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Abstract: Cytomegalovirus (CMV) disease occurs occasionally before allogeneic hematopoietic cell transplantation (HCT) and is associated with poor post-HCT outcomes; however, the impact of pre-HCT CMV reactivation is unknown. Pre-HCT CMV reactivation was assessed in HCT candidates from the preemptive antiviral therapy (2007-2017) and letermovir prophylaxis (2018-2021) eras. CMV DNA polymerase chain reaction (PCR) surveillance was routinely performed during the pre-HCT workup period, and antiviral therapy was recommended according to risk of progression to CMV disease. Risk factors for pre-HCT CMV reactivation were characterized, and the associations of pre-HCT CMV reactivation with post-HCT outcomes were examined using logistic regression and Cox proportional hazard models, respectively. A total of 1694 patients were identified, and 11% had pre-HCT CMV reactivation 14 days (median; interquartile range [IQR], 6-23) before HCT. Lymphopenia (≤0.3 × 103/μL) was the strongest risk factor for pre-HCT CMV reactivation at multiple PCR levels. In the preemptive therapy era, patients with pre-HCT CMV reactivation had a significantly increased risk of CMV reactivation by day 100 as well as CMV disease and death by 1 year after HCT. Clearance of pre-HCT CMV reactivation was associated with a lower risk of post-HCT CMV reactivation. Similar associations with post-HCT CMV end points were observed in a cohort of patients receiving letermovir prophylaxis. Pre-HCT CMV reactivation can be routinely detected in high-risk HCT candidates and is a significant risk factor for post-HCT CMV reactivation and disease. Pre-HCT CMV DNA PCR surveillance is recommended in high-risk HCT candidates, and antiviral therapy may be indicated to prevent post-HCT CMV reactivation., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Maternal investment theory is the study of how breeding females allocate resources between offspring size and brood size to achieve reproductive success. In classical trade-off models, r/K-selection and bet-hedging selection, the primary predictors of maternal investments in offspring are population density and resource stability. In crowded, stable environments, K-selected females invest in large offspring at an equivalent cost in brood size. In uncrowded, unstable environments, r-selected females invest in large broods at an equivalent cost in offspring size. In unpredictable resource environments, bet-hedging females invest moderately in brood size and offspring size. The maternal risk-management model represents a profound departure from classical trade-off models. Maternal investments in offspring size, brood size, and brood number are shaped independently by autonomous risk factors: the duration of gaps in resources during seasonal cycles, rates of predation, and unpredictable catastrophic events. To date, no single model has risen to a position of preeminence. Here in sharks, we show that maternal investments within and across species do not agree with the predictions of trade-off models and instead agree with the predictions of the maternal risk-management model. Within and across shark species, offspring size and brood size were independent maternal investment strategies. The risk of starvation favored investments in larger offspring. The risk of predation favored investments in larger broods. If empirical studies continue to confirm its predictions, maternal-risk management may yet emerge as a unifying model of diverse reproductive adaptations by means of natural selection., (© 2024. The Author(s).)

Abstract: Preemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: With the elimination in 2021 of the United States Medical Licensing Examination Step 2 Clinical Skills test, it is incumbent upon U.S. medical schools to develop local validated assessments of clinical reasoning. While much attention has been paid to summative exams for graduating students, formative exams for pre-clerkship students have not been well studied., Methods: We applied the University of Illinois at Chicago College of Medicine (UIC-COM) Patient Note (PN) Scoring Rubric to templated PNs written by 103 pre-clerkship students for two cases in an objective structured clinical examination (OSCE) at the Yale School of Medicine. The rubric consists of four section scores (Documentation, Differential Diagnosis, Justification, and Workup, each scored 1 to 4) and a composite score (scaled 23 to 100). We calculated item discrimination for each section score and Cronbach's alpha for each case. We surveyed students about their experience writing the templated PN., Results: Mean Documentation, Differential Diagnosis, Justification, Workup, and composite scores for case A were 2.16, 1.80, 1.65, 2.29, and 47.67, respectively. For case B, the scores were 2.13, 1.21, 1.60, 1.67, and 40.54, respectively. Item discrimination ranged from 0.41 to 0.80. Cronbach's alpha for cases A and B was 0.48 and 0.25, respectively. A majority of the students felt that the exercise was useful and appropriate to their level of training., Conclusions: Despite performing poorly, pre-clerkship students found the note-writing task beneficial. Reliability of the scoring rubric was suboptimal, and modifications are needed to make this exercise a suitable measure of clinical reasoning., (© 2023. The Author(s).)

Bacterial superinfection and antibiotic prescribing in the setting of the current mpox outbreak are not well described in the literature. This retrospective observational study revealed low prevalence (11%) of outpatient antibiotic prescribing for bacterial superinfection of mpox lesions; at least 3 prescriptions (23%) were unnecessary., Competing Interests: R.J. serves as a clinical consultant for Wolters-Kluwer for their online content. All other authors report no conflicts related to this article., (© The Author(s) 2023.)

Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD., (© 2022 Global Blood Therapeutics, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Sickle cell disease (SCD) is characterized by the production of sickle hemoglobin (HbS), which when deoxygenated, polymerizes leading to red blood cell damage and hemolytic anemia, a defining feature of SCD. Voxelotor (Oxbryta) is a small molecule inhibitor of HbS polymerization that disrupts the polymerization mechanism by binding HbS to increase HbS oxygen affinity. Voxelotor is approved in the United States for the treatment of SCD in patients greater than or equal to 12 years of age at a 1500 mg once-daily (q.d.) dose. These exposure-response analyses aimed to evaluate the relationships between voxelotor whole blood concentration and change from baseline (CFB) in clinical measures of anemia and hemolysis and between voxelotor whole blood and plasma concentrations and the incidence of selected safety end points to confirm the voxelotor mechanism of action and to support the clinical dose recommendation. In patients treated with voxelotor up to 72 weeks, CFB hemoglobin (Hb) increased linearly (p < 0.001) with increasing voxelotor concentration and percent Hb occupancy and increases in CFB Hb corresponded to improvements in measures of hemolysis. The target 1 g/dl increase in CFB Hb was achieved with 1500 mg voxelotor q.d. Significant relationships were observed between voxelotor exposures and grade greater than or equal to 1 increased alanine aminotransferase and decreased white blood cell count; however, most events were grade 1. No clinically important covariate effects on voxelotor efficacy or safety were observed. Overall, these analyses support 1500 mg q.d. as the therapeutic dose for voxelotor in adults and adolescents., (© 2022 Global Blood Therapeutics, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Remnants of native tallgrass prairie experience elevated atmospheric nitrogen (N) deposition in urban areas, with potential effects on species traits that are important for N cycling and species composition. We quantified bulk (primarily wet) inorganic N (NH4+-N + NO3--N) deposition at six sites along an urban development gradient (6-64% urban) in the Dallas-Fort Worth metropolitan area from April 2014 to October 2015. In addition, we conducted a phytometer experiment with two common native prairie bunchgrass species--one well studied (Schizachyrium scoparium) and one little studied (Nasella leucotricha)--to investigate ambient N deposition effects on plant biomass and tissue quality. Bulk inorganic N deposition ranged from 6.1-9.9 kg ha-1 yr-1, peaked in spring, and did not vary consistently with proportion of urban land within 10 km of the sites. Total (wet + dry) inorganic N deposition estimated using bulk deposition measured in this study and modeled dry deposition was 12.9-18.2 kg ha-1 yr-1. Although the two plant species studied differ in photosynthetic pathway, biomass, and tissue N, they exhibited a maximum 2-3-fold and 2-4-fold increase in total biomass and total plant N, respectively, with 1.6-fold higher bulk N deposition. In addition, our findings indicate that while native prairie grasses may exhibit a positive biomass response to increased N deposition up to ~18 kg ha-1 yr-1, total inorganic N deposition is well above the estimated critical load for herbaceous plant species richness in the tallgrass prairie of the Great Plains ecoregion and thus may negatively affect these plant communities., Competing Interests: The authors have declared that no competing interests exist.

Background: Observational studies have suggested increased arrhythmic and cardiovascular risk with the combination use of hydroxychloroquine (HCQ) and azithromycin in patients with coronavirus disease 2019 (COVID-19)., Objective: The arrhythmic safety profile of HCQ monotherapy, which remains under investigation as a therapeutic and prophylactic agent in COVID-19, is less established and we sought to evaluate this., Methods: In 245 consecutive patients with COVID-19 admitted to the University of Washington hospital system between March 9, 2020, and May 10, 2020, we identified 111 treated with HCQ monotherapy. Patients treated with HCQ underwent a systematic arrhythmia and QT interval surveillance protocol including serial electrocardiograms (ECG) (baseline, following second HCQ dose). The primary endpoint was in-hospital sustained ventricular arrhythmia or arrhythmic cardiac arrest. Secondary endpoints included clinically significant QTc prolongation., Results: A total of 111 patients with COVID-19 underwent treatment with HCQ monotherapy (mean age 62 ± 16 years, 44 women [39%], serum creatinine 0.9 [interquartile range 0.4] mg/dL). There were no instances of sustained ventricular arrythmia or arrhythmic cardiac arrest. In 75 patients with serial ECGs, clinically significant corrected QT (QTc) prolongation was observed in a minority (n = 5 [7%]). In patients with serial ECGs, there was no significant change in the QTc interval in prespecified subgroups of interest, including those with prevalent cardiovascular disease or baseline use of renin-angiotensin-aldosterone axis inhibitors., Conclusions: In the context of a systematic monitoring protocol, HCQ monotherapy in hospitalized COVID-19 patients was not associated with malignant ventricular arrhythmia. A minority of patients demonstrated clinically significant QTc prolongation during HCQ therapy., (© 2020 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)

This is a review of the first 50 patients attending a colocated continuity clinic with harm reduction services to women experiencing homelessness in north Seattle. Among those tested, patients had high rates of curable sexually transmitted infections (44%), injection opioid use (36%), transactional sex (69%), unintended pregnancy (10%), and human immunodeficiency virus infections (10%).

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min)., (© 2018 University of Liverpool. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

A high number of human islets can be isolated by using modern purified tissue dissociation enzymes; however, this requires the use of >20 Wunsch units (WU)/g of pancreas for digestion. Attempts to reduce this dose have resulted in pancreas underdigestion and poor islet recovery but improved islet function. In this study, we achieved a high number of functional islets using a low dose of recombinant collagenase enzyme mixture (RCEM-1200 WU rC2 and 10 million collagen-degrading activity [CDA] U of rC1 containing about 209 mg of collagenase to digest a 100-g pancreas). The collagenase dose used in these isolations is about 42% of the natural collagenase enzyme mixture (NCEM) dose commonly used to digest a 100-g pancreas. Low-dose RCEM was efficient in digesting entire pancreases to obtain higher yield (5535 ± 830 and 2582 ± 925 islet equivalent/g, P < .05) and less undigested tissue (16.7 ± 5% and 37.8 ± 3%, P < .05) compared with low-dose NCEM (12WU/g). Additionally, low-dose RCEM islets retained better morphology (confirmed with scanning electron microscopy) and higher in vitro basal insulin release (2391 ± 1342 and 1778 ± 978 μU/mL; P < .05) compared with standard-dose NCEM. Nude mouse bioassay demonstrated better islet function for low-dose RCEM (area under the curve [AUC] 24 968) compared with low-dose (AUC-38 225) or standard-dose NCEM (AUC-38 685), P < .05. This is the first report indicating that islet function can be improved by using low-dose rC1rC2 (RCEM)., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62). There were 43 infections in 30 of 133 patients (23%) within 28 days after CAR-T-cell infusion with an infection density of 1.19 infections for every 100 days at risk. There was a lower infection density of 0.67 between days 29 and 90 ( P = .02). The first infection occurred a median of 6 days after CAR-T-cell infusion. Six patients (5%) developed invasive fungal infections and 5 patients (4%) had life-threatening or fatal infections. Patients with ALL, ≥4 prior antitumor regimens, and receipt of the highest CAR-T-cell dose (2 × 10 7 cells per kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome (CRS) severity was the only factor after CAR-T-cell infusion associated with infection in a multivariable analysis. The incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients. This trial was registered at www.clinicaltrials.gov as #NCT01865617., (© 2018 by The American Society of Hematology.)

