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The document titled "Zolbetuximab in Gastric or Gastroesophageal Junction Adenocarcinoma" presents the findings of two phase 3 trials that investigated the use of zolbetuximab, an IgGl monoclonal antibody, in the treatment of advanced gastric or gastroesophageal junction adenocarcinoma. The results showed that when combined with first-line chemotherapy, zolbetuximab led to significantly longer progression-free survival and overall survival compared to placebo plus chemotherapy. This treatment was particularly effective for patients with HER2-negative tumors that were positive for claudin 18.2. The study provides valuable information for clinicians and researchers in the field of gastric cancer treatment. [Extracted from the article]

Background: Geriatric emergency department (GED) guidelines endorse screening older patients for geriatric syndromes in the ED, but there have been significant barriers to widespread implementation. The majority of screening programs require engagement of a clinician, nurse, or social worker, adding to already significant workloads at a time of record‐breaking ED patient volumes, staff shortages, and hospital boarding crises. Automated, electronic health record (EHR)‐embedded risk stratification approaches may be an alternate solution for extending the reach of the GED mission by directing human actions to a smaller subset of higher risk patients. Methods: We define the concept of automated risk stratification and screening using existing EHR data. We discuss progress made in three potential use cases in the ED: falls, cognitive impairment, and end‐of‐life and palliative care, emphasizing the importance of linking automated screening with systems of healthcare delivery. Results: Research progress and operational deployment vary by use case, ranging from deployed solutions in falls screening to algorithmic validation in cognitive impairment and end‐of‐life care. Conclusions: Automated risk stratification offers a potential solution to one of the most pressing problems in geriatric emergency care: identifying high‐risk populations of older adults most appropriate for specific GED care. Future work is needed to realize the promise of improved care with less provider burden by creating tools suitable for widespread deployment as well as best practices for their implementation and governance. [ABSTRACT FROM AUTHOR]

This editorial comments on the article by Jones et al. in this issue. [ABSTRACT FROM AUTHOR]

Bleach baths are an important adjunct in the management of atopic dermatitis. However, many homes do not have bath tubs. We tried to overcome this by soaking a cotton pajama suit or Indian kurta pajama in dilute bleach solution and then having the child wear it for ten minutes. This is done two to three times a week, as in standard bleach tub baths. We have tried this technique in eleven patients with satisfactory outcomes and no adverse effects. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Rhinoscleroma is an infectious granulomatous disease. It is important to identify pathognomonic Mikulicz cells on microscopy, as these can be rare and the chronic inflammatory infiltrate can appear otherwise nonspecific on biopsies. [ABSTRACT FROM AUTHOR]

The lipid-regulating drug gemfibrozil is a useful medication for reducing high cholesterol and triglycerides in the blood. In addition to oxidation, it undergoes extensive glucuronidation to produce gemfibrozil acyl glucuronide, which is a known mechanism-based inactivator of cytochrome P450 (CYP) 2C8. Such selective and time-dependent inhibition results in clinically important drug–drug interactions (DDI) with the drugs metabolized by CYP2C8. Similarly, the acyl glucuronide of clopidogrel, a widely used antiplatelet agent, is a potent time-dependent inhibitor of CYP2C8 that demonstrated significant DDI with the substrates of CYP2C8. Current progress in atomic-level understanding mostly involves studying how different drugs bind and undergo oxidation in the active site of CYPs. It is not clear how an acyl glucuronide metabolite of the drug gemfibrozil or clopidogrel interacts in the active site of CYP2C8 and selectively inhibit the enzyme. This mini-review summarizes the current knowledge on some of the important clinical DDI caused by gemfibrozil and clopidogrel due to the inhibition of CYP2C8 by acyl glucuronide metabolites of these drugs. Importantly, it examines recent developments and potential applications of structural biology tools to elucidate the binding and orientation of gemfibrozil acyl glucuronide and clopidogrel acyl glucuronide in the active site near heme that contributes to the inhibition and inactivation of CYP2C8. [ABSTRACT FROM AUTHOR]

Background: The femoral component is generally aligned perpendicularly to the distal femoral intramedullary axis with conventional instruments. Various aids like computer navigation, patient-specific instrumentation and robotic surgery use the mechanical axis as the reference for the femoral component alignment. We studied the flexion of the distal femoral intramedullary axis compared to the mechanical axis using an interactive 3D tool in 407 Indian osteoarthritic knees undergoing total knee replacement to better understand optimal flexion alignment. Materials and Methods: 407 knees (301-Female, 106-Male) in Indian patients undergoing total knee replacement underwent CT scans. A 3D interactive knee system was used for 3D reconstruction and planning. Distal femoral flexion angle (DFFA) was calculated between the anatomic distal femoral (intramedullary) axis and the mechanical axis. Statistical analysis was performed using ANOVA test and Chi-square test using a data analysis tool pack (Analysis ToolPak by Excel Easy) additionally installed in Microsoft Excel 2010. Results: The mean DFFA was found to be 2.54 with a standard deviation of 1.38. The maximum and minimum values noted were 7.5 and 0.5 respectively. There was no correlation found between sex, age, height or weight (p > 0.05). Conclusions: While taking the distal femur cut with systems other than an intramedullary rod, in Indian osteoarthritic knees, it would be safer to take the distal femoral cut between 2 and 3 degrees of flexion to mechanical axis, as it would ensure that the cut is within 3 degrees from the anatomic axis for 98% patients. Most surgeons routinely using navigation or similar aids take the cut at 0 degrees of flexion to the mechanical axis. This will lead to more than 3 degrees of extension with reference to the intramedullary axis in more than 39% patients. This would result in either an increase in femoral component sizing or an increased risk of notching. [ABSTRACT FROM AUTHOR]

