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BACKGROUND AND OBJECTIVES Establishing peripheral intravenous catheter (PIVC) access in infants and children is a common procedure but can be technically difficult. The primary objective was to determine the effect ultrasound had on first attempt PIVC insertion success rates in the pediatric population. Secondary objectives included overall success rates and subgroups analyses. METHODS A systematic review of articles using Medline, Embase, CENTRAL, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. Randomized trials evaluating ultrasound-guided PIVC insertion against the landmark approach in pediatric patients who reported at least 1 outcome of success rate (first attempt or overall) were included. Methodological quality of the literature was assessed using the Revised Cochrane risk-of-bias tool for randomized trials. A meta-analysis using a random-effects model was performed. RESULTS Nine studies with 1350 patients, from a total of 1033 studies, were included for analysis. Ultrasound showed a statistically significant improvement in PIVC insertion success on first attempt in 5 of 8 studies, with an overall success rate of 78% in the ultrasound group and 66% in the control group. The secondary outcome of overall success was improved by ultrasound in studies that allowed ≥3 attempts (pooled OR 3.57, 95% CI 2.05 to 6.21, P < .001, I2 = 0.0%). CONCLUSIONS This systematic review suggested that ultrasound improves pediatric PIVC first pass and overall success rates. Subgroup analysis showed improvement in PIVC success rates for patients with difficult intravenous access and a single operator, dynamic, short-axis ultrasound technique.

Background:Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation.Results:Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity, searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile.Conclusion:In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs.

An increasing elderly population in the United Kingdom has led to an increasing number of older patients with head and neck cancer, resulting in a greater demand for complex head and neck reconstructive surgery in this potentially high-risk age group. A possible perceived poorer tolerance to such major treatment risks under-treating some of these patients. The purpose of this study was to assess the outcomes in the elderly population (older than 80 years) who had undergone free flap reconstruction following head and neck cancer resection. A retrospective review of 127 patients was performed. Eighteen patients were 80 or older (14.2%) and 109 under 80 (85.8%). The elderly group experienced increased number of postoperative medical complications (p=0.01), but the surgical complications were not significantly different in the two groups (p=0.4). The average length of hospital stay was significantly longer in the older group (p=0.01). There was one flap failure during the study period, which belonged to the younger group of patients. Elderly patients undergoing free flap reconstruction experience an increased rate of postoperative medical complications resulting in an increased length of hospital stay. However, good surgical outcomes can still be achieved in this age group, and therefore age alone should not be considered as a primary factor in head and neck cancer management.

Introduction Increasingly, health care is delivered through a patient-centered model, and patients engage in shared decision-making with their medical providers. As a result, medical educators are placing more emphasis on patient-centered communication skills. However, few published curricula currently offer a comprehensive discussion of skills for providing patient-centered education (PCE), a key component of shared decision-making. We developed an interactive, two-session workshop aiming to improve students’ abilities to provide PCE. Methods Our workshop included didactic instruction, group discussion, and interactive simulations. The workshop was delivered to 50 clinical clerkship medical students. The first session concentrated on educating patients about their diagnoses, while the second session focused on providing patients with information about medications and other treatments. We used detailed and realistic role-play exercises as a core tool for student practice and demonstration of confidence. To evaluate the workshop, we used pre- and postsurveys. Results The sessions were well received by students, who strongly agreed both before and after the workshop that PCE was an important skill. Students also strongly agreed that the role-play exercises were an effective tool for learning PCE. They demonstrated significant improvements in their confidence to name important elements of PCE and to deliver PCE in the future. Discussion This workshop fills a curricular gap in offering a comprehensive and interactive curriculum for improving students’ abilities to provide critical PCE. The format and content should be easily adaptable to various disciplines, learners, and teaching modalities.

The unprecedented impact of COVID-19 has raised concern for the potential of increased suicides due to a convergence of suicide risk factors. We obtained suicide mortality data to assess completed suicides during the period of strict stay-at-home quarantine measures in Connecticut and compared this data with previous years. While the total age-adjusted suicide mortality rate decreased by 13% during the lockdown period compared with the 5-year average, a significantly higher proportion of suicide decedents were from racial minority groups. This finding may provide early evidence of a disproportionate impact from the social and economic challenges of COVID-19 on minority populations.

Current risk assessment models for surgical site occurrence (SSO) and surgical site infection (SSI) after open ventral hernia repair (VHR) have limited external validation. Our aim was to determine (1) whether existing models stratify patients into groups by risk and (2) which model best predicts the rate of SSO and SSI.Patients who underwent open VHR and were followed for at least 1 mo were included. Using two data sets-a retrospective multicenter database (Ventral Hernia Outcomes Collaborative) and a single-center prospective database (Prospective)-each patient was assigned a predicted risk with each of the following models: Ventral Hernia Risk Score (VHRS), Ventral Hernia Working Group (VHWG), Centers for Disease Control and Prevention Wound Class, and Hernia Wound Risk Assessment Tool (HW-RAT). Patients in the Prospective database were also assigned a predicted risk from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). Areas under the receiver operating characteristic curve (area under the curve [AUC]) were compared to assess the predictive accuracy of the models for SSO and SSI. Pearson's chi-square was used to determine which models were able to risk-stratify patients into groups with significantly differing rates of actual SSO and SSI.The Ventral Hernia Outcomes Collaborative database (n = 795) had an overall SSO and SSI rate of 23% and 17%, respectively. The AUCs were low for SSO (0.56, 0.54, 0.52, and 0.60) and SSI (0.55, 0.53, 0.50, and 0.58). The VHRS (P = 0.01) and HW-RAT (P 0.01) significantly stratified patients into tiers for SSO, whereas the VHWG (P 0.05) and HW-RAT (P 0.05) stratified for SSI. In the Prospective database (n = 88), 14% and 8% developed an SSO and SSI, respectively. The AUCs were low for SSO (0.63, 0.54, 0.50, 0.57, and 0.69) and modest for SSI (0.81, 0.64, 0.55, 0.62, and 0.73). The ACS-NSQIP (P 0.01) stratified for SSO, whereas the VHRS (P 0.01) and ACS-NSQIP (P 0.05) stratified for SSI. In both databases, VHRS, VHWG, and Centers for Disease Control and Prevention overestimated risk of SSO and SSI, whereas HW-RAT and ACS-NSQIP underestimated risk for all groups.All five existing predictive models have limited ability to risk-stratify patients and accurately assess risk of SSO. However, both the VHRS and ACS-NSQIP demonstrate modest success in identifying patients at risk for SSI. Continued model refinement is needed to improve the two highest performing models (VHRS and ACS-NSQIP) along with investigation to determine whether modifications to perioperative management based on risk stratification can improve outcomes.

