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Modifications to the method for estimating aryl hydrocarbon hydroxylase (AHH) activity in cultured human lymphocytes are described. Despite the improvements to the technique it was not possible to show significant 'repeatability' of values for AHH induction over a period of 2 weeks or more. Significant repeatability could be seen when a blood sample from each subject was split into duplicates. However, this level of repeatability was low when considered for quantitative genetics purposes. Possible reasons for the poor repeatability have been discussed. [ABSTRACT FROM PUBLISHER]

Salmonella is estimated to be the leading bacterial cause of U.S. domestically acquired foodborne illness. Large outbreaks of Salmonella attributed to ground beef have been reported in recent years. The demographic and sociodemographic characteristics of infected individuals linked to these outbreaks are poorly understood. We employed a retrospective case-control design; case-patients were people with laboratory-confirmed Salmonella infections linked to ground beef-associated outbreaks between 2012 and 2019, and controls were respondents to the 2018-2019 FoodNet Population Survey who reported eating ground beef and denied recent gastrointestinal illness. We used county-level CDC/ATSDR Social Vulnerability Index (SVI) to compare case-patient and controls. Case-patient status was regressed on county-level social vulnerability and individual-level demographic characteristics. We identified 376 case-patients and 1,321 controls in the FoodNet sites. Being a case-patient was associated with increased overall county-level social vulnerability (OR: 1.21 [95% CI: 1.07-1.36]) and socioeconomic vulnerability (OR: 1.24 [1.05-1.47]) when adjusted for individual-level demographics. Case-patient status was not strongly associated with the other SVI themes of household composition and disability, minority status and language, and housing type and transportation. Data on individual-level factors such as income, poverty, unemployment, and education could facilitate further analyses to understand this relationship., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Over 20% of E. coli O157 illnesses and over 5% of Salmonella illnesses are estimated to be attributable to beef consumption in the United States. Irradiating ground beef is one possible method to reduce disease burden. We simulated the effect of ground beef irradiation on illnesses, hospitalizations, deaths, and direct healthcare costs from ground beef-associated E. coli O157 and Salmonella illnesses in the United States. To estimate the fraction of illnesses, hospitalizations, deaths, and direct healthcare costs preventable by ground beef irradiation, we multiplied the disease burden attributable to ground beef; the estimated percentage of ground beef sold that is not currently irradiated; the percentage of unirradiated ground beef that would be irradiated; and the percentage reduction in risk of illness after irradiation. We multiplied this fraction by estimates of burden and direct healthcare costs to calculate the numbers or amounts averted. Model inputs were obtained from the literature and expert opinion. We used Monte Carlo simulation to incorporate uncertainty in inputs into model estimates. Simulation outcomes were summarized with means and 95% uncertainty intervals (UI). Irradiating 50% of the currently unirradiated ground beef supply would avert 3,285 (95% UI: 624-9,977) E. coli O157 illnesses, 135 (95% UI: 24-397) hospitalizations, 197 (95% UI: 34-631) hemolytic uremic syndrome cases, 2 (95% UI: 0-16) deaths, and $2,972,656 (95% UI: $254,708-$14,496,916) in direct healthcare costs annually. For Salmonella, irradiation would avert 20,308 (95% UI: 9,858-38,903) illnesses, 400 (95% UI: 158-834) hospitalizations, 6 (95% UI: 0-18) deaths, and $7,318,632 (95% UI: $1,436,141-$26,439,493) in direct healthcare costs. Increasing ground beef irradiation could reduce E. coli O157 and Salmonella burden in the United States. Additional studies should assess whether targeted irradiation of higher-risk ground beef products could prevent similar numbers of illnesses with less total product irradiated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Digital transformation in healthcare improves the safety of health systems. Within our health service, a new digital hospital has been established and two wards from a neighbouring paper-based hospital transitioned into the new digital hospital. This created an opportunity to evaluate the impact of complete digital transformation on medication safety. Here we discuss the impact of transition from a paper-based to digital hospital on voluntarily reported medication incidents and prescribing errors. This study utilises an interrupted time-series design and takes place across two wards as they transition from a paper to a digital hospital. Two data sources are used to assess impacts on medication incidents and prescribing errors: (1) voluntarily reported medication incidents and 2) a chart audit of medications prescribed on the study wards. The chart audit collects data on procedural, dosing and therapeutic prescribing errors. There are 588 errors extracted from incident reporting software during the study period. The average monthly number of errors reduces from 12.5 pre- to 7.5 post-transition (p < 0.001). In the chart audit, 5072 medication orders are reviewed pre-transition and 3699 reviewed post-transition. The rates of orders with one or more error reduces significantly after transition (52.8% pre- vs. 15.7% post-, p < 0.001). There are significant reductions in procedural (32.1% pre- vs. 1.3% post-, p < 0.001), and dosing errors (32.3% pre- vs. 14% post-, p < 0.001), but not therapeutic errors (0.6% pre- vs. 0.7% post-, p = 0.478). Transition to a digital hospital is associated with reductions in voluntarily reported medication incidents and prescribing errors., (© 2023. The Author(s).)