This is a joint policy statement from the American Academy of Pediatrics, American College of Emergency Physicians, Emergency Nurses Association, National Association of Emergency Medical Services Physicians, and National Association of Emergency Medical Technicians on pediatric readiness in emergency medical services systems. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to characterize language comprehension in mild traumatic brain injury (mTBI) by testing a speed-based hypothesis. We hypothesized that adults with mTBI would perform worse than a group of adults with orthopedic injuries (OIs) on an experimental language comprehension task. Method: The study employed a prospective experimental design. Participants were 19 adults with mTBI and 19 adults with OI ages 18–55 years. Participants completed the Whatdunit task, a sentence agent selection task in speeded and unspeeded conditions. Results: In the unspeeded condition, the mTBI group performed with a marginally significant higher accuracy than the OI group. In the speeded condition, the mTBI group performed with lower accuracy than the OI group; however, this difference did not reach statistical significance. There was a marginally significant interaction of Sentence Type × Group for reaction time in the speeded condition. Conclusions: While our task might have been sensitive to cognitive processing abilities in both groups (as evidenced by the main effects of condition and sentence type), the task was not specific enough to capture mTBI-related deficits. The similarities in performance between both groups have clinical implications for the treatment of not just brain-related trauma but also trauma in general. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to characterize cognitive-linguistic performance in adults with mild traumatic brain injury (mTBI) to advance assessment and treatment practices. We hypothesized that individuals with mTBI would demonstrate longer reaction times (RTs) and greater error rates when compared to an orthopedic injury (OI) group on a category-naming task. Method: Participants were age and education-matched adults with mTBI (n = 20; 12 females) and adults with OI (n = 21; 5 females) who were discharged to home after an Emergency Department visit. Our primary task was a category-naming task shown to be sensitive to language deficits after mTBI. The task was adapted and administered under speeded and unspeeded conditions. Results: There was a significant main effect of condition on RT (speeded faster than unspeeded) and accuracy (more errors in the speeded condition). There was a marginally significant effect of group on errors, with more errors in the mTBI group than the OI group. Naming RT and accuracy in both conditions were moderately correlated with injury variables and symptom burden. Conclusions: Our data showed a marginal effect of group on accuracy of performance. Correlations found between naming and neurobehavioural symptoms, including sleep quality, suggest that the latter should be considered in future research. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the accuracy and feasibility of transcutaneous laryngeal ultrasonography as an alternative to videolaryngoscopy for assessing vocal cord mobility to rule out recurrent laryngeal nerve injury following thyroidectomy.Methods: Forty-five adult patients scheduled to undergo elective thyroidectomy under general anesthesia were included. Preoperatively, indirect laryngoscopy and transcutaneous laryngeal ultrasonography was done for assessing vocal cord mobility. Intraoperatively, following induction, patients were intubated using videolaryngoscope. On completion of the surgical procedure, one anesthetist performed videolaryngoscopy so as to record vocal cord mobility while the patients were being extubated in deep plane of anesthesia. Simultaneously another anesthesiologist performed transcutaneous laryngeal ultrasonography.Vocal cord mobility, changes in hemodynamics and total time duration for the two procedures was recorded. Indirect laryngoscopic assessment and flexible fiberoptic laryngoscopy was done on postoperative day 1 and 7 respectively.Results: Postoperative videolaryngoscopy picked up bilaterally mobile vocal cords in 88.8% cases. Transcutaneous laryngeal ultrasonography could correctly identify 39(86.6%) of these patients, with 1(2.5%) patient being misdiagnosed as having bilaterally immobile vocal cords. Further, videolaryngoscopy identified 5 patients of vocal cord palsy, of which transcutaneous laryngeal ultrasonography correctly identified 3 (60%) patients. Hence, in comparison to videolaryngoscopy, the sensitivity, specificity, positive predictive value, and negative predictive value of transcutaneous laryngeal ultrasonography for assessment of vocal cords was 75%, 95.1%, 60%, and 97.5% respectively.Conclusion: In patients undergoing thyroidectomy, transcutaneous laryngeal ultrasonography can serve as a non-invasive, bedside screening tool for assessing vocal cord palsy postoperatively. [ABSTRACT FROM AUTHOR]

Background: Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. Methods: Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. Results: Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68–1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94–2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. Conclusions: Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. Clinical trials registration: NCT01641939 (https://clinicaltrials.gov/ct2/show/NCT01641939). [ABSTRACT FROM AUTHOR]