Impotence, bladder dysfunction, GI symptoms, and orthostatic hypotension can signal autonomic dysfunction. Here's what you'll see and how to respond.

Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the sinonasal tract that arises from olfactory epithelium. There have been reports, mainly in tumors treated with chemoradiation or with distant metastases, describing focal histologic changes of divergent cell populations within archetypal ONB. Only three cases have been reported of ONB coexisting with non-neuroendocrine tumors. We describe our experience with a 35-year-old male with a nasal cavity mass extending into the anterior cranial fossa. Pathology revealed this to be a high grade malignant neoplasm with features of olfactory neuroblastoma and a significant divergent population of pancytokeratin and epithelial membrane antigen-reactive cells. The patient underwent combined endoscopic and open craniofacial resection followed by adjuvant chemoradiation. We describe the clinical presentation, treatment, and outcome followed by a review of the literature. Surgical pathology clearly demonstrated two cell populations evenly distributed and displaying classic histologic and immunohistochemical markers of ONB, as well as poorly differentiated cells with an epithelial immunophenotype. The patient is now 16 months status post completion of treatment with no evidence of recurrence. Our patient's presentation is unique and unusual in that the tumor demonstrated a high grade olfactory neuroblastoma and a divergent, epithelial-marker reactive cell population in the same tumor. This combined appearance is unusual and may represent an "olfactory carcinoma". Only one previous case has reported carcinomatous involvement of an ONB. There is insufficient information in the literature to draw conclusions on the impact these divergent cell populations have on prognosis or treatment.

In this study, two probabilistic machine-learning algorithms were compared for in silico target prediction of bioactive molecules, namely the well-established Laplacian-modified Naïve Bayes classifier (NB) and the more recently introduced (to Cheminformatics) Parzen-Rosenblatt Window. Both classifiers were trained in conjunction with circular fingerprints on a large data set of bioactive compounds extracted from ChEMBL, covering 894 human protein targets with more than 155,000 ligand-protein pairs. This data set is also provided as a benchmark data set for future target prediction methods due to its size as well as the number of bioactivity classes it contains. In addition to evaluating the methods, different performance measures were explored. This is not as straightforward as in binary classification settings, due to the number of classes, the possibility of multiple class memberships, and the need to translate model scores into "yes/no" predictions for assessing model performance. Both algorithms achieved a recall of correct targets that exceeds 80% in the top 1% of predictions. Performance depends significantly on the underlying diversity and size of a given class of bioactive compounds, with small classes and low structural similarity affecting both algorithms to different degrees. When tested on an external test set extracted from WOMBAT covering more than 500 targets by excluding all compounds with Tanimoto similarity above 0.8 to compounds from the ChEMBL data set, the current methodologies achieved a recall of 63.3% and 66.6% among the top 1% for Naïve Bayes and Parzen-Rosenblatt Window, respectively. While those numbers seem to indicate lower performance, they are also more realistic for settings where protein targets need to be established for novel chemical substances.

Background A multi-center study was conducted to evaluate the Bio-Rad GS HIV Combo Ag/Ab EIA, a 4th generation HIV-1/HIV-2 assay for the simultaneous detection of HIV p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2 in human serum or plasma in adult and pediatric populations. Objectives The objectives of the study were to assess assay performance for the detection of acute HIV infections; sensitivity in known HIV positive samples; percent agreement with HIV status; specificity in low and high risk individuals of unknown HIV status; and to compare assay performance to a 3rd generation HIV assay. Study design The evaluation included testing 9150 samples at four U.S. clinical trial sites, using three kit lots. Unlinked samples were from routine testing, repositories or purchased from vendors. Results GS HIV Combo Ag/Ab EIA detection in samples from individuals in two separate populations with acute HIV infection was 95.2% (20/21) and 86.4% (38/44). Sensitivity was 100% (1603/1603) in known antibody positive [HIV-1 Groups M and O, and HIV-2] samples. HIV p24 antigen detection was 100% (53/53) in HIV-1 culture supernatants. HIV-1 seroconversion panel detection improved by a range of 0–20 days compared to a 3rd generation HIV test. Specificity was 99.9% (5989/5996) in low risk, 99.9% (959/960) in high risk and 100% (100/100) in pediatric populations. Conclusion The GS HIV Combo Ag/Ab EIA significantly reduced the diagnostic window when compared to the 3rd generation screening assay, enabling earlier diagnosis of HIV infection. The performance parameters of the Bio-Rad GS HIV Combo Ag/Ab EIA are well suited for use in HIV diagnostic settings.