Managing and controlling the spread of diseases in wild animal populations is challenging, especially for social and mobile species. Effective management benefits from information about disease susceptibility, allowing limited resources to be focused on areas or populations with a higher risk of infection. Chronic wasting disease (CWD), a transmissible spongiform encephalopathy that affects cervids, was detected in Colorado in the late 1960s. CWD was detected in Illinois and Wisconsin in 2002 and has since spread through many counties. Specific nucleotide variations in the prion protein gene (PRNP) sequence have been associated with reduced susceptibility to CWD in white-tailed deer. Though genetic resistance is incomplete, the frequency of deer possessing these mutations in a population is an important factor in disease spread (i.e. herd immunity). In this study we sequenced 625 bp of the PRNP gene from a sampling of 2433 deer from Illinois and Wisconsin. In north-central Illinois where CWD was first detected, counties had a low frequency of protective haplotypes (frequency <0.20); whereas in northwestern Illinois counties, where CWD cases have only more recently been detected, the frequency of protective haplotypes (frequency >0.30) was much higher (p < 0.05). Protective haplotype frequencies varied significantly among infected and uninfected geographic areas. The frequency of protective PRNP haplotypes may contribute to population level susceptibility and may shape the way CWD has spread through Illinois. Analysis of PRNP haplotype distribution could be a useful tool to assess CWD risk and allocate resources to contain and reduce the spread of infection.

Environmental reservoirs are important to infectious disease transmission and persistence, but empirical analyses are relatively few. The natural environment is a reservoir for prions that cause chronic wasting disease (CWD) and influences the risk of transmission to susceptible cervids. Soil is one environmental component demonstrated to affect prion infectivity and persistence. Here we provide the first landscape predictive model for CWD based solely on soil characteristics. We built a boosted regression tree model to predict the probability of the persistent presence of CWD in a region of northern Illinois using CWD surveillance in deer and soils data. We evaluated the outcome for possible pathways by which soil characteristics may increase the probability of CWD transmission via environmental contamination. Soil clay content and pH were the most important predictive soil characteristics of the persistent presence of CWD. The results suggest that exposure to prions in the environment is greater where percent clay is less than 18% and soil pH is greater than 6.6. These characteristics could alter availability of prions immobilized in soil and contribute to the environmental risk factors involved in the epidemiological complexity of CWD infection in natural populations of white-tailed deer.

Over the last 20 years, significant habitat shifts have been documented in some populations of cetaceans. On Little Bahama Bank (LBB) there are sympatric communities of resident Atlantic spotted dolphins (Stenella frontalis) and bottlenose dolphins (Tursiops truncatus), monitored since 1985. The size and social structure (three clusters: Northern, Central, Southern) have been stable among the spotted dolphin community with little immigration/emigration, even after large demographic losses (36%) following two major hurricanes in 2004. In 2013 an unprecedented exodus of over 50% (52 individuals) of the spotted dolphin community was documented. The entire Central cluster and a few Northern and Southern individuals relocated 161 km south to Great Bahama Bank (GBB), also home to two sympatric resident communities of spotted dolphins and bottlenose dolphins. During the late summer of 2013 and the summers of 2014 and 2015 both sites were regularly monitored but no former LBB dolphins returned to LBB. Uncharacteristic matriline splits were observed. Social analyses revealed random associations for those spotted dolphins and very little integration between spotted dolphins that moved to GBB (MGBB) and those dolphin resident to GBB (RGBB). Male alliances among spotted dolphins were present, with some altered patterns. On LBB, the operational sex ratio (OSR) was reduced (.40 to .25). OSR for MGBB and RGBB dolphins were similar (.45 and .43). A significant steady decrease in sea surface temperature and chlorophyll a (a proxy for plankton production) occurred on LBB leading up to this exodus. Similar trends were not present over the same period on GBB. The sudden large-scale shift of spotted dolphins from LBB to GBB in association with the gradual decline in certain environmental factors suggests that a possible "tipping point" was reached in prey availability. This study provides a unique view into social and genetic implications of large-scale displacement of stable dolphin communities.

Slow electron velocity map imaging (SEVI) spectroscopy was used to examine the BeS - anion to neutral ground-state transition, X 2 Σ + → X 1 Σ + . Rotational constants, vibrational intervals, and the electron binding energy of BeS - were determined. Partially resolved rotational contours were seen due to the relatively small moment of inertia of beryllium sulfide. Upon analysis of the rotational contours, it was found that changes in the molecular rotational angular momentum, ΔN = -1, -2, -3, and -4, facilitated photodetachment at near-threshold photon energies. The electron affinity of BeS was found to be 2.3346(2) eV. SEVI spectra recorded using photon energies near the threshold for Δv = -1 processes exhibited features that were associated with a dipole-bound state (DBS) of BeS - . Autodetachment spectroscopy was used to probe this state, and rotationally resolved data were obtained for the DBS 2 Σ + , v' = 0 - X 2 Σ + , v″ = 0 transition. Analysis of this structure provided the rotational constants for BeS - X, v″ = 0, and the electron binding energy of the DBS. Electronic structure calculations, performed at the RCCSD(T) and MRCI levels of theory, gave predictions that were in good agreement with the experimental observations.