The Centers for Disease Control and Prevention (CDC) has identified nontyphoidal Salmonella as one of the top five pathogens contributing to foodborne illnesses in the United States. Beef continues to be a common source of Salmonella outbreaks, despite the implementation of interventions at slaughter and processing facilities to reduce contamination of beef. We described Salmonella outbreaks linked to beef in the United States during 2012-2019, examined trends, and identified potential targets for intervention and prevention strategies. We queried CDC's Foodborne Disease Outbreak Surveillance System (FDOSS) for all foodborne nontyphoidal Salmonella outbreaks linked to beef as the single contaminated ingredient or implicated food, with the date of first illness onset from 2012 to 2019. Information on antimicrobial resistance (AR) for outbreak-related isolates was obtained from CDC's National Antimicrobial Resistance Monitoring System (NARMS). We calculated the number of outbreaks, outbreak-related illnesses, hospitalizations, and deaths overall, by beef processing category and Salmonella serotype. During 2012-2019, 27 Salmonella outbreaks were linked to beef consumption, resulting in 1103 illnesses, 254 hospitalizations, and two deaths. The most common category of beef implicated was nonintact raw, ground beef (12 outbreaks, 44%), followed by intact raw (six outbreaks, 22%). Ground beef was responsible for the most illnesses (800, 73%), both of the reported deaths, and was the source of the largest outbreak. AR data were available for 717 isolates from 25 (93%) outbreaks. Nine (36%) of these outbreaks had isolates resistant to one or more of the antibiotics tested by NARMS, of which eight (89%) contained multidrug-resistant isolates. Several outbreaks reported highlight challenges faced during investigations, areas where further research may be warranted, and opportunities to prevent future outbreaks along the farm-to-fork continuum., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

As of November 14, 2022, monkeypox (mpox) cases had been reported from more than 110 countries, including 29,133 cases in the United States.* Among U.S. cases to date, 95% have occurred among males (1). After the first confirmed U.S. mpox case on May 17, 2022, limited supplies of JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic) were made available to jurisdictions for persons exposed to mpox. JYNNEOS vaccine was approved by the Food and Drug Administration (FDA) in 2019 as a 2-dose series (0.5 mL per dose, administered subcutaneously) to prevent smallpox and mpox disease. † On August 9, 2022, FDA issued an emergency use authorization to allow administration of JYNNEOS vaccine by intradermal injection (0.1 mL per dose) (2). A previous report on U.S. mpox cases during July 31-September 3, 2022, suggested that 1 dose of vaccine offers some protection against mpox (3). This report describes demographic and clinical characteristics of cases occurring ≥14 days after receipt of 1 dose of JYNNEOS vaccine and compares them with characteristics of cases among unvaccinated persons with mpox and with the vaccine-eligible vaccinated population in participating jurisdictions. During May 22-September 3, 2022, among 14,504 mpox cases reported from 29 participating U.S. jurisdictions, § 6,605 (45.5%) had available vaccination information and were included in the analysis. Among included cases, 276 (4.2%) were among persons who had received 1 dose of vaccine ≥14 days before illness onset. Mpox cases that occurred in these vaccinated persons were associated with lower percentage of hospitalization (2.1% versus 7.5%), fever, headache, malaise, myalgia, and chills, compared with cases in unvaccinated persons. Although 1 dose of JYNNEOS vaccine offers some protection from disease, mpox infection can occur after receipt of 1 dose, and the duration of protection conferred by 1 dose is unknown. Providers and public health officials should therefore encourage persons at risk for acquiring mpox to complete the 2-dose vaccination series and provide guidance and education regarding nonvaccine-related prevention strategies (4)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Emma Creegan reports receiving an honorarium for a fall 2021 speaking event at Brown University. No other potential conflicts of interest were disclosed.