Phospholipidosis is an adverse effect caused by numerous cationic amphiphilic drugs and can affect many cell types. It is characterized by the excess accumulation of phospholipids and is most reliably identified by electron microscopy of cells revealing the presence of lamellar inclusion bodies. The development of phospholipidosis can cause a delay in the drug development process, and the importance of computational approaches to the problem has been well documented. Previous work on predictive methods for phospholipidosis showed that state of the art machine learning methods produced the best results. Here we extend this work by looking at a larger data set mined from the literature. We find that circular fingerprints lead to better models than either E-Dragon descriptors or a combination of the two. We also observe very similar performance in general between Random Forest and Support Vector Machine models.

The combination of models for protein target prediction with large databases containing toxicological information for individual molecules allows the derivation of "toxiclogical" profiles, i.e., to what extent are molecules of known toxicity predicted to interact with a set of protein targets. To predict protein targets of drug-like and toxic molecules, we built a computational multiclass model using the Winnow algorithm based on a dataset of protein targets derived from the MDL Drug Data Report. A 15-fold Monte Carlo cross-validation using 50% of each class for training, and the remaining 50% for testing, provided an assessment of the accuracy of that model. We retained the 3 top-ranking predictions and found that in 82% of all cases the correct target was predicted within these three predictions. The first prediction was the correct one in almost 70% of cases. A model built on the whole protein target dataset was then used to predict the protein targets for 150000 molecules from the MDL Toxicity Database. We analysed the frequency of the predictions across the panel of protein targets for experimentally determined toxicity classes of all molecules. This allowed us to identify clusters of proteins related by their toxicological profiles, as well as toxicities that are related. Literature-based evidence is provided for some specific clusters to show the relevance of the relationships identified.

Recently developed multi-targeted ligands are novel drug candidates able to interact with monoamine oxidase A and B; acetylcholinesterase and butyrylcholinesterase; or with histamine N-methyltransferase and histamine H3-receptor (H3R). These proteins are drug targets in the treatment of depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease. A probabilistic method, the Parzen-Rosenblatt window approach, was used to build a >predictor> model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Molecular structures were represented based on the circular fingerprint methodology. The same approach was used to build a >predictor> model from the DrugBank dataset to determine the main pharmacological groups of the compound. The study of off-target interactions is now recognised as crucial to the understanding of both drug action and toxicology. Primary pharmaceutical targets and off-targets for the novel multi-target ligands were examined by use of the developed cheminformatic method. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. The cheminformatic targets identifications were in agreement with four 3D-QSAR (H3R/D1R/D2R/5-HT2aR) models and by in vitro assays for serotonin 5-HT1a and 5-HT2a receptor binding of the most promising ligand (71/MBA-VEG8).

BACKGROUND The current study was conducted to evaluate the efficacy of paclitaxel, administered weekly or once every 3 weeks, in combination with oral estramustine phosphate (EMP) in patients with recurrent or refractory aggressive non-Hodgkin lymphoma (NHL). METHODS Between February 1996 and February 2001, 23 patients with recurrent NHL were enrolled onto this Phase II trial. The median age for all patients was 65 years (range, 27–80 years). The initial 12 patients (who received a mean number of 2.4 prior treatments, including 1 patient who received a prior peripheral blood stem cell transplant) received paclitaxel at a dose of 175 mg/m2 given as a 3-hour intravenous infusion every 21 days. The next 11 patients (who received a mean number of 2.8 prior treatments, including 1 patient who received prior peripheral blood stem cell transplant) were registered (1 patient refused treatment) to receive paclitaxel at a dose of 80 mg/m2 as a 1-hour intravenous infusion weekly for 6 weeks of an 8-week cycle. All patients received EMP at a dose of 600 mg/m2 orally per day beginning the day prior to each dose of paclitaxel for a total of 3 days. RESULTS When paclitaxel was administered every 21 days, 4 partial responses were observed in 12 evaluable patients (33.3%). The median survival was 147 days. The median duration of response was 102 days (range, 42–127 days) and the median time to disease progression was 66 days. Grade 3 and Grade 4 neutropenia (according to the revised version of the Common Toxicity Criteria of the National Cancer Institute) were observed in 5 patients (42%) in this group. In an attempt to reduce the incidence of myelosuppression, paclitaxel dosing was changed to weekly dosing. In the cohort of patients receiving weekly paclitaxel, an objective response was reported to occur in 3 (1 complete response and 2 partial responses) of 11 evaluable patients (27%). The median survival was 132 days (range, 33–462 days). The median duration of response was 64 days and the median time to disease progression was 57 days. There was no significant difference noted between the cohort receiving paclitaxel three times weekly and those receiving paclitaxel weekly with regard to overall survival and time to disease progression (P = 0.7 and P = 0.8, respectively by the log-rank test). Grade 3 or 4 neutropenia was observed in only 2 of 11 patients (18%) in the weekly paclitaxel group. There were no significant differences noted in terms of thrombocytopenia, anemia, nausea, anorexia, or fatigue between the treatment groups. CONCLUSIONS Paclitaxel given once weekly or three times weekly, in combination with oral EMP, was found to have comparable efficacy in patients with recurrent NHL, with an overall response rate of 30%. The response rate was found to be higher than that reported in prior studies of paclitaxel as a single agent in the treatment of NHL, suggesting that EMP may enhance paclitaxel efficacy in patients with NHL. Hematologic toxicity was diminished when paclitaxel was administered on a weekly schedule. The minimal myelotoxicity of weekly paclitaxel makes this a potentially attractive agent for combination regimens for patients with recurrent/refractory NHL. Cancer 2004. © 2004 American Cancer Society.