Purpose: The logistics of conducting double-blinded phase III clinical trials with participants residing in remote locations are complex. Here we describe the implementation of an interventional trial for the prevention of late cytomegalovirus (CMV) disease in hematopoietic cell transplantation (HCT) subjects in a long-term follow-up environment., Methods: A total of 184 subjects at risk for late CMV disease surviving 80 days following allogeneic HCT were randomized to receive six months of valganciclovir or placebo. Subjects were followed through day 270 post-transplant at their local physician's office within the United States. Anti-viral treatment interventions were based on CMV DNAemia as measured by polymerase chain reaction (PCR) (>1000 copies/mL) and granulocyte colony stimulating factor (G-CSF) was prescribed for neutropenia (absolute neutrophil count (ANC <1.0 × 10 9 cells/L). Blood samples for viral testing and safety monitoring were shipped to a central laboratory by overnight carrier. Real-time communication was established between the coordinating center and study sites, primary care physicians, and study participants to facilitate starting, stopping and dose adjustments of antiviral drugs and G-CSF. The time required to make these interventions was analyzed., Results: Of the 4169 scheduled blood specimens, 3832 (92%) were received and analyzed; the majority (97%) arriving at the central site within 2 days. Among subjects with positive CMV DNAemia (N=46), over 50% received open label antiviral medication within one day. The median time to start G-CSF for neutropenia was <1 day after posting of laboratory results (range 0-6; N=38). Study drug dose adjustments for abnormal renal function were implemented 203 times; within one day for 48% of cases and within 2 days for 80% of cases., Conclusion: Complex randomized, double-blind, multicenter interventional trials with treatment decisions made at a central coordinating site can be conducted safely and effectively according to Good Clinical Practice (GCP) guidelines over a large geographic area., Competing Interests: Conflict of Interest Statement:

In the pharmaceutical industry, preclinical developmental and reproductive toxicity studies are conducted in laboratory animals in order to predict and prevent adverse effects of drugs on human reproductive health and development. However, these studies require a relatively large number of animals and are usually conducted late in the drug development process. Early, simple, and inexpensive screening assays could facilitate smarter decisions, reductions in animal use, and development of safe drugs. The current state and future needs for alternative models of developmental and reproductive toxicity are reviewed here. The most popular predictive developmental toxicity assays are embryonic stem cells, rodent whole embryo culture, and zebrafish, each of which involves fairly well-developed techniques with demonstrated utility in drug discovery and development. In vitro or ex vivo methods for male and female reproductive toxicity are less established, but there are promising assays available or being developed that may be useful in drug development, especially for elucidating mechanisms or screening backup compounds. While a number of challenges remain, much progress has been made in alternative developmental and reproductive toxicity models to date, and there is a strong collective enthusiasm in the industry to continue moving them forward. Therefore, it appears that these approaches may be widely used in the near future., (Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The aberration-corrected scanning transmission electron microscope (STEM) has emerged as a key tool for atomic resolution characterization of materials, allowing the use of imaging modes such as Z-contrast and spectroscopic mapping. The STEM has not been regarded as optimal for the phase-contrast imaging necessary for efficient imaging of light materials. Here, recent developments in fast electron detectors and data processing capability is shown to enable electron ptychography, to extend the capability of the STEM by allowing quantitative phase images to be formed simultaneously with incoherent signals. We demonstrate this capability as a practical tool for imaging complex structures containing light and heavy elements, and use it to solve the structure of a beam-sensitive carbon nanostructure. The contrast of the phase image contrast is maximized through the post-acquisition correction of lens aberrations. The compensation of defocus aberrations is also used for the measurement of three-dimensional sample information through post-acquisition optical sectioning., Competing Interests: M.S., H.R., M.H. and H.S. are employed by PNsensor and PNdetector, which are commercial suppliers of detector hardware. R.S. and Y.K. are employed by JEOL Ltd, which supply electron microscopes. All remaining authors declare no competing financial interests.

Background: Pediatric critical care medicine requires the acquisition of procedural skills, but to date no criteria exist for assessing trainee competence in central venous catheter (CVC) insertion., Objective: The goal of this study was to create and demonstrate validity evidence for a direct observation tool for assessing CVC insertion., Methods: Ten experts used the modified Delphi technique to create a 15-item direct observation tool to assess 5 scripted and filmed simulated scenarios of CVC placement. The scenarios were hosted on a dedicated website from March to May 2013, and respondents recruited by e-mail completed the observation tool in real time while watching the scenarios. The goal was to obtain 50 respondents and a total of 250 scenario ratings., Results: A total of 49 pediatrics intensive care faculty physicians (6.3% of 780 potential subjects) responded and generated 188 scenario observations. Of these, 150 (79.8%) were recorded from participants who scored 4 or more on the 5 scenarios. The tool correctly identified the expected reference standard in 96.8% of assessments with an interrater agreement kappa (standard error) = 0.94 (0.07) and receiver operating characteristic = 0.97 (95% CI 0.94-0.99)., Conclusions: This direct observation assessment tool for central venous catheterization demonstrates excellent performance in identifying the reference standard with a high degree of interrater reliability. These assessments support a validity construct for a pediatric critical care medicine faculty member to assess a provider placing a CVC in a pediatrics patient.

Background: Human allogeneic islet transplantation for treatment of type 1 diabetes provides numerous clinical benefits, such as fewer episodes of hypoglycemic unawareness and tighter control of blood glucose levels. Availability of human pancreas for clinical and research use, however, is severely limited. Porcine pancreas offers an abundant source of tissue for optimization of islet isolation methodology and future clinical transplantation, thereby increasing patient access to this potentially lifesaving procedure., Methods: Porcine islet isolations were performed using varying amounts of collagenase (7.5, 3.75, or 2.5 Wunsch units per gram tissue) and neutral protease activity (12 000, 6000, or 4000 neutral protease units per gram tissue) and perfusion volumes (1.7 or 0.85 mL/g tissue) to assess their effects on isolation outcomes. Retention of dissociative enzymes within the pancreas during perfusion and digestion was evaluated, along with distribution of the perfusion solution within the tissue., Results: Reducing enzyme usage by as much as 67% and perfusion volume by 50% led to equally successful islet isolation outcomes when compared with the control group (48 ± 7% of tissue digested and 1088 ± 299 islet equivalents per gram of pancreas vs 47 ± 11% and 1080 ± 512, respectively). Using margin-marking dye in the perfusion solution to visualize enzyme distribution demonstrated that increasing perfusion volume did not improve tissue infiltration., Conclusions: Current protocols for porcine islet isolation consume excessive amounts of dissociative enzymes, elevating cost and limiting research and development. These data demonstrate that islet isolation protocols can be optimized to significantly reduce enzyme usage while maintaining yield and function and thus accelerating progress toward clinical application., Competing Interests: M.L.G. and A.G.B. are employees of VitaCyte, LLC. All other authors declare no conflicts of interest.