As of October 28, 2022, a total of 28,244* monkeypox (mpox) cases have been reported in the United States during an outbreak that has disproportionately affected gay, bisexual, and other men who have sex with men (MSM) (1). JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic), administered subcutaneously as a 2-dose (0.5 mL per dose) series (with doses administered 4 weeks apart), was approved by the Food and Drug Administration (FDA) in 2019 to prevent smallpox and mpox disease (2); an FDA Emergency Use Authorization issued on August 9, 2022, authorized intradermal administration of 0.1 mL per dose, increasing the number of persons who could be vaccinated with the available vaccine supply † (3). A previous comparison of mpox incidence during July 31-September 3, 2022, among unvaccinated, but vaccine-eligible men aged 18-49 years and those who had received ≥1 JYNNEOS vaccine dose in 32 U.S. jurisdictions, found that incidence among unvaccinated persons was 14 times that among vaccinated persons (95% CI = 5.0-41.0) (4). During September 4-October 1, 2022, a total of 205,504 persons received JYNNEOS vaccine dose 2 in the United States. § To further examine mpox incidence among persons who were unvaccinated and those who had received either 1 or 2 JYNNEOS doses, investigators analyzed data on 9,544 reported mpox cases among men ¶ aged 18-49 years during July 31-October 1, 2022, from 43 U.S. jurisdictions,** by vaccination status. During this study period, mpox incidence (cases per 100,000 population at risk) among unvaccinated persons was 7.4 (95% CI = 6.0-9.1) times that among persons who received only 1 dose of JYNNEOS vaccine ≥14 days earlier and 9.6 (95% CI = 6.9-13.2) times that among persons who received dose 2 ≥14 days earlier. The observed distribution of subcutaneous and intradermal routes of administration of dose 1 among vaccinated persons with mpox was not different from the expected distribution. This report provides additional data suggesting JYNNEOS vaccine provides protection against mpox, irrespective of whether the vaccine is administered intradermally or subcutaneously. The degree and durability of such protection remains unclear. Persons eligible for mpox vaccination should receive the complete 2-dose series to optimize strength of protection †† (5)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Frozen stuffed breaded raw chicken products have repeatedly been implicated in Salmonella outbreaks (1). These products are partially cooked to set the breading, often making them appear cooked (2). Despite their appearance, these products need to be cooked to an internal temperature of 165°F (74°C) to ensure that they are safe to eat. Producers began implementing labeling changes in 2006 to more clearly identify these products as raw; many warn against using microwave ovens (microwaves) to prepare them and provide validated cooking instructions solely for conventional ovens (ovens) (3,4). However, outbreaks continued to occur after implementation of these labeling changes (4). To describe the demographic characteristics of persons who prepare frozen stuffed chicken products and which appliances they use to prepare them, data from a May-July 2022 representative panel survey were analyzed. Although most (82.7%) respondents used an oven as one of their cooking methods, more than one half (54.0%) of respondents also used another appliance, including 29.0% who used a microwave. Oven use was lower among respondents with household income <$25,000 (68.9%), and who lived in mobile homes or other portable types of homes (66.5%). Among respondents who reported using microwaves to cook these products, 8% reported using a microwave with ≤750 W of power, which might be insufficient to thoroughly cook such products (1,5,6). Economic and other factors might influence some groups' access to recommended cooking appliances. Companies could consider implementing additional interventions that rely less on labeling and consumer preparation practices and focus on controlling or reducing levels of Salmonella in these products, such as selling them fully cooked, or monitoring and testing Salmonella levels, to ensure safety. These findings highlight challenges consumers might face in preparing frozen stuffed chicken products safely and can guide strategies for regulatory authorities and industry to prevent outbreaks and illnesses associated with them., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Human monkeypox is caused by Monkeypox virus (MPXV), an Orthopoxvirus, previously rare in the United States (1). The first U.S. case of monkeypox during the current outbreak was identified on May 17, 2022 (2). As of September 28, 2022, a total of 25,341 monkeypox cases have been reported in the United States.* The outbreak has disproportionately affected gay, bisexual, and other men who have sex with men (MSM) (3). JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic), administered subcutaneously as a 2-dose (0.5 mL per dose) series with doses administered 4 weeks apart, was approved by the Food and Drug Administration (FDA) in 2019 to prevent smallpox and monkeypox infection (4). U.S. distribution of JYNNEOS vaccine as postexposure prophylaxis (PEP) for persons with known exposures to MPXV began in May 2022. A U.S. national vaccination strategy † for expanded PEP, announced on June 28, 2022, recommended subcutaneous vaccination of persons with known or presumed exposure to MPXV, broadening vaccination eligibility. FDA emergency use authorization (EUA) of intradermal administration of 0.1 mL of JYNNEOS on August 9, 2022, increased vaccine supply (5). As of September 28, 2022, most vaccine has been administered as PEP or expanded PEP. Because of the limited amount of time that has elapsed since administration of initial vaccine doses, as of September 28, 2022, relatively few persons in the current outbreak have completed the recommended 2-dose series. § To examine the incidence of monkeypox among persons who were unvaccinated and those who had received ≥1 JYNNEOS vaccine dose, 5,402 reported monkeypox cases occurring among males ¶ aged 18-49 years during July 31-September 3, 2022, were analyzed by vaccination status across 32 U.S. jurisdictions.