Adequate muscle mass and function are critical for human health. Several types of skeletal muscle growth, including regeneration and growth after atrophy, can occur in the rehabilitative period after orthopaedic surgery. The molecular pathways regulating growth of skeletal muscle in adults are understood poorly. The role of calcineurin in regulating regeneration and growth of atrophied skeletal muscle is discussed. Understanding the molecular and cellular pathways that regulate such muscle growth may lead to the development of strategies to enhance muscle growth, thereby facilitating rehabilitation after orthopaedic surgery.

Adequate muscle mass is critical for human health. The molecular pathways regulating maintenance and growth of adult skeletal muscle are little understood. Calcineurin (CN) is implicated as a key signaling molecule in hypertrophy. Whether CN is involved in all forms of muscle growth or in different muscles is unknown. Here, we examine the role of CN in regulating maintenance of muscle size and growth of atrophied muscle in the soleus (slow) and plantaris (fast). The CN inhibitor cyclosporin A (CsA) differentially affects muscle growth and maintenance depending on muscle phenotype. The plantaris is more severely affected by CsA than the soleus in both growth conditions. One-week vs. 2-wk CsA treatment suggests that both CN-dependent and CN-independent growth occur in the atrophied soleus, whereas plantaris growth appears to be totally CN dependent. Our results suggest that CN regulates multiple types of muscle growth, depending both on muscle phenotype and stage of myofiber growth. Differential expression of components of the CN pathway occurs and may contribute to the differences between muscles.

Background The purpose of this study was to identify issues important to patients in their decision-making, expectations, and satisfaction when seeking treatment for a ventral hernia. Study Design An exploratory qualitative study was conducted of adult patients with ventral hernias seeking care at a safety-net hospital. Two semi-structured interviews were conducted with each patient: before and 6 months after surgical consultation. Interviews were audiotaped, transcribed, and coded using latent content analysis until data saturation was achieved. Results Of patients completing an initial interview (n = 30), 27 (90%) completed follow-up interviews. Half of the patients were Spanish-speaking, one-third had a previous ventral hernia repair, and two-thirds underwent initial nonoperative management after surgical consultation. Patient-described factors guiding management decisions included impact on quality of life, primarily pain and limited function; overwhelming challenges to meeting surgical criteria, primarily obesity; and assuming responsibility to avoid recurrence. Patients were uninformed regarding potential poor outcomes and contributing factors, even among patients with a previous ventral hernia repair, with most attributing recurrence to inadequate self-management. Conclusions Understanding patients' perspective is crucial to engaging them as stakeholders in their care, addressing their concerns, and improving clinical and patient-centered outcomes. Patient reports suggest how care can be improved through developing more effective strategies for addressing patients' concerns during nonoperative management, preoperative risk reduction strategies that are sensitive to their sociodemographic characteristics, treatment plans that harness patients' willingness for self-management, and patient education and decision-making tools.

Intro Langerhans cell histiocytosis (LCH) is a rare disease involving the proliferation of histiocytes in one or more organ systems. The presentation of LCH is more common in the pediatric population and rarely occurs within the adult population. Isolated lymph node involvement is an extremely rare presentation of the disease. The authors present a case of isolated lymph node LCH in an otherwise healthy adult female and discuss management strategies for these unusual findings. Methods A case report of a patient at a tertiary care facility in June 2014 is discussed. Results/Discussion The diagnosis, clinical course, and management strategies for isolated adult LCH are discussed and reviewed. Conclusion Langerhans cell histiocytosis rarely presents with isolated lymph node involvement in adults. Management and surveillance algorithms are discussed in this unusual case of seemingly benign lymphadenopathy.

The USNS Comfort (T-AH-20) is 1 of 2 United States Navy hospital ships. In 2011, she deployed to 9 countries in Central and South America including Jamaica, Peru, Colombia, Ecuador, Nicaragua, Guatemala, El Salvador, Costa Rica, and Haiti. Eight surgical specialties including otolaryngology were involved, for a combined total of about 150 cases per country. An advance team coordinated patients with the Host Nation to be seen for presurgical screening. Selected patients were then taken aboard the ship for surgery and recovered in either the ship’s intensive care unit or ward. They were then discharged prior to ship embarkment to the next country. A total of 95 otolaryngology cases were performed during 9 mission stops. The mean number of procedures performed was 12 per country, with thyroidectomy being the most common. A wide variety of general otolaryngology procedures were performed without significant complications, markedly impacting the quality of life in these underserved countries.

We have incorporated a bicyclic β-turn mimetic (BTD; β-turn dipeptide) into a zinc finger, creating a zinc finger with an artificial β-turn. The designed peptide chelates zinc and has the same fold as the unmodified native zinc finger (finger 3 of the human YY1 protein). A combination of 1 H NMR and structure calculations reveals that, in solution, this zinc finger has a fold similar to the known wild-type crystal structure and to other zinc fingers containing the consensus sequence X 3 -Cys-X 4 -Cys-X 12 -His-X 3 -His-X. The peptide was designed with BTD between the chelating cysteine residues, with BTD forming a type II′ β-turn linking the two strands of a distorted anti-parallel β-sheet. The C-terminal portion of the peptide forms a helix with zinc co-ordinating histidine residues on successive turns of the helix. This work represents a step towards developing methods by which parts of a target protein may be replaced by peptide mimetics.