Study Design: This was a prospective study of 50 patients of thoracolumbar fracture dislocation treated at a single institution with short-segment fixation with the inclusion of fracture level. Purpose: To assess the outcomes of including the fracture level in short-segment fixation for thoracolumbar fracture dislocation. Overview of Literature: Traditionally, thoracolumbar fracture dislocation is treated with long-segment posterior fixation. However, to save motion segments, short-segment fixation has been used instead in many cases of thoracolumbar trauma. Methods: In this study, 50 patients with thoracolumbar fracture dislocation were treated with short-segment fixation with inclusion of the fracture level; patients with pathological fractures or with a McCormack load-sharing score >6 were excluded. The 50 patients were prospectively followed for at least 1 year. The duration of surgery, blood loss, and complications were noted. The Visual Analog Scale (VAS) score was used to measure pain, and the American Spinal Injury Association (ASIA) scale was used to determine the neurological status at follow-up. Preoperative, immediate postoperative, and final follow-up X-rays were used to measure the kyphotic angle using Cobb's method. Results: The mean age of our patients was 33.4 years, and the male:female ratio was 1.9:1. The mean follow-up period was 18.4 months (range, 12-23 months). Injuries were mainly at the thoracolumbar junction area (T11-L2, 41 cases, 82%). The average duration of surgery was 94.6 minutes, and the average blood loss was 394.8 mL. Postoperative infection occurred in two cases and implant failure in one case. The kyphosis angle values were as follows: average preoperative, 26.80°±14.50°; immediate postoperative, 4.30°±8.70°; and final follow-up, 5.50°±110°. The ASIA scale and VAS score at final follow-up showed improvement. Conclusions: Inclusion of the fracture level in short-segment fixation for thoracolumbar fracture dislocation (McCormack load-sharing score ≤6) gives good kyphosis correction and correction maintenance. It can also obviate the need for traditional long-segment fixation. [ABSTRACT FROM AUTHOR]

Objectives: To describe a novel model of care that uses community‐based paramedics to deliver a modified version of the evidence‐based hospital‐to‐home Care Transitions Intervention (CTI) to a new context: the emergency department (ED)‐to‐home transition. Design: Single‐blind randomized controlled trial. Setting: Three EDs in 2 cities. Participants: Through June 2017, 422 individuals discharged home from the EDs who provided consent and were randomized to receive the modified CTI. Intervention: We modified the hospital‐to‐home CTI, applying it to the ED‐to‐home transition and delivering services through community paramedics, allowing the program to benefit from the unique attributes of paramedics to deliver care. Measurements: Through surveys of participants, medical record review, and documentation of activities by CTI coaches, we characterize the participants and program, including feasibility and acceptability. Results: Median age of participants was 70.7, 241 (57.1%) were female, and 385 (91.2%) were white. Coaches successfully completed 354 (83.9%) home visits and 92.7% of planned telephone follow‐up for call 1, 90.9% for call 2, and 85.8% for call 3. We found high levels of acceptability among participants, with most participants (76.2%) and their caregivers (83.1%) reporting themselves likely or extremely likely to choose an ED featuring the CTI program in the future. Coaches reported delivering expected services during contact at least 88% of the time. Conclusion: Although final conclusions about program effectiveness must await the results of the randomized controlled trial, the findings reported here are promising and provide preliminary support for an ED‐to‐home CTI Program's ability to improve outcomes. The coaches' identity as community paramedics is particularly noteworthy, because this is a unique role for this provider type. J Am Geriatr Soc 66:2213–2220, 2018. [ABSTRACT FROM AUTHOR]

Purpose: Temporal lobe epilepsy (TLE) affects resting state brain networks in adults. This study aims to correlate resting state functional MRI (rsMRI) signal latency in pediatric TLE patients with their laterality.Methods: From 2006 to 2016, 26 surgical TLE patients (12 left, 14 right) with a mean age of 10.7 years (range 0.9-18) were prospectively studied. Preoperative rsMRI was obtained in patients with concordant lateralizing structural MRI, EEG, and PET studies. Standard preprocessing techniques and seed-based rsMRI analyses were performed. Additionally, the latency in rsMRI signal between each 6 mm voxel sampled was examined, compared to the global mean signal, and projected onto standard atlas space for individuals and the cohort.Results: All but one of the 26 patients improved seizure frequency postoperatively with a mean follow-up of 2.9 years (range 0-7.7), with 21 patients seizure-free. When grouped for epileptogenic laterality, the latency map qualitatively demonstrated that the right TLE patients had a relatively early signal pattern, whereas the left TLE patients had a relatively late signal pattern compared to the global mean signal in the right temporal lobe. Quantitatively, the two groups had significantly different signal latency clusters in the bilateral temporal lobes (p < 0.001).Conclusion: There are functional MR signal latency changes in medical refractory pediatric TLE patients. Qualitatively, signal latency in the right temporal lobe precedes the mean signal in right TLE patients and is delayed in left TLE patients. With larger confirmatory studies, preoperative rsMRI latency analysis may offer an inexpensive, noninvasive adjunct modality to lateralize pediatric TLE. [ABSTRACT FROM AUTHOR]