Age is associated with reductions in surface area and cortical thickness, particularly in prefrontal regions. There is also evidence of greater thickness in some regions at older ages. Non-linear age effects in some studies suggest that age may continue to impact brain structure in later decades of life, but relatively few studies have examined the impact of age on brain structure within middle-aged to older adults. We investigated age differences in prefrontal surface area and cortical thickness in healthy adults between the ages of 51 and 81 years. Participants received a structural 3-Tesla magnetic resonance imaging scan. Based on a priori hypotheses, primary analyses focused on surface area and cortical thickness in the dorsolateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex. We also performed exploratory vertex-wise analyses of surface area and cortical thickness across the entire cortex. We found that older age was associated with smaller surface area in the dorsolateral prefrontal and orbitofrontal cortices but greater cortical thickness in the dorsolateral prefrontal and anterior cingulate cortices. Vertex-wise analyses revealed smaller surface area in primarily frontal regions at older ages, but no age effects were found for cortical thickness. Results suggest age is associated with reduced surface area but greater cortical thickness in prefrontal regions during later decades of life, and highlight the differential effects age has on regional surface area and cortical thickness.

Unlabelled: Isolation following a good manufacturing practice-compliant, human islet product requires development of a robust islet isolation procedure where effective limits of key reagents are known. The enzymes used for islet isolation are critical but little is known about the doses of class I and class II collagenase required for successful islet isolation., Methods: We used a factorial approach to evaluate the effect of high and low target activities of recombinant class I (rC1) and class II (rC2) collagenase on human islet yield. Consequently, 4 different enzyme formulations with divergent C1:C2 collagenase mass ratios were assessed, each supplemented with the same dose of neutral protease. Both split pancreas and whole pancreas models were used to test enzyme targets (n = 20). Islet yield/g pancreas was compared with historical enzymes (n = 42)., Results: Varying the Wunsch (rC2) and collagen degradation activity (CDA, rC1) target dose, and consequently the C1:C2 mass ratio, had no significant effect on tissue digestion. Digestions using higher doses of Wunsch and CDA resulted in comparable islet yields to those obtained with 60% and 50% of those activities, respectively. Factorial analysis revealed no significant main effect of Wunsch activity or CDA for any parameter measured. Aggregate results from 4 different collagenase formulations gave 44% higher islet yield (>5000 islet equivalents/g) in the body/tail of the pancreas (n = 12) when compared with those from the same segment using a standard natural collagenase/protease mixture (n = 6). Additionally, islet yields greater than 5000 islet equivalents/g pancreas were also obtained in whole human pancreas., Conclusions: A broader C1:C2 ratio can be used for human islet isolation than has been used in the past. Recombinant collagenase is an effective replacement for the natural enzyme and we have determined that high islet yield can be obtained even with low doses of rC1:rC2, which is beneficial for the survival of islets.

We conducted a phase III study to test the hypothesis that initial therapy with "lower dose" prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with grade IIa manifestations (upper gastrointestinal symptoms, stool volumes <1.0 L/day, rash involving <50% of the body surface, no hepatic dysfunction; n=102) were randomized to start treatment with prednisone at 1 mg/kg/day or 0.5 mg/kg/day. Those with grade IIb or higher manifestations (rash involving ≥50% of the body surface, stool volumes ≥1.0 L/day or hepatic involvement; n=62) were randomized to start treatment with prednisone at 2 mg/kg/day or 1 mg/kg/day. The primary study end point (a ≥33% relative reduction of the mean cumulative prednisone dose by day 42 after initial treatment with lower dose prednisone) was not reached. With a median follow up of 36 months (range 7-53), initial treatment with lower dose prednisone appeared to be effective for patients presenting with grade IIa manifestations since it did not increase the likelihood of requiring secondary immunosuppressive therapy. Further exploratory analyses suggested that for patients presenting with skin-predominant grade IIb or higher manifestations, initial treatment with lower dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy (41% vs. 7%; P=0.001). In summary, initial treatment of newly diagnosed acute graft-versus-host disease with lower dose prednisone is effective. Within the statistical limitations of the study, results showed no suggestion that initial use of lower dose prednisone adversely affected survival., (Copyright© Ferrata Storti Foundation.)

Similar to other small cetacean species, Atlantic spotted dolphins (Stenella frontalis) have been the object of concentrated behavioral study. Although mating and courtship behaviors occur often and the social structure of the population is well-studied, the genetic mating system of the species is unknown. To assess the genetic mating system, we genotyped females and their progeny at ten microsatellite loci. Genotype analysis provided estimates of the minimum number of male sires necessary to account for the allelic diversity observed among the progeny. Using the estimates of male sires, we determined whether females mated with the same or different males during independent estrus events. Using Gerud2.0, a minimum of two males was necessary to account for the genetic variation seen among progeny arrays of all tested females. ML-Relate assigned the most likely relationship between offspring pairs; half or full sibling. Relationship analysis supported the conservative male estimates of Gerud2.0 but in some cases, half or full sibling relationships between offspring could not be fully resolved. Integrating the results from Gerud2.0, ML-Relate with previous observational and paternity data, we constructed two-, three-, and four-male pedigree models for each genotyped female. Because increased genetic diversity of offspring may explain multi-male mating, we assessed the internal genetic relatedness of each offspring's genotype to determine whether parent pairs of offspring were closely related. We found varying levels of internal relatedness ranging from unrelated to closely related (range -0.136-0.321). Because there are several hypothesized explanations for multi-male mating, we assessed our data to determine the most plausible explanation for multi-male mating in our study system. Our study indicated females may benefit from mating with multiple males by passing genes for long-term viability to their young.

The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection--while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas.