In May 1994 an outbreak of vomiting and diarrhoea occurred in a 28-bed long-stay ward for the mentally infirm. The predominant symptoms were vomiting, diarrhoea, malaise and abdominal pain lasting for approximately 12 h in most cases. The attack rate was 62% (13/21) for patients and 46% (16/35) for staff members. Infection control measures were implemented (containment of infectious individuals, hand hygiene among staff and environmental decontamination) and the ward was closed to admissions. Affected staff were excluded from contact with patients and their food until asymptomatic for 72 h. The outbreak lasted for 17 days. Faecal samples from nine symptomatic persons were negative for bacterial enteric pathogens, Giardia, Cryptosporidium and group A rotavirus. Electron microscopy of 12 faecal samples and one sample of vomitus revealed small round structured virus (SRSV) particles in one faecal sample. A further 30 faecal samples and seven vomitus samples were tested by reverse transcription polymerase chain reaction (RT-PCR) for SRSV of which 12 (40%) and 1 (14%) were positive respectively. Twenty-eight throat swabs from symptomatic and asymptomatic patients were collected, three (9.5%) of which were positive for SRSV by RT-PCR. Thirty-six environmental swabs were collected on the affected ward, and 11 (30%) were positive by RT-PCR. Positive swabs were from lockers, curtains and commodes and confined to the immediate environment of symptomatic patients. The distribution of contamination supports the rationale of cohorting sick patients.

Background A multisite study was conducted to evaluate the performance of the Bio-Rad 4th generation GS HIV Combo Ag/Ab EIA versus Abbott 4th generation ARCHITECT HIV Ag/Ab Combo. The performance of two 3rd generation EIAs, Ortho Diagnostics Anti-HIV 1 + 2 EIA and Siemens HIV 1/O/2 was also evaluated. Objective Study objective was comparison of analytical HIV-1 p24 antigen detection, sensitivity in HIV-1 seroconversion panels, specificity in blood donors and two HIV false reactive panels. Study design Analytical sensitivity was evaluated with International HIV-1 p24 antigen standards, the AFFSAPS (pg/mL) and WHO 90/636 (IU/mL) standards; sensitivity in acute infection was compared on 55 seroconversion samples, and specificity was evaluated on 1000 negative blood donors and two false reactive panels. Results GS HIV Combo Ag/Ab demonstrated better analytical HIV antigen sensitivity compared to ARCHITECT HIV Ag/Ab Combo: 0.41 IU/mL versus 1.2 IU/mL (WHO) and 12.7 pg/mL versus 20.1 pg/mL (AFSSAPS); GS HIV Combo Ag/Ab EIA also demonstrated slightly better specificity compared to ARCHITECT HIV Ag/Ab Combo (100% versus 99.7%). The 4th generation HIV Combo tests detected seroconversion 7–11 days earlier than the 3rd generation HIV antibody only EIAs. Conclusion Both 4th generation immunoassays demonstrated excellent performance in sensitivity, with the reduction of the serological window period (7–11 days earlier detection than the 3rd generation HIV tests). However, GS HIV Combo Ag/Ab demonstrated improved HIV antigen analytical sensitivity and slightly better specificity when compared to ARCHITECT HIV Ag/Ab Combo assay, with higher positive predictive values (PPV) for low prevalence populations.

Background: Teaching bioinformatics at universities is complicated by typical computer classroom settings. As well as running software locally and online, students should gain experience of systems administration. For a future career in biology or bioinformatics, the installation of software is a useful skill. We propose that this may be taught by running the course on GNU/Linux running on inexpensive Raspberry Pi computer hardware, for which students may be granted full administrator access. Results: We release 4273π, an operating system image for Raspberry Pi based on Raspbian Linux. This includes minor customisations for classroom use and includes our Open Access bioinformatics course, 4273π Bioinformatics for Biologists. This is based on the final-year undergraduate module BL4273, run on Raspberry Pi computers at the University of St Andrews, Semester 1, academic year 2012–2013. Conclusions: 4273π is a means to teach bioinformatics, including systems administration tasks, to undergraduates at low cost. Publisher PDF

Proposed regulations set forth detailed rules for implementing the new tax-exemption requirements of Section 501(r) of the Internal Revenue Code for not-for-profit organizations operating hospital facilities. The proposed regulations provide guidance on the written financial assistance policies (FAPs) that hospital facilities are required to establish. The regulations propose methodologies for determining the amounts that a hospital facility can charge FAP-eligible individuals for emergency and other medically necessary care. They prescribe procedures that hospital facilities would be required to follow before engaging in extraordinary collection actions against an individual.

Quaternized triflupromazine derivatives (QTDs) must possess benzyl groups attached to the quaternary nitrogen in order to have significant antitubercular potency. Replacing the quaternary amine with a triazole abolishes antitubercular activity. A modest halogen substitution effect exists, with the 4-bromophenyl QTD 3 having the best selectivity index (>21). All N-benzyl QTDs 1 – 4 similarly inhibit non-replicating, persistent Mycobacterium tuberculosis with MIC 1 – 3 were all nontoxic to mammalian cells in vitro (IC 50 >128 μM).