The over two dozen CYP2B structures of human, rabbit, and woodrat enzymes solved in the last decade have significantly enhanced our understanding of the structure-function relationships of drug metabolizing enzymes. More recently, an important role has emerged for halogen-π interactions in the CYP2B6 active site in substrate selectivity, explaining in part the preference for halogenated ligands as substrates. The mechanism by which such ligands interact with CYP2B enzymes involves conserved phenylalanine side chains, in particular F108, F115, or F297, in the active site, which form π bonds with halogens. To illustrate such halogen-π interactions using drugs that are major substrates of CYP2B6, we present here a crystal structure of CYP2B6 in complex with an analog of the widely used anti-HIV drug efavirenz, which contains a methyl group in place of the carbonyl oxygen. The chlorine of the efavirenz analog forms a π bond with the aromatic ring of F108, whereas the putative metabolism site on the distal end of the molecule is oriented towards the heme iron. The crystal structure showcases how CYP2B6 accommodates this important drug analog of considerable size in the active site by movement of various side chains without substantially increasing the active site volume. Furthermore, the CYP2B6-efavirenz analog complex provides a useful platform to investigate computationally as well as biophysically the effect of genetic polymorphisms on binding of the widely studied efavirenz. [ABSTRACT FROM AUTHOR]

Background: There is global variation in the ability of hospital-based emergency centres to provide paediatric emergency medicine (PEM) services. Although minimum standards have been proposed, they may not be applicable in resource-limited settings. Objective:The goal was to identify reasonable minimum standards to provide safe and effective care for acutely ill children in resource-limited settings. Methods: Using previously proposed standards from the International Federation of Emergency Medicine (IFEM), a modified Delphi approach was used to reach agreement regarding minimum standards for PEM in resource-limited settings. Three rounds of surveys were electronically distributed to physicians working in resource-limited settings. Those standards with >67% agreement advanced to the subsequent round. Results: The categories of the surviving criteria included integrated service design, child and family-friendly care, initial assessment of the ill child, stabilising and treating an ill child, staff training and competence, equipment, supplies and medications, quality and safety, child protection, and advanced training and academic research. Conclusions: Experts with experience in acute care of children in resource-limited settings have prioritised standards for paediatric emergency care. They identified 26 variables in nine domains from the original IFEM list of standards and two additional free text standards for the care of acutely ill children. This list may serve as a helpful guide for emergency centres to provide medical treatment for acutely ill children in resource-limited settings. [ABSTRACT FROM AUTHOR]

Background: Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction).Methods: This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939.Findings: Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1-23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2-18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7-9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1-11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87-1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group.Interpretation: Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited.Funding: F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Introduction: There is paucity of literature about antibiotic uptake in bone grafts soaked in antibiotic solutions at room temperature in the operation theatre. We hypothesized that if bone grafts are dipped in different strengths of antibiotic solutions for sufficient period, their utilization at the target site helps in localized release of antibiotics in adequate inhibitory concentration to achieve the bacterial regression. The purpose of the study was to find out: (1) Optimum duration, strength, and volume of antibiotic solution required for dipping bone grafts at room temperature prior to the use. (2) What could be the clinical implications of the results obtained? Materials and Methods: Bone shavings from total knee replacements were processed, frozen and transported to bio-analytical laboratory. The bone fragments were then impregnated with different volume and different strength of gentamicin and vancomycin over different time periods. The soaked bone samples underwent further processing for analysis on liquid chromatography tandem mass spectrometry (LC-MS/MS) system. Results: After series of bio-analytical estimation for the soaked drug concentration among bone fragments; the optimal estimation was found with 0.2 mL of 2% strength of gentamicin and vancomycin, the optimal time was found with soakage up to 30 min. These estimated values of soaked antibiotics were five 5 times higher than required minimal inhibitory concentration (MIC) values for bacterial regression. Conclusion: Use of antibiotic soaked bone allografts at target sites as potential drug carrier can be a hassle- free yet cost- effective and safe process for achieving maximum bacterial regression. [ABSTRACT FROM AUTHOR]

Multiple crystal structures of CYP2B4 have demonstrated the binding of the detergent 5-cyclohexyl-1-pentyl-β-D-maltoside (CYMAL-5) in a peripheral pocket located adjacent to the active site. To explore the consequences of detergent binding, X-ray crystal structures of the peripheral pocket mutant CYP2B4 F202W were solved in the presence of hexaethylene glycol monooctyl ether (C 8 E 6 ) and CYMAL-5. The structure in the presence of CYMAL-5 illustrated a closed conformation indistinguishable from the previously solved wild-type. In contrast, the F202W structure in the presence of C 8 E 6 revealed a detergent molecule that coordinated the heme-iron and extended to the protein surface through the substrate access channel 2 f . Despite the overall structural similarity of these detergent complexes, remarkable differences were observed in the A, A′, and H helices, the F-G cassette, the C-D and β 4 loop region. Hydrogen-deuterium exchange mass spectrometry (DXMS) was employed to probe these differences and to test the effect of detergents in solution. The presence of either detergent increased the H/D exchange rate across the plastic regions, and the results obtained by DXMS in solution were consistent in general with the relevant structural snapshots. The study provides insight into effect of detergent binding and the interpretation of associated conformational dynamics of CYP2B4. [ABSTRACT FROM AUTHOR]