** Average monkeypox incidence (cases per 100,000) among unvaccinated persons was 14.3 (95% CI = 5.0-41.0) times that among persons who received 1 dose of JYNNEOS vaccine ≥14 days earlier. Monitoring monkeypox incidence by vaccination status in timely surveillance data might provide early indications of vaccine-related protection that can be confirmed through other well-controlled vaccine effectiveness studies. This early finding suggests that a single dose of JYNNEOS vaccine provides some protection against monkeypox infection. The degree and durability of such protection is unknown, and it is recommended that people who are eligible for monkeypox vaccination receive the complete 2-dose series., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: Development and prioritization of quality measures typically relies on experts in clinical medicine, but patients and their caregivers may have different perspectives on quality measurement priorities., Objective: To inform priorities for health system implementation of palliative cancer and end-of-life care quality measures by eliciting perspectives of patients and caregivers., Design: Using modified RAND-UCLA Appropriateness Panel methods and materials tailored for knowledgeable lay participants, we convened a panel to rate cancer palliative care process quality measure concepts before and after a 1-day, in-person meeting., Participants: Nine patients and caregivers with experience living with or caring for patients with cancer., Main Measures: Panelists rated each concept on importance for providing patient- and family-centered care on a nine-point scale and each panelist nominated five highest priority measure concepts ("top 5")., Key Results: Cancer patient and caregiver panelists rated all measure concepts presented as highly important to patient- and family- centered care (median rating ≥ 7) in pre-panel (mean rating range, 6.9-8.8) and post-panel ratings (mean rating range, 7.2-8.9). Forced choice nominations of the "top 5" helped distinguish similarly rated measure concepts. Measure concepts nominated into the "top 5" by three or more panelists included two measure concepts of communication (goals of care discussions and discussion of prognosis), one measure concept on providing comprehensive assessments of patients, and three on symptoms including pain management plans, improvement in pain, and depression management plans. Patients and caregivers nominated one additional measure concept (pain screening) back into consideration, bringing the total number of measure concepts under consideration to 21., Conclusions: Input from cancer patients and caregivers helped identify quality measurement priorities for health system implementation. Forced choice nominations were useful to discriminate concepts with the highest perceived importance. Our approach serves as a model for incorporating patient and caregiver priorities in quality measure development and implementation., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Influenza may be associated with increased stroke and myocardial infarction (MI) risk. We hypothesized that risk of stroke and MI after influenza-like illness (ILI) would be higher in patients in New York State. We additionally assessed whether this relationship differed across a series of sociodemographic factors., Methods: A case-crossover analysis of the 2012-2014 New York Statewide Planning and Research Cooperative System (SPARCS) was used to estimate odds of ischemic stroke and MI after ILI. Each patient's case window (the time period preceding event) was compared to their control windows (same dates from the previous 2 years) in conditional logistic regression models used to estimate odds ratios and 95% confidence intervals (OR, 95% CI). We varied the case windows from 15 to 365 days preceding event as compared to control windows constructed using the same dates from the previous 2 years. Analyses were stratified by sex, race, and urban-rural status based on residential zip code., Results: A total of 33,742 patients were identified as having ischemic stroke and 53,094 had MI. ILI events in the 15 days prior were associated with a 39% increase in odds of ischemic stroke (95% CI 1.09-1.77), increasing to an almost 70% increase in odds when looking at ILI events over the last year (95% CI 1.56, 1.83). In contrast, the effect of ILI hospitalization on MI was strongest in the 15 days prior (OR = 1.24, 95% CI 1.06-1.44). The risk of ischemic stroke after ILI was higher among individuals living in rural areas in the 90 days prior to stroke and among men in the year prior to event. In contrast, the association between ILI and MI varied only across race with whites having significantly higher ILI associated MI., Conclusion: This study highlights risk period differences for acute cardiovascular events after ILI, indicating possible differences in mechanism behind the risk of stroke after ILI compared to the risk of MI. High risk populations for stroke after ILI include men and people living in rural areas, while whites are at high risk for MI after ILI. Future studies are needed to identify ways to mitigate these risks.