N-(4-chlorobenzyl)triflupromazinium chloride, a known antitubercular agent, has been found to also be active against HSV-1. A preliminary structure-activity relation has been explored to determine which groups are crucial to viral inhibition. Antiviral assessments such as GFP reduction, plaque reduction, treatment timing and wash-out studies have also been probed to determine a mode of action for QPD-1. Based on this preliminary data, it appears that QPD-1 is a reversible inhibitor, suspected to inhibit early stages of viral replication of HSV-1 at 50 μM, equipotent to acyclovir.

Study Design. Prospective single-center case cohort study. Objective. Evaluation of clinical and radiographic outcomes of a consecutive 122-patient cohort with discogenic back pain, at 2 - to 10-year follow-up periods, treated by a single surgeon, with CHARITE® Artificial Disc (DePuy Spine, Raynham, MA, USA). Summary of Background Data. Minimum two-year clinical and radiographic Level 1 data for the first lumbar artificial disc, the CHARITE® Artificial Disc, has recently been published, demonstrating sustained clinical benefit of the device for the treatment of degenerative disc disease (DDD). Methods. Patients were assessed preoperatively using clinical outcome measures, including Visual Analogue Score (VAS) back and leg, Oswestry Disability Index (ODI), Short Form - 36 (SF-36), and Roland-Morris Questionnaires (RMDQ), and further assessed postoperatively, 3-months, 6-months, 12-months, and yearly thereafter. Results. Average follow-up was 44.9±23.3 months (n = 122). The median age at surgery was 43.0±9.0 years. Preoperative diagnosis included DDD in 118 (96.7%) and internal disc disruption (IDD) in 4 (3.3%). Surgery was performed at L5-S1 in 96 (77.9%) patients and at L4-5 in 27 (22.1%). Statistically significant clinical improvements from baseline were observed on VAS (back and leg), ODI, SF-36 PCS, SF-36 MCS, and RMDQ from 3 months onwards. Back VAS scores decreased from 78.2±21.3 preoperatively to 21.9±27.8 by final follow-up. ODI scores decreased from 51.1±17.3 to 16.2±17.9 at last follow-up. The RMDQ scores also decreased, from 16.7±4.7 to 4.2±5.8. SF-36 PCS and MCS increased from 25.7±11.0 to 46.4±10.3 for PCS and from 35.5±17.4 to 51.6±10.8 for MCS. Patient satisfaction surveys indicated that 90.56% patients rated their satisfaction with the surgery as “excellent” or “good” at 2 years. Range of motion averaged 8.6°±3.5° (median: 8.0°) at the last follow-up time point. Conclusions. Outcomes verify the clinical efficacy of total disc replacement (TDR) for treatment of discogenic back pain with or without radiculopathy. The outcomes instruments demonstrated statistically significant improvements from 3 months onwards.

Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients.This single-center retrospective observational study, of patients transplanted from January 1, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (≥International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded.The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P.0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004).In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation.

Selective human butyrylcholinesterase (BChE) inhibitors such as cymserine have shown considerable promise for restoring cognition in Alzheimer's disease. Recently, (-)-debromoflustramine B, 1, a hexahydropyrrolo-[2,3-b]indole natural product isolated from the marine bryozoan Flustra foliacea, has demonstrated micromolar potency as a selective BChE inhibitor. Since (±)-demethyldebromoflustramine B, (±)-2, has an even lower IC(50), and the active enantiomer is (-)-2, derivatives of (-)-2 were constructed in silico and docked into the active site of BChE. Several compounds exhibited improved inhibitor potency and could be candidates for future synthesis and in vitro enzyme inhibition study.

Dietary fluid and sodium intake may influence the risk for vasoocclusive events in persons with sickle cell anemia (SCA). The objective of this study was to examine the dietary intake of water and sodium in children and adolescents with SCA and identify possible factors influencing intake. We compared water (mL) and sodium (mg) intake in 21 patients with SCA, aged 5 to 18 years, to reported adequate intake for water, daily fluid requirement, upper limit for sodium, and National Health and Nutrition Examination Survey 2005 to 2006 data for sodium, and sociodemographic factors. Dietary intake from 3-day food records was evaluated retrospectively. Median water intake was significantly lower than adequate intake, and median sodium intake was significantly higher than sodium upper limit. Sociodemographic factors were not associated with dietary water or sodium intake. Our results suggest that children and adolescents with SCA would benefit from education regarding increasing fluid intake and limiting high sodium foods.

Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation. We hypothesized that Receptor for Advanced Glycation End-products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation. We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (transbronchial biopsy) from recipients with and without PGD. RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD versus transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/mL increase in donor RAGE level). In addition, RAGE levels remained high for 14 days in those recipients that developed severe graft dysfunction. Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD posttransplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD.

Thoracic aortic aneurysms (TAA) have remained a formidable operative challenge. Open surgical techniques have been associated with high rates of morbidity and mortality. Thoracic endovascular aneurysm repair (TEVAR) has produced results equal to or better than the traditional open surgical approach. This report presents a patient with a complex thoracic aortic aneurysm involving the ascending, transverse, and proximal descending thoracic aorta. This patient was successfully managed by the creation of Landing Zone-Zero, arch vessel debranching, and endografting the entire aortic arch without the need for hypothermic circulatory arrest or cerebral perfusion strategies. Computer tomographic images demonstrate the repair to be durable at 18 months.

Type B aortic dissections have remained a difficult management problem. Open surgical techniques have had a very high perioperative mortality, and medical management has not produced satisfactory long-term results. Endovascular grafting techniques may provide a favorable alternative therapy. However, there are currently no endovascular stents approved by the United States Food and Drug Administration for treating Type B aortic dissections. Also, there is very little data from United States centers on the long-term efficacy of endovascular stents used "off-label" to treat aortic dissections. This report discusses the care of a patient with a Type B aortic dissection successfully treated by an endograft in a community hospital. In addition, serial follow-up computerized tomography demonstrates the durability of this repair at three years.