Using a combined structural and biochemical approach, the functional importance of a recently described peripheral pocket bounded by the E-, F-, G-, and I-helices in CYP2B4 and 2B6 was probed. Three series of 4-substituted-7-alkoxycoumarin derivatives with -H, -CH3, or -CF3 at the 4 position of the coumarin core were used initially to monitor functional differences between CYP2B4 and 2B6. 7-Ethoxy-4-(trifluoromethyl)coumarin (7-EFC) displayed the highest catalytic efficiency among these substrates. Mutants were made to alter side-chain polarity (V/E194Q) or bulk (F/Y244W) to alter access to the peripheral pocket. Modest increases in catalytic efficiency of 7-EFC O-deethylation by the mutants were magnified considerably by chlorination or bromination of the substrate ethoxy chain. A structure of CYP2B6 Y244W in complex with (+)-α-pinene was solved at 2.2 Å and showed no CYMAL-5 in the peripheral pocket. A ligand free structure of CYP2B4 F244W was solved at 3.0 Å with CYMAL-5 in the peripheral pocket. In both instances, comparison of the respective wild-type and mutant CYP2B enzymes revealed that CYMAL-5 occupancy of the peripheral pocket had little effect on the topology of active site residue side-chains, despite the fact that the peripheral pocket and active site are located on opposite sides of the I-helix. Analysis of available CYP2B structures suggest that the effect of the amino acid substitutions within the peripheral pocket derive from altered interactions between the F and G helices. [ABSTRACT FROM AUTHOR]

Background: The failure to provide timely acute illness care can lead to adverse consequences or emergency department (ED) use. We evaluated the effect on ED use of a high-intensity telemedicine program that provides acute illness care for senior living community (SLC) residents. Materials and Methods: We performed a prospective cohort study over 3.5 years. Six SLCs cared for by a primary care geriatrics practice were intervention facilities, with the remaining 16 being controls. Consenting patients at intervention facilities could access telemedicine for acute illness care. Patients were provided patient-to-provider, real-time, or store-and-forward high-intensity telemedicine (i.e., technician-assisted with resources beyond simple videoconferencing) to diagnose and treat acute illnesses. The primary outcome was the rate of ED use. Results: We enrolled 494 of 705 (70.1%) subjects/proxies in the intervention group; 1,058 subjects served as controls. Control and intervention subjects visited the ED 2,238 and 725 times, respectively, with 47.3% of control and 43.4% of intervention group visits resulting in discharge home. Among intervention subjects, ED use decreased at an annualized rate of 18% (rate ratio [RR]=0.82; 95% confidence interval [CI], 0.70-0.95), whereas in the control group there was no statistically significant change in ED use (RR=1.01; 95% CI, 0.95-1.07; p =0.009 for group-by-time interaction). Primary care use and mortality were not significantly different. Conclusions: High-intensity telemedicine significantly reduced ED use among SLC residents without increasing other utilization or mortality. This alternative to traditional acute illness care can enhance access to acute illness care and should be integrated into population health programs. [ABSTRACT FROM AUTHOR]

The novel 4-(4,5-dimethoxy-2-nitrophenyl)-2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine was synthesized through multicomponent one pot Hantzsch ester synthesis using 4,5-dimethoxy-2-nitrobenzaldehyde, ethyl 3-oxobutanoate, and ammonium carbonate under microwave irradiation and subsequently characterized by several spectroscopic techniques, i.e., ESI mass, IR,1H, and13C NMR along with single crystal X-ray diffraction method. The single crystal of 4-(4,5-dimethoxy-2-nitrophenyl)-2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine (C21H26N2O8) was developed in 0.35 × 0.30 × 0.25 mm dimension in methanol. The crystal structure parades only intermolecular hydrogen bonding of the N(2)-H(2A) … O(2) type and the boat conformation of the dihydropyridine ring. [ABSTRACT FROM PUBLISHER]

Background Emergency department (ED) visits for ambulatory care sensitive conditions (ACSCs) are common among older adults. The high-intensity telemedicine model of care has been proposed as an innovative approach to expand access to acute illness care, thereby preventing ED visits. The aim of this study was to assess the effect of a high-intensity telemedicine program for senior living community (SLC) residents on the rate of ED use for ACSCs. Methods We performed a prospective cohort study at a primary care geriatrics practice that provides care to 22 SLCs. Six SLCs selected as intervention facilities, with the remaining SLCs serving as controls. Consenting practice patients at intervention facilities could have patient-to-provider, real-time, or store-and-forward high-intensity telemedicine services to diagnose and treat illnesses. The primary outcome was the rate of ED visits for which the primary diagnosis was an “ambulatory-care-sensitive” condition by the Institute of Medicine, which we compared between control and intervention participants. Results During the study period, control participants had 310 ED visits for ACSCs, for a rate of 0.195 visits/person-year. Intervention participants visited the ED for ACSCs 85 times, for a rate of 0.138 visits/person-year [unadjusted rate ratio (RR): 0.71, 95% confidence interval (CI): 0.53–0.94]. Among intervention participants, ED use for ACSCs decreased at an annual rate of 34% (RR: 0.661, 95% CI: 0.444–0.982), whereas, in the control group there was no statistically significant change in ED use over time (RR: 1.01, 95% CI: 0.90–1.14). Conclusions Providing acute illness care by high-intensity telemedicine to older adults residing in SLCs significantly decreases the rate of ED use for ACSCs over 1 year, compared with no change in the rate of ED use for ACSCs among the control group. [ABSTRACT FROM AUTHOR]

Due to globalization, dermatologists routinely see patients of different ethnicities and skin tones. Surveys from the US have shown that dermatologists felt that their training was lacking in diagnosing dermatoses in skin‐of‐color patients. Underrepresentation of skin of color in dermatology textbooks has been reported. We evaluated clinical images in selected pediatric dermatology textbooks with regard to skin color. [ABSTRACT FROM AUTHOR]