Background: Describe the indications for surgical interventions in asymptomatic patients with SARS-CoV-2. We are unaware of previous reports of an association between SARS-CoV-2 and acute appendicitis., Methods: We performed a single institution retrospective review of SARS-CoV-2 pre-procedure testing and indications for surgical intervention. Statistical comparisons were performed using Chi Square analysis or two-tailed Student T test., Results: We report a high prevalence of SARS-CoV-2 in both all testing and pre-procedure testing during the enrollment period. We observe a high prevalence of acute appendicitis among patients identified to be SARS-CoV-2 positive during pre-procedure testing and without recognized symptoms of COVID19., Conclusion: We report a previously unrecognized association between SARS-CoV-2 and acute appendicitis.

Background Influenza has been identified as a trigger for stroke and myocardial infarction (MI) with prior studies demonstrating that influenza vaccination may decrease risk of stroke and MI. Methods and Results We used data from the New York Department of Health Statewide Planning and Research Cooperative System to evaluate whether annual variability in influenza vaccination effectiveness (VE) would be associated with cardiovascular events. Daily and monthly counts of outpatient and inpatient visits for influenza-like illness (ILI), stroke, and MI were identified using International Classification of Diseases, Ninth Revision ( ICD-9 ) codes; VE data for each year are publicly available. We identified pertinent lags between ILI, stroke, and MI using prewhitening cross-correlation functions and applied them to autoregressive integrated moving average time series regression models. Time series forecasting systems assessed correlations among ILI, stroke, and MI, and the effect of VE on these relationships. Cross-correlation functions indicated stroke events increased 1 month after increases in ILI rates; MIs increased immediately. Accounting for seasonality and lag, peaks in ILI rates were significantly related to peaks in stroke ( P =0.04) and MI ( P =0.01). Time forecasting analyses indicated no relationship between VE and cardiovascular events. Conclusions We identified that seasonality of cardiovascular events may be associated with seasonality in ILI, though VE did not modify this relationship.