Chronic hypoxia contributes to pulmonary hypertension through complex mechanisms that include enhanced NADPH oxidase expression and reactive oxygen species (ROS) generation in the lung. Stimulation of peroxisome proliferator-activated receptor gamma (PPARgamma) reduces the expression and activity of NADPH oxidase. Therefore, we hypothesized that activating PPARgamma with rosiglitazone would attenuate chronic hypoxia-induced pulmonary hypertension, in part, through suppressing NADPH oxidase-derived ROS that stimulate proliferative signaling pathways. Male C57Bl/6 mice were exposed to chronic hypoxia (CH, Fi(O2) 10%) or room air for 3 or 5 weeks. During the last 10 days of exposure, each animal was treated daily by gavage with either the PPARgamma ligand, rosiglitazone (10 mg/kg/d) or with an equal volume of vehicle. CH increased: (1) right ventricular systolic pressure (RVSP), (2) right ventricle weight, (3) thickness of the walls of small pulmonary vessels, (4) superoxide production and Nox4 expression in the lung, and (5) platelet-derived growth factor receptor beta (PDGFRbeta) expression and activity and reduced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression. Treatment with rosiglitazone prevented the development of pulmonary hypertension at 3 weeks; reversed established pulmonary hypertension at 5 weeks; and attenuated CH-stimulated Nox4 expression and superoxide production, PDGFRbeta activation, and reductions in PTEN expression. Rosiglitazone also attenuated hypoxia-induced increases in Nox4 expression in pulmonary endothelial cells in vitro despite hypoxia-induced reductions in PPARgamma expression. Collectively, these findings indicate that PPARgamma ligands attenuated hypoxia-induced pulmonary vascular remodeling and hypertension by suppressing oxidative and proliferative signals providing novel insights for mechanisms underlying therapeutic effects of PPARgamma activation in pulmonary hypertension.

Toxicology has the goal of ensuring the safety of humans, animals and the environment. Computational toxicology is an area of active development and great potential. There are tangible reasons for the emerging interest in this discipline from academia, industry, regulatory bodies and governments.Pharmaceuticals, personal health care products, nutritional ingredients and products of the chemical industries are all potential hazards and need to be assessed. Toxicological tests for these products are costly, frequently use laboratory animals and are time-consuming. This delays end-user access to improved products or, conversely, the timely withdrawal of dangerous substances from the market. The aim of computational toxicology is to accelerate the assessment of potentially dangerous substances through in silico models.In this review, we provide an overview of the development of models for computational toxicology. Addressing the significant divide between the experimental and computational worlds-believed to be a prime hindrance to computational toxicology-we briefly consider the fundamental issue of toxicological data and the assays they stem from. Different kinds of models that can be built using such data are presented: computational filters, models for specific toxicological endpoints and tools for the generation of testable hypotheses.

BACKGROUND Using an experimental model of airway fibrosis following lung transplantation, we recently showed that chronic alcohol ingestion by donor rats amplifies airway fibrosis in the recipient. Associated with alcohol-mediated amplification of airway fibrosis is increased transforming growth factor beta-1(TGFbeta(1)) and alpha-smooth muscle actin expression. Other studies have shown that interleukin-13 (IL-13) modulates TGFbeta(1) signaling during experimentally-induced airway fibrosis. Therefore, we hypothesized that IL-13 is a component of alcohol-mediated amplification of pro-fibrotic mediators in the alcoholic lung. METHODS To test this hypothesis, we analyzed tracheal epithelial cells and type II alveolar cells from control- or alcohol-fed rats, alcohol-treated mouse lung fibroblasts, and human bronchial epithelial cells in vitro for expression of various components of the IL-13 signaling pathway. Signaling via the IL-13 pathway was assessed by measuring levels of phosphorylated signal transducers and activators of transcription-6 (STAT6). In addition, we performed heterotopic tracheal transplantation using control-fed and alcohol-fed donor rats and analyzed tracheal allografts for expression of components of the IL-13 signaling pathway by RT-PCR and immunocytochemical analyses. RESULTS Interleukin-13 expression was detected in type II alveolar epithelial cells and human bronchial epithelial cells, but not in lung fibroblasts. IL-13 expression was decreased in whole lung and type II cells in response to alcohol exposure. In all cell types analyzed, expression of IL-13 signaling receptor (IL-13R alpha(1)) mRNA was markedly increased. In contrast, mRNA and protein expression of the IL-13 decoy receptor (IL-13R alpha(2)) were decreased in all cells analyzed. Exposure to alcohol also increased STAT6 phosphorylation in response to IL-13 and lipopolysaccharide. CONCLUSIONS Data from multiple cell types in the pulmonary system suggest that IL-13 and its receptors play a role in alcohol-mediated activation of pro-fibrotic pathways. Taken together, these data suggest that alcohol primes the airway for increased IL-13 signaling and subsequent tissue remodeling upon injury such as transplantation.