Background: To identify prognostic factors in patients with parotid gland carcinomas who were treated at the Princess Margaret Hospital. Methods: Clinical outcome of two hundred fifteen patients with malignancies of the parotid gland was evaluated over a 16-year period. Results: Two-hundred-fifteen patients with adenoid cystic carcinoma (n = 20), adenocarcinoma (n = 19), acinic cell carcinoma (n = 62), basal cell adenocarcinoma (n = 7), carcinoma-ex-pleomorphic adenoma (n = 18), mucoepidermoid carcinoma (n = 70) and salivary duct carcinoma (n = 19) have been included. The 5- and 10-year overall and disease-free survivals were 80.62 %/69.48 % and 74.37 %/62.42 %, respectively. Multivariable analysis showed that age greater than 60 years, advanced pN classification, histopathological grade and the presence of lymphovascular invasion significantly worsened overall and disease-free survival. Univariable analysis revealed periparotid lymph node involvement was associated with decreased overall (p < 0.0001) and disease-free survival (p < 0.0001). Conclusions: In addition to age, pN classification, histopathological grade, perineural invasion, and lymphovascular involvement, periparotid lymph node metastasis appears to be an important prognosticator in parotid gland malignancy. [ABSTRACT FROM AUTHOR]

A series of Co(II) complexes 3'a-g of 2-(2-chloro-6,7-substituted quinolin-3-yl)-1Hbenzo[ d]imidazole ligands 3a-g were prepared and characterized by various spectroscopic and physicochemical methods viz. FT-IR, ESI mass, ¹H NMR, 13C NMR and UV-Visible spectroscopy, Thermogravimetric analysis, Magnetic susceptibility, Molar conductance and Elemental analysis. The 2-(2- chloro-6,7-substituted quinolin-3-yl)-1H-benzo[d]imidazole ligands 3a-g have been synthesized by cyclocondensation of benzene-1,2-diamine with 2-chloroquinoline-3-carbaldehydes by using ceric ammonium nitrate as a catalyst in presence of hydrogen peroxide as an oxidant. The structures of all ligands were confirmed by IR, Mass, UV-Visible, ¹H NMR and 13C NMR spectroscopy. All ligands 3a-g and their Co(II) complexes 3'a-g were screened for their in vitro antimicrobial activity using twofold serial dilution technique against standard MTCC strains of two Gram-positive Staphylococcus aureus and Streptococcus pyogenes, two Gram-negative Escherichia coli and Pseudomonas aeruginosa bacteria and three Candida albicans, Aspergillus niger and Aspergillus clavatus fungus in comparison with standard drugs. All ligands 3a-g and complexes 3'a-g also evaluated for antimycobacterial activity against standard Mycobacterium tuberculosis H37Rv strain. [ABSTRACT FROM AUTHOR]

The use of oral and topical beta blockers has revolutionized the management of infantile hemangiomas. Oral propranolol at 2 mg/kg/d in divided doses not only prevents further proliferation, but actually shrinks IH. Propranolol should be administered for at least 6 months or until the baby reaches one year of age. Side effects to be watched out for include hypoglycaemia, bradycardia and hypotension. Oral propranolol should be prescribed only in those IH where clearly indicated. More cardioselective beta blockers like atenolol are also being explored for treating IH. Topical timolol has been prescribed for smaller and superficial IH or when propranolol is contraindicated. [ABSTRACT FROM AUTHOR]

Already crowded and stressful, US emergency departments (EDs) are facing the challenge of serving an aging population that requires complex and lengthy evaluations. Creative solutions are necessary to improve the value and ensure the quality of emergency care delivered to older adults while more fully addressing their complex underlying physical, social, cognitive, and situational needs. Developing models of geriatric emergency care, including some that are already in use at dedicated geriatric EDs, incorporate a variety of physical, procedural, and staffing changes. Among the options for "geriatricizing" emergency care are approaches that may eliminate the need for an ED visit, such as telemedicine; for initial hospitalization, such as patient observation units; and for rehospitalization, such as comprehensive discharge planning. By transforming their current safety-net role to becoming a partner in care coordination, EDs have the opportunity to become better integrated into the broader health care system, improve patient health outcomes, contribute to optimizing the health care system, and reduce overall costs of care-keys to improving emergency care for patients of all ages. [ABSTRACT FROM AUTHOR]