Iron staining is an unwanted and in some cases permanent adverse effect of intravenous iron administration. Cosmetically unacceptable staining may cause distress and have psychological implications for the patient There should be a suitable indication for parenteral iron therapy. Patients must be advised of the risk of harm and give their informed consent before receiving parenteral iron Strategies to minimise the risks of staining with intravenous iron include appropriate cannulation and close monitoring of the infusion. Stop the infusion if there are signs of extravasation Laser therapy may be a treatment option in cases of persistent discolouration due to iron staining, Competing Interests: Conflict of interest: none declared, ((c) NPS MedicineWise.)

CD73, an ecto-5'-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A 2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73 hi population in human colorectal cancers (CRCs) and two CD73 - murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A 2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A 2A and A 2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A 2B -mediated ADO-CAF-CD73 feedforward circuit and A 2A -mediated immune suppression is crucial for improving therapeutic outcomes.

Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive, multi-factorial tumors in the upper aerodigestive tract affecting more than half a million patients worldwide each year. Alcohol, tobacco, and human papillomavirus (HPV) infection are well known causative factors for HNSCCs. Current treatment options for HNSCCs are surgery, radiotherapy, chemotherapy, or combinatorial remedies. Over the past decade, despite the marked improvement in clinical outcome of many tumor types, the overall 5-year survival rate of HNSCCs remained ∼40-50% largely due to poor availability of effective therapeutic options for HNSCC patients with recurrent disease. Therefore, there is an urgent and unmet need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as better therapeutic targets. With recent technological advances in genomic and epigenetic analyses, our knowledge of HNSCC molecular characteristics and classification has been greatly enriched. Clinical and genomic meta-analysis of multicohort HNSCC gene expression profile has clearly demonstrated that HPV + and HPV - HNSCCs are not only derived from tissues of different anatomical regions, but also present with different mutation profiles, molecular characteristics, immune landscapes, and clinical prognosis. Here, we briefly review our current understanding of the biology, molecular profile, and immunological landscape of the HPV + and HPV - HNSCCs with an emphasis on the diversity and heterogeneity of HNSCC clinicopathology and therapeutic responses. After a review of recent advances and specific challenges for effective immunotherapy of HNSCCs, we then conclude with a discussion on the need to further enhance our understanding of the unique characteristics of HNSCC heterogeneity and the plasticity of immune landscape. Increased knowledge regarding the immunological characteristics of HPV + and HPV - HNSCCs would improve therapeutic targeting and immunotherapy strategies for different subtypes of HNSCCs.

Background and Purpose- Hospitals are increasingly using 30-day readmission (30dRA) to define the quality of care and reimbursement. We hypothesized that common infections occurring during the stroke stay are associated with 30dRA. Methods- We conducted a weighted analysis of the federally managed 2013 National Readmission Database to assess the relationship between infection during a stroke hospitalization and 30dRA among ischemic stroke survivors. Ischemic stroke, common infections (defined as sepsis, pneumonia, and urinary tract infection), and comorbidities were identified using International Classification of Diseases Ninth Revision ( ICD-9) diagnosis codes, and intravenous tPA (tissue-type plasminogen activator) or intra-arterial therapy was identified using ICD-9 procedure codes. Survey design logistic regression models were fit to estimate crude and adjusted odds ratios and 95% CI for the association between infections and 30dRA. Results- Among 319 317 ischemic stroke patients, 12.1% were readmitted within 30 days, and 29% had an infection during their index hospitalization. Patients with infection during their stroke admission had a 21% higher odds of being readmitted than patients without any type of infection (adjusted odds ratio, 1.21; 95% CI, 1.16-1.26). The association between infection and unplanned readmission was similar with an increased odds of unplanned readmission (adjusted odds ratio, 1.23; 95% CI, 1.18-1.29). When assessing specific types of infections, only urinary tract infections were associated with 30dRA in adjusted models (odds ratio, 1.10; 95% CI, 1.04-1.16). Conclusions- In a nationally representative cohort, patients who had a common infection during their stroke hospitalization were at increased odds of being readmitted. Patients with infection may benefit from earlier poststroke follow-up or closer monitoring.