Background Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infection (LRI) and is a risk factor for the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Currently, the most widely used therapy for RSV is inhaled ribavirin. However, this therapy is costly and cumbersome. We investigated the utility of using oral ribavirin for the treatment of RSV infection after LTx. Methods RSV was identified in nasopharyngeal swabs (NPS) or bronchoalveolar lavage (BAL) using direct fluorescent antibody (DFA) in 5 symptomatic LTx patients diagnosed with LRI. Data were collected from December 2005 and August 2007 and included: age; gender; type of LTx; underlying disease; date of RSV; pulmonary function prior to, during and up to 565 days post-RSV infection; need for mechanical ventilation; concurrent infections; and radiographic features. Patients received oral ribavirin for 10 days with solumedrol (10 to 15 mg/kg/day intravenously) for 3 days, until repeat NPS were negative. Results Five patients had their RSV–LRI diagnosis made at a median of 300 days post-LTx. Mean forced expiratory volume in 1 second (FEV 1 ) fell 21% ( p 1 returned to baseline and was maintained at follow-up of 565 days. There were no complications and no deaths with oral therapy. A 10-day course of oral ribavirin cost $700 compared with $14,000 for nebulized ribavirin at 6 g/day. Conclusions Treatment of RSV after LTx with oral ribavirin and corticosteroids is well tolerated, effective and less costly than inhaled ribavirin. Further studies are needed to directly compare the long-term efficacy of oral vs nebulized therapy for RSV.

Vibration perception threshold (VPT) is increasingly used as a measure of large nerve fibre function in studies of patients with diabetes and in other disorders. In order to establish the influence of age, height, sex, and smoking on VPT values in the normal population and to allow the calculation of accurate age-related percentile charts, 1365 healthy volunteers were studied using a biothesiometer. Measurements were made bilaterally on thumbs, great toes, and over medial malleoli. Multivariate regression analysis confirmed age to be the major determinant of VPT levels at all sites (p less than 0.001). Height was a significant factor for toes and ankles (p less than 0.001) but not thumbs. Sex had no overall effect at toe or thumb but there were differences regarding ankle VPT (p less than 0.01). Log transformation of VPT data produced a linear relationship with age at all sites except at the thumbs in elderly females where there was significant deviation from this model (p less than 0.001) and inverse square root transformation was more appropriate. Smoking had no effect on VPT levels. Age-related centile charts were produced for each site and an easy-to-use computer program was developed to calculate centile values based on raw VPT data, age, height, and sex.

Representative molecules from 10 classes of prohibited substances were taken from the World Anti-Doping Agency (WADA) list, augmented by molecules from corresponding activity classes found in the MDDR database. Together with some explicitly allowed compounds, these formed a set of 5245 molecules. Five types of fingerprints were calculated for these substances. The random forest classification method was used to predict membership of each prohibited class on the basis of each type of fingerprint, using 5-fold cross-validation. We also used a k-nearest neighbors (kNN) approach, which worked well for the smallest values of k. The most successful classifiers are based on Unity 2D fingerprints and give very similar Matthews correlation coefficients of 0.836 (kNN) and 0.829 (random forest). The kNN classifiers tend to give a higher recall of positives at the expense of lower precision. A naïve Bayesian classifier, however, lies much further toward the extreme of high recall and low precision. Our results suggest that it will be possible to produce a reliable and quantitative assignment of membership or otherwise of each class of prohibited substances. This should aid the fight against the use of bioactive novel compounds as doping agents, while also protecting athletes against unjust disqualification.

Pediatric rhabdomyosarcoma is not exclusive to the head and neck. However, the unique anatomy of the head and neck requires special consideration and treatment modifications. The low incidence of these tumors has prevented the development of rigorous treatment protocols. Treatment strategies must be individualized on the basis of histopathologic subtype, prognostic indicators, tumor location, tumor extent, available clinical trial data, and hospital resources. The primary treatment of these tumors typically involves a combination of surgery, radiation, and chemotherapy. Advancements in surgical and radiotherapy techniques have reduced patient morbidity, whereas new chemotherapeutic protocols have improved local disease control and overall survival. Because of the infrequency and complexity of these tumors, patients may benefit from referral to centers with a comprehensive multidisciplinary team that has experience treating these tumors in the pediatric population. If possible, patients should be enrolled and treated on the current Children's Oncology Group protocol.

Blunt trauma causing a retropharyngeal hematoma without an associated cervical fracture is a relatively rare occurrence. This article presents the case of a patient with airway compromise from a retropharyngeal hematoma, and discusses the diagnosis, airway management, and treatment of this condition.

This is a clinical report of a young girl who presented with a large left lung mass, which was found to be alveolar rhabdomyosarcoma, a rare clinical entity. This was successfully treated with surgery, radiation, and chemotherapy. To our knowledge, this is the longest survivor with this disease.

Pulmonary carcinosarcoma is a rare malignancy, comprising less than 0.3% of all malignant neoplasms of the lung. Since the first report of this tumor by Kika in 1908, approximately 100 cases have been described in the literature. In this report, we present five cases treated by our group over a period of 20 years.

Pulmonary arteriovenous malformation (AVM) is a congenital condition, but because the symptoms usually do not occur until middle age, the diagnosis is often delayed. The authors report on a neonate, diagnosed at 2 weeks of age, who was treated by lobectomy at 35 months of age. This prompted a review of the diagnosis, pathophysiology, and treatment of pulmonary AVM. In the literature there are approximately 500 cases of pulmonary AVM. Special attention is given to the reports involving children. Eight cases have been reported in which the diagnosis was made in the first year of life. In two series, a chest roentgenogram showed abnormalities in all affected patients. Because of the strong association of pulmonary AVM with hereditary telangiectasia (Rendu-Osler-Weber syndrome), it is recommended that family members of affected patients be screened by chest roentgenograms for pulmonary AVM.