Norovirus is the most commonly reported virus in shellfish related gastroenteritis outbreaks. In March 2013 an investigation was conducted following the receipt of reports of gastroenteritis after the consumption of oysters at private functions in Tasmania. Cases were ascertained through general practitioners, emergency departments, media releases and self-reporting. Of the 306 cases identified in Tasmania, ten faecal specimens were collected for laboratory testing and eight were positive for norovirus (GII.g). The most common symptoms were vomiting (87%), diarrhoea (85%), myalgia (82%) and fever (56%). The implicated oysters were traced to a single lease from which they were harvested and distributed locally and interstate. Nationally 525 cases were identified from Tasmania (306), Victoria (209), New South Wales (8) and Queensland (2). This report highlights the consequences of norovirus outbreaks in shellfish, even with rapid identification, trace back and removal of the implicated product from the market., (copyright@health.gov.au)

Discussions of the source of the Stroop interference effect continue to pervade the literature. Semantic competition posits that interference results from competing semantic activation of word and color dimensions of the stimulus prior to response selection. Response competition posits that interference results from competing responses for articulating the word dimension vs. the color dimension at the time of response selection. We embedded Stroop stimuli into a delayed match-to-sample (DMTS) task in an attempt to test semantic and response competition accounts of the interference effect. Participants viewed a sample color word in black or colored fonts that were congruent or incongruent with respect to the color word itself. After a 5 s delay, participants were presented with two targets (i.e., a match and a foil) and were instructed to select the correct match. We probed each dimension independently during target presentations via color targets (i.e., two colors) or word targets (i.e., two words) and manipulated whether the semantic content of the foil was related to the semantic content of the irrelevant sample dimension (e.g., word sample "red" in blue font with the word "red" as the match and the word "blue" as the foil). We provide evidence for Stroop interference such that response times (RTs) increased for incongruent trials even in the presence of a response option with semantic content unrelated to the semantic content of the irrelevant sample dimension. Accuracy also deteriorated during the related foil trials. A follow-up experiment with a 10 s delay between sample and targets replicated the results. Results appear to provide converging evidence for Stroop interference in a DMTS task in a manner that is consistent with an explanation based upon semantic competition and inconsistent with an explanation based upon response competition.

The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival.

Introduction: The U.S. faces a critical gap between residency training and clinical practice that affects the recruitment and preparation of internal medicine residents for primary care careers. The patient-centered medical home (PCMH) represents a new clinical microsystem that is being widely promoted and implemented to improve access, quality, and sustainability in primary care practice., Aim: We address two key questions regarding the training of internal medicine residents for practice in PCMHs. First, what are the educational implications of practice transformations to primary care home models? Second, what must we do differently to prepare internal medicine residents for their futures in PCMHs?, Program Description: The 2011 Society of General Internal Medicine (SGIM) PCMH Education Summit established seven work groups to address the following topics: resident workplace competencies, teamwork, continuity of care, assessment, faculty development, 'medical home builder' tools, and policy. The output from the competency work group was foundational for the work of other groups. The work group considered several educational frameworks, including developmental milestones, competencies, and entrustable professional activities (EPAs)., Results: The competency work group defined 25 internal medicine resident PCMH EPAs. The 2011 National Committee for Quality Assurance (NCQA) PCMH standards served as an organizing framework for EPAs., Discussion: The list of PCMH EPAs has the potential to begin to transform the education of internal medicine residents for practice and leadership in the PCMH. It will guide curriculum development, learner assessment, and clinical practice redesign for academic health centers.

View-based matching theories of orientation suggest that mobile organisms encode a visual memory consisting of a visual panorama from a target location and maneuver to reduce discrepancy between current visual perception and this stored visual memory to return to a location. Recent success of such theories to explain the orientation behavior of insects and birds raises questions regarding the extent to which such an explanation generalizes to other species. In the present study, we attempted to determine the extent to which such view-based matching theories may explain the orientation behavior of a mammalian species (in this case adult humans). We modified a traditional enclosure orientation task so that it involved only the use of the haptic sense. The use of a haptic orientation task to investigate the extent to which view-based matching theories may explain the orientation behavior of adult humans appeared ideal because it provided an opportunity for us to explicitly prohibit the use of vision. Specifically, we trained disoriented and blindfolded human participants to search by touch for a target object hidden in one of four locations marked by distinctive textural cues located on top of four discrete landmarks arranged in a rectangular array. Following training, we removed the distinctive textural cues and probed the extent to which participants learned the geometry of the landmark array. In the absence of vision and the trained textural cues, participants showed evidence that they learned the geometry of the landmark array. Such evidence cannot be explained by an appeal to view-based matching strategies and is consistent with explanations of spatial orientation related to the incidental learning of environmental geometry.

Exposure to an imbalance of nutrients prior to conception and during critical developmental periods can have lasting consequences on physiological processes resulting in chronic diseases later in life. Developmental programming has been shown to involve structural and functional changes in important tissues. The aim of the present study was to investigate whether early life diet has a programming effect on the mammary gland. Wild-type mice were exposed from 2 weeks prior to conception to 6 weeks of age to a regular low-fat diet, or to high-fat diets based on either corn oil or flaxseed oil. At 6 weeks of age, all mice were shifted to the regular low-fat diet until termination at 10 weeks of age. Early life exposure to a high-fat diet, either high in n-6 (corn oil) or in n-3 (flaxseed oil) polyunsaturated fatty acids, did not affect birth weight, but resulted in an increased body weight at 10 weeks of age. Transcriptome analyses of the fourth abdominal mammary gland revealed differentially expressed genes between the different treatment groups. Exposure to high-fat diet based on flaxseed oil, but not on corn oil, resulted in regulation of pathways involved in energy metabolism, immune response and inflammation. Our findings suggest that diet during early life indeed has a lasting effect on the mammary gland and significantly influences postnatal body weight gain, metabolic status, and signaling networks in the mammary gland of female offspring.