This study tests the sensitivity of genetically based pest control options based on sex ratio distortion to intra- and intersexual aggressive interactions that affect male and female survival and fitness. Data on these interactions and their impacts were gathered for the mosquitofish Gambusia holbrooki (Poeciliidae), a promiscuous species with a strongly male-biased operational sex ratio and well-documented male harassment of females. The experimental design consisted of an orthogonal combination of two population densities and three sex ratios, ranging from strongly male-biased to strongly female-biased, and long-term observations of laboratory populations. Contrary to expectations, the number of males in a population had little evident effect on population demographics. Rather, the density of adult females determined population fecundity (as a result of a stock-recruitment relationship involving females, but not males), constrained male densities (apparently as a result of cannibalism or intersexual aggression), and regulated itself (most likely through effects of intrasexual aggression on female recruitment). The principal effect of males was to constrain their own densities via effects of male-male aggression on adult male mortality rates. Through use of a realistically parameterized genetic/demographic model, we show that of three different genetic options applied to control G. holbrooki, one based on recombinant sex ratio distortion (release of Female Lethal carriers) is marginally more efficient than a sterile male release program, and both outperform an option based on chromosomal sex ratio distortion (Trojan W). Nonlinear dependence of reproductive rate on female density reduces the efficacy of all three approaches. The major effect of intra- and intersexual aggression is mediated through females, whose interactions reduce female numbers and increase the efficacy of a control program based on sex ratio. Socially mediated male mortality has a small impact on control programs due to operational sex ratios that are heavily male-biased. The sensitivity of sex ratio-based control options to social factors will depend on the mating system of the targeted pest, but evidence of widespread density-dependent population regulation suggests that, for most species, the effects of elevated adult mortality (due to intra- and intersexual aggression) on control programs are likely to be slight.

The deleterious effects of tributyltin (TBT) on spermiation in fish have been attributed to its role in inhibiting aromatisation of androgens to estrogens, and the critical role of the latter in sperm development. We test this hypothesis by examining sperm parameters, fertilisation and hatching success in males of two fish species exposed throughout life to doses of Fadrozole, a non-steroidal aromatase inhibitor (AI), provided in their diets. AI-treatment caused 100% male development in zebrafish, but only partial masculinisation in medaka, in both cases supporting previous studies and suggesting different roles of estrogen in sexual differentiation in the two species. Milt volume, initial sperm motility, maximum sperm swimming duration and sperm morphology did not differ significantly between Control and AI-dosed fish in either species, after excluding low milt volumes in sex-changed females in medaka. Fertilisation rates were also unaffected by the aromatase inhibition, but hatching success in medaka was 31% lower than in Control males, suggesting a previously unreported effect of aromatase on sperm quality. The slight effect of aromatase inhibition on sperm parameters in general contrasts with the marked effect of TBT on fish sperm, and suggests that a mechanism other than depressed estrogen levels is involved., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Most veteran research is conducted in Department of Veterans Affairs (VA) healthcare settings, although most veterans obtain healthcare outside the VA. Our objective was to determine the adequacy and relative contributions of Veterans Health Administration (VHA), Veterans Benefits Administration (VBA), and Department of Defense (DOD) administrative databases for representing the U.S. veteran population, using as an example the creation of a sampling frame for the National Survey of Women Veterans. In 2008, we merged the VHA, VBA, and DOD databases. We identified the number of unique records both overall and from each database. The combined databases yielded 925,946 unique records, representing 51% of the 1,802,000 U.S. women veteran population. The DOD database included 30% of the population (with 8% overlap with other databases). The VHA enrollment database contributed an additional 20% unique women veterans (with 6% overlap with VBA databases). VBA databases contributed an additional 2% unique women veterans (beyond 10% overlap with other databases). Use of VBA and DOD databases substantially expands access to the population of veterans beyond those in VHA databases, regardless of VA use. Adoption of these additional databases would enhance the value and generalizability of a wide range of studies of both male and female veterans.

Herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 stimulates lytic infection and the reactivation of quiescent viral genomes. These roles of ICP0 require its RING finger E3 ubiquitin ligase domain, which induces the degradation of several cellular proteins, including components of promyelocytic leukemia nuclear bodies and centromeres. ICP0 also interacts very strongly with the cellular ubiquitin-specific protease USP7 (also known as HAUSP). We have shown previously that ICP0 induces its own ubiquitination and degradation in a RING finger-dependent manner, and that its interaction with USP7 regulates this process. In the course of these studies we found and report here that ICP0 also targets USP7 for ubiquitination and proteasome-dependent degradation. The reciprocal activities of the two proteins reveal an intriguing situation that poses the question of the balance of the two processes during productive HSV-1 infection. Based on a thorough analysis of the properties of an HSV-1 mutant virus that expresses forms of ICP0 that are unable to bind to USP7, we conclude that USP7-mediated stabilization of ICP0 is dominant over ICP0-induced degradation of USP7 during productive HSV-1 infection. We propose that the biological significance of the ICP0-USP7 interaction may be most pronounced in natural infection situations, in which limited amounts of ICP0 are expressed.

Herpes simplex virus type 1 immediate-early regulatory protein ICP0 stimulates lytic infection and reactivation from latency, processes that require the ubiquitin E3 ligase activity mediated by the RING finger domain in the N-terminal portion of the protein. ICP0 stimulates the production of polyubiquitin chains by the ubiquitin-conjugating enzymes UbcH5a and UbcH6 in vitro, and in infected and transfected cells it induces the proteasome-dependent degradation of a number of cellular proteins including PML, the major constituent protein of PML nuclear bodies. However, ICP0 binds strongly to the cellular ubiquitin-specific protease USP7, a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors. The region of ICP0 that is required for its interaction with USP7 has been mapped, and mutations in this domain reduce the functionality of ICP0. These findings pose the question: why does ICP0 include domains that are associated with the potentially antagonistic functions of ubiquitin conjugation and deconjugation? Here we report that although neither protein affected the intrinsic activities of the other in vitro, USP7 protected ICP0 from autoubiquitination in vitro, and their interaction can greatly increase the stability of ICP0 in vivo. These results demonstrate that RING finger-mediated autoubiquitination of ICP0 is biologically relevant and can be regulated by interaction with USP7. This principle may extend to a number of cellular RING finger E3 ubiquitin ligase proteins that have analogous interactions with ubiquitin-specific cleavage enzymes.

The potential for leukocyte-mediated host tissue damage during resolution of inflammatory responses is influenced by the rate at which extravasated apoptotic leukocytes are cleared from inflammatory sites. Regulation of macrophage capacity for clearance of apoptotic granulocytes is likely to be an important factor determining whether inflammation ultimately resolves or progresses to a chronic state. In this study we have investigated the molecular basis for rapid augmentation of macrophage phagocytosis of apoptotic neutrophils, which was observed following macrophage adhesion to fibronectin. We used a combination of monoclonal antibodies, blocking peptides, and recombinant fibronectin fragments to investigate the role of beta1 integrins in mediating the fibronectin effects. Blockade of alpha5beta1 or alpha4beta1 alone did not attenuate fibronectin-augmentation of phagocytosis. In addition, adhesion of macrophages to recombinant fibronectins lacking alpha4beta1 recognition motifs failed to promote phagocytosis of apoptotic neutrophils. Our results would be consistent with a model in which multiple fibronectin receptors, including beta1 integrins, act co-operatively to augment macrophage phagocytic responses. Together, these data suggest that the extracellular matrix environment of macrophages may provide regulatory signals that act indirectly to rapidly alter the potential for removal of apoptotic cells and influence the process of resolution of inflammation.