Simple Summary: Ramucirumab is indicated at a dosage of 8 mg/kg every 2 weeks as monotherapy or in combination with paclitaxel for second-line advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. A post hoc analysis of the phase III trials REGARD and RAINBOW suggested a positive correlation between ramucirumab exposure and efficacy. Studies JVDB and JVCZ explored different ramucirumab dosing regimens as monotherapy and in combination with paclitaxel, respectively. Here we report results from these studies, in which JVDB evaluated the pharmacokinetics and safety of the currently registered dosing regimen for ramucirumab monotherapy and three exploratory dosing regimens, and JVCZ evaluated the efficacy and safety of a higher dosing regimen of ramucirumab in combination with paclitaxel in second-line gastric/GEJ adenocarcinoma. Overall, the safety profiles were similar between the registered dose and the exploratory dosing regimens. However, a lack of a dose/exposure-response relationship supports the standard dose of ramucirumab as second-line treatment for patients with advanced/metastatic gastric/GEJ adenocarcinoma. Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. For JVDB, randomized patients (N = 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks (Q2W) (registered dose), 12 mg/kg Q2W, 6 mg/kg weekly (QW), or 8 mg/kg on days 1 and 8 (D1D8) every 3 weeks (Q3W). The primary objectives were the safety and pharmacokinetics of ramucirumab monotherapy. For JVCZ, randomized patients (N = 245) received paclitaxel (80 mg/m2-D1D8D15) plus ramucirumab (8 mg/kg- or 12 mg/kg-Q2W). The primary objective was progression-free survival (PFS) of 12 mg/kg-Q2W arm versus placebo from RAINBOW using meta-analysis. Relative to the registered dose, exploratory dosing regimens (EDRs) led to higher ramucirumab serum concentrations in both studies. EDR safety profiles were consistent with previous studies. In JVDB, serious adverse events occurred more frequently in the 8 mg/kg-D1D8-Q3W arm versus the registered dose; 6 mg/kg-QW EDR had a higher incidence of bleeding/hemorrhage. In JVCZ, PFS was improved with the 12 mg/kg plus paclitaxel combination versus placebo in RAINBOW; however, no significant PFS improvement was observed between the 12 mg/kg and 8 mg/kg arms. The lack of a dose/exposure-response relationship in these studies supports the standard dose of ramucirumab 8 mg/kg-Q2W as monotherapy or in combination with paclitaxel as second-line treatment for advanced/metastatic gastric/GEJ adenocarcinoma. [ABSTRACT FROM AUTHOR]

Accessing timely acute medical care is a challenge for older adults. This article describes an innovative healthcare model that uses high-intensity telemedicine services to provide rapid acute care for older adults without requiring them to leave their senior living community ( SLC) residences. This program, based in a primary care geriatrics practice that cares for SLC residents, is designed to offer acute care through telemedicine for complaints that are felt to need attention before the next available outpatient visit but not to require emergency department ( ED) resources. This option gives residents access to care in their residence. Measures used to evaluate the program include successful completion of telemedicine visits, satisfaction of residents and caregivers with telemedicine care, and site of care that would have been recommended had telemedicine been unavailable. During the first 2 years of the program's operation, 281 of 301 requested telemedicine visits were completed successfully. Twelve residents were sent to an ED for care after the telemedicine visit. Ninety-four percent of residents reported being satisfied or very satisfied with telemedicine care. Had telemedicine not been available, residents would have been sent to an ED (48.1%) or urgent care center (27.0%) or been scheduled for an outpatient visit (24.4%). The project demonstrated that high-intensity telemedicine services for acute illnesses are feasible and acceptable and can provide definitive care without requiring ED or urgent care use. Continuation of the program will require evaluation demonstrating equal or better resident-level outcomes and the development of sustainable business models. [ABSTRACT FROM AUTHOR]

Despite recent advances in atomic-level understanding of drug and inhibitor interactions with human cytochromes P450, the decades-old questions of chemical and structural determinants of hydrocarbon binding are still unanswered. (+)-α-Pinene is a monoterpene hydrocarbon that is widely distributed in the environment and a potent P450 2B inhibitor. Therefore, a combined biophysical and structural analysis of human P450 2B6 interactions with (+)-α-pinene was undertaken to elucidate the basis of the very high affinity binding. Binding of (+)-α-pinene to the P450 active site was demonstrated by a Type I spectral shift. Thermodynamics of ligand binding were explored using isothermal titration calorimetry and compared to those of P450 2A6, which is much less flexible than 2B6 based on comparison of multiple X-ray crystal structures. Consistent with expectation, entropy is the major driving force for hydrocarbon binding to P450 2A6, as evidenced by the calorimetric results. However, formation of the 2B6-(+)-α-pinene complex has a significant enthalpic component. A 2.0 Å resolution crystal structure of this enzyme–ligand complex reveals that the highly plastic 2B6 utilizes previously unrecognized rearrangements of protein motifs. The results indicate that the specific components of enthalpic contribution to ligand binding are closely tied to the degree of enzyme flexibility. [ABSTRACT FROM AUTHOR]

A novel three-component one-pot synthesis of 4-(4,5-dimethoxy-2-nitrophenyl)-2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine from methyl 3-oxobutanoate, ammonium carbonate, and 4,5-dimethoxy-2-nitrobenzaldehyde has been carried out by typical Hantzsch synthesis. The single crystal was obtained by crystallization from methanol in 0.30 × 0.20 × 0.20 mm dimensional of 4-(4,5-dimethoxy-2-nitrophenyl)-2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine (C19H22N2O8), which was investigated by X-ray diffraction. The compound crystallizes in the monoclinic P21/c space group with unit cell dimensions a = 14.4830(3) Å, b = 8.66000(10) Å, c = 15.1036(3) Å, α = 90°, β = 90.0870(10)°, γ = 90°.1H NMR (hydrogen-1 nuclear magnetic resonance), mass, and IR (infrared) spectroscopic methods of the compound are also described. [ABSTRACT FROM PUBLISHER]