Cytomegalovirus (CMV) surveillance and preemptive therapy is the most commonly used strategy for CMV disease prevention in hematopoietic cell transplantation recipients. In 2007, we introduced a CMV prevention strategy for patients at risk for CMV disease using quantitative PCR surveillance, with treatment thresholds determined by patient risk factors. Patients (N = 367) received preemptive therapy either at a plasma viral load of ≥500 copies/mL, at ≥100 copies/mL if receiving ≥1 mg/kg of prednisone or anti-T cell therapies, or if a ≥5-fold viral load increase from baseline was detected. Compared with patients before 2007 undergoing antigenemia-based surveillance (n = 690) with preemptive therapy initiated for any positive level, the risk-adapted PCR-based strategy resulted in similar use of antiviral agents, and similar risks of CMV disease, toxicity, and nonrelapse mortality in multivariable models. The cumulative incidence of CMV disease by day 100 was 5.2% in the PCR group compared with 5.8% in the antigenemia group (1 year: 9.1% PCR vs 9.6% antigenemia). Breakthrough CMV disease in the PCR group was predominantly in the gastrointestinal (GI) tract (15 of 19 cases; 79%). However, unlike CMV pneumonia, CMV GI disease was not associated with increased nonrelapse mortality (adjusted hazard ratio, 1.19; P = .70 [GI disease] vs 8.18; P < .001 [pneumonia]). Thus, the transition to a preemptive therapy strategy based on CMV viral load and host risk factors successfully prevented CMV disease without increasing the proportion of patients receiving preemptive therapy and attributable toxicity. Breakthrough disease in PCR-based preemptive therapy occurs at a low incidence and presents primarily as GI disease, which is more likely to be responsive to antiviral therapy., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Many residency programs offer training in evidence-based medicine (EBM). However, these curricula often fail to achieve optimal learning outcomes, perhaps because they neglect various contextual factors in the learning environment. We developed and validated an instrument to characterize the environment for EBM learning and practice in residency programs., Methods: An EBM Environment Scale was developed following scale development principles. A survey was administered to residents across six programs in primary care specialties at four medical centers. Internal consistency reliability was analyzed with Cronbach's coefficient alpha. Validity was assessed by comparing predetermined subscales with the survey's internal structure as assessed via factor analysis. Scores were also compared for subgroups based on residency program affiliation and residency characteristics., Results: Out of 262 eligible residents, 124 completed the survey (response rate 47%). The overall mean score was 3.89 (standard deviation=0.56). The initial reliability analysis of the 48-item scale had a high reliability coefficient (Cronbach α=.94). Factor analysis and further item analysis resulted in a shorter 36-item scale with a satisfactory reliability coefficient (Cronbach α=.86). Scores were higher for residents with prior EBM training in medical school (4.14 versus 3.62) and in residency (4.25 versus 3.69)., Conclusions: If further testing confirms its properties, the EBM Environment Scale may be used to understand the influence of the learning environment on the effectiveness of EBM training. Additionally, it may detect changes in the EBM learning environment in response to programmatic or institutional interventions.

This study retrospectively evaluated long-term outcomes of 18 cats diagnosed with small intestinal adenocarcinoma, based on surgical versus non-surgical treatment and the presence or absence of metastasis at the time of surgery. Ten cats had surgery and histopathologic confirmation of adenocarcinoma and 8 cats did not have surgery but had cytologic diagnosis of adenocarcinoma. Median survival of cats with adenocarcinoma that underwent surgical excision was 365 days and 22 days for those with suspected adenocarcinoma that did not undergo surgery (P = 0.019). Median survival of cats was 843 days for those without evidence of metastatic disease at the time of surgery and 358 days for those that had (P = 0.25). In conclusion, surgical excision is beneficial in the treatment of small intestinal adenocarcinoma in the cat, including those patients with metastasis, and may result in a significantly longer survival time compared with patients which do not have their mass surgically excised.

Background: The placement of nasal or oral gastric tubes is one of the most frequently performed procedures in critically ill children; tube malposition, particularly in the trachea, is an important complication. Neurally adjusted ventilatory assist (NAVA) ventilation (available only on the Servo-i ventilator, Maquet Critical Care, Solna, Sweden) requires a proprietary-design catheter (Maquet Critical Care, Solna, Sweden) with embedded electrodes that detect the electrical activity of the diaphragm (EA(di)). The EA(di) catheter has the potential benefit of confirming proper positioning of a gastric catheter, based on and the EA(di) waveforms., Methods: In a case series study, our multidisciplinary team used EA(di) guidance for immediate, real-time confirmation of proper nasal or oral gastric tube placement in 20 mechanically ventilated pediatric patients who underwent 23 oral or nasal gastric tube placements. The catheters were placed with our standard practice, with the addition of a team member monitoring the EA(di) waveforms. As the tube passes down the esophagus and posterior to the heart, a characteristic EA(di) pattern is identified and the position of the atrial signal confirms correct placement of the gastric tube. If the EA(di) waveforms indicate incorrect placement, the tube is repositioned until the proper EA(di) waveform pattern is obtained. Then proper tube placement is reconfirmed via auscultation over the stomach while air is injected into the catheter, checking the pH of fluid suctioned from the catheter (gastric pH indicates correct positioning), and/or radiograph., Results: The group's median age was 3 years (range 4 d to 16 y). All 20 patients had successful gastric catheter placement. The EA(di) catheter provided characteristic patterns for correctly placed tubes, tubes malpositioned above or below the gastroesophageal junction, and curled tubes. Proper catheter position was confirmed via radiograph and/or gastric pH in all 20 patients., Conclusions: EA(di) guidance helps confirm proper gastric catheter position, is equivalent to our standard practice for confirming gastric catheter placement, and may reduce the need for radiographs and improve patient safety by avoiding catheter malpositions.

Objective: Ample research has examined physicians' evidence-based medicine (EBM) knowledge and skills; however, previous research has not linked EBM knowledge to objective measures of process of care., Design: A cross-sectional study of quality of care measures extracted from electronic medical records and EBM knowledge assessed via a validated questionnaire., Setting: One region of the largest Health Maintenance Organization in Israel., Participants: Seventy-four physicians and their 8334 diabetic patients, 7092 coronary heart disease patients and 17 132 hypertensive patients., Main Outcome Measures: Outcome measures were four diabetes quality of care indicators (LDL tests, microalbumin tests, hemoglobin A1C tests, eye examination referrals), and two drug prescription indicators (statin prescription for coronary heart disease patients, and thiazide prescription for hypertensive patients). Independent variables were total EBM knowledge and its components: critical appraisal and information retrieval., Results: Total EBM knowledge was independently and significantly associated with LDL testing (b = 0.13; P = 0.036), microalbumin testing (b = 0.33; P = 0.001), hemoglobin A1C testing (b = 0.17; P = 0.036), eye examination referrals (b = 0.16; P = 0.021) and statin prescriptions (b = 0.18; P = 0.025). Critical appraisal was independently associated with microalbumin tests (b = 0.46; P = 0.002) and eye examination referrals (b = 0.20; P = 0.048). Information retrieval was only independently associated with hemoglobin A1C testing (b = 0.43; P = 0.004). Thiazide prescription was not associated with EBM knowledge scores., Conclusions: Physicians' higher total EBM knowledge primarily correlates with better quality of care; however, correlations were modest and explained only a small portion in the variance of clinical performance. Results indicate that there might be a need to focus on teaching all the components of EBM rather than EBM microskills.

