal glands were reviewed, and samples were examined for mutations in known disease genes by Sanger or exome sequencing., Results: Mutation frequencies were as follows: KCNJ5, 37·1%; CACNA1D, 10·3%; ATP1A1, 8·2%; ATP2B3, 3·1%; and CTNNB1, 2·1%. Previously unidentified mutations included I157K, F154C and two insertions (I150&#95;G151insM and I144&#95;E145insAI) in KCNJ5, all close to the selectivity filter, V426G&#95;V427Q&#95;A428&#95;L433del in ATP2B3 and A39Efs*3 in CTNNB1. Mutations in KCNJ5 were associated with female and other mutations with male gender (P = 0·007). On computed tomography, KCNJ5-mutant tumours displayed significantly greater diameter (P = 0·023), calculated area (P = 0·002) and lower precontrast Hounsfield units (P = 0·0002) vs tumours with mutations in other genes. Accordingly, KCNJ5-mutant tumours were predominantly comprised of lipid-rich fasciculata-like clear cells, whereas other tumours were heterogeneous (P = 5 × 10(-6) vs non-KCNJ5 mutant and P = 0·0003 vs wild-type tumours, respectively). CACNA1D mutations were present in two samples with hyperplasia without adenoma., Conclusions: KCNJ5-mutant tumours appear to be associated with fasciculata-like clear cell predominant histology and tend to be larger with a characteristic imaging phenotype. Novel somatic KCNJ5 variants likely cause adenomas by loss of potassium selectivity, similar to previously described mutations., (© 2015 John Wiley & Sons Ltd.)

Background: The localization and role of the calcium-sensing receptor (CaSR) along the nephron including the collecting ducts is still open to debate., Methods: Using the quantitative, highly sensitive in situ hybridization technique and a double-staining immunohistochemistry technique, we investigated the axial distribution and expression of CaSR along the nephron in mice (C57B/6J) treated for 6 days with acid or alkali diets., Results: Under control condition, CaSR was specifically localized in the cortical and medullary thick ascending limb of Henle's loop (CTAL and MTAL), macula densa (MD), distal convoluted tubule (DCT), and CCD (TALs, MD > DCT, CCD). Along the CCD, CaSR was co-localized with an anion exchanger type 4 (AE4), a marker of the basolateral membrane of type-B intercalated cell (IC-B) in mice. On the contrary, CaSR was not detected either in principal cells (PC) or in type-A intercalated cell (IC-A). CaSR expression levels in IC-B significantly (P < 0.005) decreased when mice were fed NH4Cl (acid) diets and increased when animals were given NaHCO3 (alkali) diets. As expected, cell heights of IC-A and IC-B significantly (P < 0.005) increased in the above experimental conditions. Surprisingly, single infusion (ip) of neomycin, an agonist of CaSR, significantly (P < 0.005) increased urinary Ca excretion without further increasing the hourly urine volume and significantly (P < 0.05) decreased urine pH., Conclusion: CaSR, cloned from rat kidney, was localized in the basolateral membrane of IC-B and was more expressed during alkali-loading. Its alkali-sensitive expression may promote urinary alkali secretion for body acid-base balance.

Background: Diabetes mellitus is postulated to be both a risk factor and manifestation of pancreatic adenocarcinoma. This study evaluated the effects of preoperative glycemic control as determined by hemoglobin A1c (HbA1c) on outcomes following pancreaticoduodenectomy (PD)., Methods: A prospective cohort study whereby HbA1c was assessed preoperatively in 243 patients undergoing PD was performed. The primary outcome measure was operative morbidity. Secondary outcomes included individual adverse events, time to dietary resumption, and length of stay., Results: Preoperative HbA1c ranged from 4.0% to 13.5%. Overall morbidity and incidence of specific adverse events were similar regardless of preoperative HbA1c. No correlation between HbA1c and length of stay, dietary resumption, or readmission was observed. Pancreatic fistula formation had a decreased incidence in patients with elevated versus normal HbA1c (2.2% vs. 9.6%, P = .083)., Conclusions: PD can be safely performed in patients with HbA1c levels suggestive of poor long-term preoperative glycemic control. Medical efforts to optimize HbA1c should not delay resection., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The International Study Group for Pancreatic Surgery (ISGPS) defined criteria to objectively standardize delayed gastric emptying (DGE) after pancreaticoduodenectomy (PD). These criteria are inclusive by design, and may overestimate actual DGE incidence. This study critically examined individual DGE cases after PD to determine which patients are misclassified by these criteria, and for what reasons. Exclusion criteria designed to optimize the accepted DGE definition are proposed and evaluated., Study Design: We performed a retrospective review of prospectively collected data. We reviewed 357 consecutive patients undergoing PD by a single surgeon; included were 52 cases of ISGPS-defined DGE (14.6%). A detailed evaluation was conducted of cases using accepted and novel diagnostic criteria., Results: Of 52 ISGPS-defined DGE cases, 12 (23%) appeared not to represent genuine DGE on clinical review. Six required nasogastric tube placement for reoperation or management of emesis secondary to non-DGE conditions, 4 for reintubation without other evidence of DGE, and 2 remained NPO to treat non-DGE conditions. The proposed exclusion criteria use absence of gastric distention, passage of oral contrast, and presence of documented non-DGE conditions to determine genuine DGE. The incidence of true DGE was 11.2% in this cohort. The overall positive predictive value of the ISGPS criteria was 76.9%. Preoperative variables, DGE class, and incidence of disease-specific outcomes were similar with both definitions., Conclusions: The ISGPS consensus guidelines promote a standardized, sensitive, and easily applicable definition of DGE, but may falsely classify DGE in approximately 23.1%. Introduction of the proposed exclusion criteria, which establish objective radiologic data as a component of the definition, could substantially limit this overestimation., (Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood., Objective: To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC., Design: Screening for somatic mutation events and copy number alterations (CNAs) was performed by comparative analysis of tumors and matched normal samples from 41 patients with ACC., Results: In total, 966 nonsynonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS, NF2, and RB1, and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27, SCN7A, and SDK1. Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41 9.8% and 3/41, 7.3%, respectively). Somatic mutations in ACC-established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs., Conclusions: These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.

Surveillance systems for West Nile virus (WNV) combine several methods to determine the location and timing of viral amplification. The value of each surveillance method must be measured against its efficiency and costs to optimize integrated vector management and suppress WNV transmission to the human population. Here we extend previous comparisons of WNV surveillance methods by equitably comparing the most common methods after standardization on the basis of spatial sampling density and costs, and by estimating optimal levels of sampling effort for mosquito traps and sentinel chicken flocks. In general, testing for evidence of viral RNA in mosquitoes and public-reported dead birds resulted in detection of WNV approximately 2-5 weeks earlier than serological monitoring of sentinel chickens at equal spatial sampling density. For a fixed cost, testing of dead birds reported by the public was found to be the most cost effective of the methods, yielding the highest number of positive results per $1000. Increased spatial density of mosquito trapping was associated with more precise estimates of WNV infection prevalence in mosquitoes. Our findings also suggested that the most common chicken flock size of 10 birds could be reduced to six to seven without substantial reductions in timeliness or sensitivity. We conclude that a surveillance system that uses the testing of dead birds reported by the public complemented by strategically timed mosquito and chicken sampling as agency resources allow would detect viral activity efficiently in terms of effort and costs, so long as susceptible bird species that experience a high mortality rate from infection with WNV, such as corvids, are present in the area.

We describe a patient who presented with multi-system organ failure due to extreme hypercalcemia (serum calcium 19.8 mg/dL), resulting from primary hyperparathyroidism. He was found to have a 4.8 cm solitary atypical parathyroid adenoma. His course was complicated by complete heart block, acute kidney injury, and significant neurocognitive disturbances. Relevant literature was reviewed and discussed. Hyperparathyroidism-induced hypercalcemic crisis (HIHC) is a rare presentation of primary hyperparathyroidism and only a small minority of these patients develop significant cardiac and renal complications. In cases of HIHC, a multidisciplinary effort can facilitate rapid treatment of life-threatening hypercalcemia and definitive treatment by surgical resection. As such, temporary transvenous cardiac pacing and renal replacement therapy can provide a life-saving bridge to definitive parathyroidectomy in cases of HIHC.