Background: The Accreditation Council for Graduate Medical Education (ACGME) Outcome Project requires that residency program directors objectively document that their residents achieve competence in 6 general dimensions of practice., Intervention: In November 2007, the American Board of Internal Medicine (ABIM) and the ACGME initiated the development of milestones for internal medicine residency training. ABIM and ACGME convened a 33-member milestones task force made up of program directors, experts in evaluation and quality, and representatives of internal medicine stakeholder organizations. This article reports on the development process and the resulting list of proposed milestones for each ACGME competency., Outcomes: The task force adopted the Dreyfus model of skill acquisition as a framework the internal medicine milestones, and calibrated the milestones with the expectation that residents achieve, at a minimum, the "competency" level in the 5-step progression by the completion of residency. The task force also developed general recommendations for strategies to evaluate the milestones., Discussion: The milestones resulting from this effort will promote competency-based resident education in internal medicine, and will allow program directors to track the progress of residents and inform decisions regarding promotion and readiness for independent practice. In addition, the milestones may guide curriculum development, suggest specific assessment strategies, provide benchmarks for resident self-directed assessment-seeking, and assist remediation by facilitating identification of specific deficits. Finally, by making explicit the profession's expectations for graduates and providing a degree of national standardization in evaluation, the milestones may improve public accountability for residency training.

In an effort to develop a Standard Reference Material (SRM™) for Seebeck coefficient, we have conducted a round-robin measurement survey of two candidate materials-undoped Bi2Te3 and Constantan (55 % Cu and 45 % Ni alloy). Measurements were performed in two rounds by twelve laboratories involved in active thermoelectric research using a number of different commercial and custom-built measurement systems and techniques. In this paper we report the detailed statistical analyses on the interlaboratory measurement results and the statistical methodology for analysis of irregularly sampled measurement curves in the interlaboratory study setting. Based on these results, we have selected Bi2Te3 as the prototype standard material. Once available, this SRM will be useful for future interlaboratory data comparison and instrument calibrations.

The hydrogen evolution from aqueous methanol solutions was found to follow two stages of zero order kinetics during photoreactions using TiO 2 as the photocatalyst. Maximal hydrogen evolution was found at the 10% (v/v) methanol solution. X-ray photoelectron spectroscopy (XPS) shows that Ti(1566) defects are formed on the surface of TiO 2 and X-ray powder diffraction (XRD) indicates that Ti(1566) defects are also formed in the bulk after photoreaction. Formation of defects is also shown by broadening of Bragg peaks and blue shifts and peak broadening in Raman spectroscopy. The defect disorder results in the increase of hydrogen evolution. UV-vis diffuse reflection spectra confirm that new absorptions in the visible light region are related to the defect content. At high methanol concentration, XPS implies that the active sites of the surface are blocked by hydroxyl groups, which results in the decrease of hydrogen evolution. TEM images showed that the photoreaction occurred on the surface of the photocatalyst as the surface of the TiO 2 became rough after the photoreaction.

Introduction: Imperfect sign-out of patient information between providers has been shown to contribute to medical error, but there are no standardized curricula to teach sign-out skills. At our institution, we identified several deficiencies in skills and a lack of any existing training., Aim: To develop a sign-out curriculum for medical house staff., Setting: Internal medicine residency program., Program Description: We developed a 1-h curriculum and implemented it in August of 2006 at three hospital sites. Teaching strategies included facilitated discussion, modeling, and observed individual practice with feedback. We emphasized interactive communication, a structured sign-out format summarized by an easy-to-remember mnemonic ("SIGNOUT"), consistent inclusion of key content items such as anticipatory guidance, and use of concrete language., Program Evaluation: We received 34 evaluations. The mean score for the course was 4.44 +/- 0.61 on a 1-5 scale. Perceived usefulness of the structured oral communication format was 4.46 +/- 0.78. Participants rated their comfort with providing oral sign-out significantly higher after the session than before (3.27 +/- 1.0 before vs. 3.94 +/- 0.90 after; p < .001)., Discussion: We developed an oral sign-out curriculum that was brief, structured, and well received by participants. Further study is necessary to determine the long-term impact of the curriculum.

Background: Hundreds of genes lacking homology to any protein of known function are sequenced every day. Genome-context methods have proved useful in providing clues about functional annotations for many proteins. However, genome-context methods detect many biological types of functional associations, and do not identify which type of functional association they have found., Results: We have developed two new genome-context-based algorithms. Algorithm 1 extends our previous algorithm for identifying missing enzymes in predicted metabolic pathways (pathway holes) to use genome-context features. The new algorithm has significantly improved scope because it can now be applied to pathway reactions to which sequence similarity methods cannot be applied due to an absence of known sequences for enzymes catalyzing the reaction in other organisms. The new method identifies at least one known enzyme in the top ten hits for 58% of EcoCyc reactions that lack enzyme sequences in other organisms. Surprisingly, the addition of genome-context features does not improve the accuracy of the algorithm when sequences for the enzyme do exist in other organisms. Algorithm 2 uses genome-context methods to predict three distinct types of functional relationships between pairs of proteins: pairs that occur in the same protein complex, the same pathway, or the same operon. This algorithm performs with varying degrees of accuracy on each type of relationship, and performs best in predicting pathway and protein complex relationships.

The impact of agostic interactions (i.e., 3-center-2-electron M-H-C bonds) on the structures and reactivity of organotransition metal compounds is reviewed.