In urban Maroua, Cameroon, improved drinking water sources are available to a large majority of the population, yet this water is frequently distributed through informal distribution systems and stored in home containers (canaries), leaving it vulnerable to contamination. We assessed where contamination occurs within the distribution system, determined potential sources of environmental contamination, and investigated potential pathogens. Gastrointestinal health status (785 individuals) was collected via health surveys. Drinking water samples were collected from drinking water sources and canaries. Escherichia coli and total coliform levels were evaluated and molecular detection was performed to measure human-associated faecal marker, HF183; tetracycline-resistance gene, tetQ; Campylobacter spp.; and Staphylococcus aureus. Statistical analyses were performed to evaluate the relationship between microbial contamination and gastrointestinal illness. Canari samples had higher levels of contamination than source samples. HF183 and tetQ were detected in home and source samples. An inverse relationship was found between tetQ and E. coli. Presence of tetQ with lower E. coli levels increased the odds of reported diarrhoeal illness than E. coli levels alone. Further work is warranted to better assess the relationship between antimicrobial-resistant bacteria and other pathogens in micro-ecosystems within canaries and this relationship's impact on drinking water quality.

Importance: Follicular thyroid hyperplasia (FTH) refers to enlargement of the thyroid gland due to cellular hyperplasia. It is frequently encountered in clinical practice in nontoxic uninodular or multinodular goiter. The genetic and epigenetic events associated with the origin and malignant potential of FTH are poorly understood., Objective: To analyze FTH samples for known recurrent genetic and epigenetic driver events in thyroid neoplasms such as activating mutations in proto-oncogenes BRAF and NRAS and promoter hypermethylation of tumor suppressor genes CDKN2A, PTEN, and RASSF1A., Design, Setting, and Participants: Clinical characteristics and thyroid specimens were prospectively obtained from 43 patients who underwent thyroid surgery at Yale-New Haven Hospital., Main Outcomes and Measures: Presence of BRAF(V600E) and NRAS codon 61 mutations were assessed in FTH. Methylation status of CDKN2A, PTEN, and RASSF1A gene promoters in FTH, follicular thyroid adenoma, and follicular thyroid carcinoma was quantified. Regulation of RASSF1A messenger RNA (mRNA) and protein expression and its potential neoplastic role in FTH were examined., Results: An exploratory cohort of FTH (n = 10) was negative for BRAF(V600E) and NRAS codon 61 mutations. In contrast, epigenetic analysis displayed significant promoter hypermethylation of the tumor-suppressor gene RASSF1A in 6 FTH samples (60%) compared with their adjacent normal tissue (P = .01). The overall genome CpG methylation and promoter methylation of PTEN and CDKN2A were unaffected in the lesions. Further analysis of an expanded cohort of patients with FTH (n = 23), follicular thyroid adenoma (n = 10), and follicular thyroid carcinoma (n = 10) showed RASSF1A promoter hypermethylation in 14 (61%), 9 (90%), and 7 (70%), respectively (P < .001). The overall hypermethylation level in FTH showed a statistically significant inverse correlation with RASSF1A mRNA expression (P = .005). Immunohistochemistry demonstrated minimal or no protein expression in most FTH samples studied. To explore the potential neoplastic contribution of RASSF1A downregulation, we analyzed the expression pattern of thyroid proliferation markers Ki-67 and NF-κB in representative samples. Although Ki-67 expression was undetectable, similar to normal tissue, FTH samples expressed high levels of NF-κB, similar to the expression levels in thyroid tumors., Conclusions and Relevance: We demonstrate silencing of tumor suppressor RASSF1A in a subset of FTH in the absence of other known thyroid cancer-associated genetic and epigenetic changes. Silencing of RASSF1A and concurrent NF-κB activation demonstrate that a subset of FTH shares epigenetic changes and downstream signaling events associated with malignant lesions, suggesting that FTH may have the potential to be a premalignant lesion.