Objectives To document the experiences of patients, their caregivers, healthcare personnel, and staff members with a program that provides telemedicine-enhanced emergency care to older adults residing in senior living communities ( SLCs) and to delineate perceived barriers and facilitators. Design Qualitative study. Setting A primary care geriatric medicine practice. Participants Stakeholders associated with telemedicine visits: patients, family caregivers, telemedicine dispatcher, certified telemedicine assistants, telemedicine providers, and SLC staff. Measurements Between June and August 2011, telemedicine encounters were observed, and field notes were recorded. After each telemedicine visit, all participants were interviewed using a semistructured guide. Discrete statements from interviews and field notes were coded and arranged into themes. Concordance or discordance in field notes and stakeholder responses were grouped for analysis. Results After 10 telemedicine visits and 34 interviews from 21 unique participants, redundancy was achieved. Participants and their families overwhelmingly reported satisfaction with their care, remarking particularly on the convenience, speed, and completeness of the evaluation. Participants reported some unmet expectations regarding provider presence at home and visit length. Providers thought telemedicine made them more efficient overall and improved diagnostic certainty but considered in-person visits to be superior. All stakeholders, including patients, noted inadequate telemedicine technician training, leading to low confidence levels and performance difficulties. Participants, providers, and telemedicine technicians cited problems with the reliability, weight, and size of the equipment as serious challenges, decreasing their satisfaction and increasing their frustration. Conclusion Telemedicine-enhanced emergency care is an acceptable method of providing emergency care to older adults in SLCs. Stakeholders report a number of advantages. Training and technology barriers require particular attention. [ABSTRACT FROM AUTHOR]

Purpose: The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. Patients and Methods: Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ≥25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity. Results: From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25–88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9–7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with foretinib treatment. Conclusion: These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer. Trial Registration: ClinicalTrials.gov NCT00725712 [ABSTRACT FROM AUTHOR]

Abstract: Prior X-ray crystal structures of cytochrome P450 2B4 revealed the pivotal role of rearrangement of the side chains of residues F206 and F297 in the active site in accommodating various inhibitors or substrates. To explore the role of these residues, 2B4 F206A and F297A were created by site-directed mutagenesis and characterized functionally. The structure of F297A with clopidogrel demonstrated the reorientation of the ligand such that the methyl ester group is oriented toward the heme, whereas the thiophene moiety now extends to the additional void in the F297A mutant. Most interestingly, movement of the I helix and several amino acid side chains within the active site was observed in apparent response to the altered binding orientation. Results of flexible docking using the 2B4 wild type or the F297A-virtual mutant positioned either the thiophene or chlorophenyl group closer to heme. However, docking of clopidogrel using the real F297A mutant or a virtual mutant with the I-helix re-positioned oriented clopidogrel preferentially with either the methyl ester or the chlorophenyl group closest to heme. The study provides insight into how the altered active site adapts to accommodate and interact with the substrate in a distinct orientation while maintaining the overall closed protein conformation. [Copyright &y& Elsevier]

Structures of human cytochrome P450 2B6 and rabbit cytochrome P450 2B4 in complex with two molecules of the calcium channel blocker amlodipine have been determined by X-ray crystallography. The presence of two drug molecules suggests clear substrate access channels in each P450. According to a previously established nomenclature, amlodipine molecules were trapped in access pathway 2f in P450 2B6 and in pathway 2a or 2f in P450 2B4. These pathways overlap for part of the length and then diverge as they extend toward the protein surface. A previously described solvent channel was also found in each enzyme. The results indicate that key residues located on the surface and at the entrance of the substrate access channels in each of these P450s may play a crucial role in guiding substrate entry. In addition, the region of P450 2E6 and 204 involving helices B', F, F', and G' and part of helix G is substantially more open in the amlodipine complexes than in the corresponding 4-(4-chlorophenyl)imidazole complexes. The increased active site volume observed results from the major retraction of helices F, F', and B' and the β4 sheet region located close to the binding cavity to accommodate amlodipine. These structures demonstrate novel insight into distinct conformational states not observed with previous P450 2B structures and provide clear evidence of the substrate access channels in two drug-metabolizing P450s. In addition, the structures exhibit the versatility that can be exploited via in silico studieswith other P450 2B6 ligands as large as raloxifene and itraconazole. [ABSTRACT FROM AUTHOR]

Despite caring for large numbers of older adults, prehospital emergency medical services ( EMS) providers receive minimal geriatrics-specific training while obtaining their certification. Studies have shown that they desire further training to improve their comfort level and knowledge in caring for older adults, but continuing education programs to address these needs must account for each EMS provider's specific needs, consider each provider's learning styles, and provide an engaging, interactive experience. A novel, Internet-based, video podcast-based geriatric continuing education program was developed and implemented for EMS providers, and their perceived value of the program was evaluated. They found this resource to be highly valuable and were strongly supportive of the modality and the specific training provided. Some reported technical challenges and the inability to engage in a discussion to clarify topics as barriers. It was felt that both of these barriers could be addressed through programmatic and technological revisions. This study demonstrates the proof of concept of video podcast training to address deficiencies in EMS education regarding the care of older adults, although further work is needed to demonstrate the educational effect of video podcasts on the knowledge and skills of trainees. [ABSTRACT FROM AUTHOR]

Abstract: Orifice meters are the most common instruments used for fluid flow measurement because of its ruggedness, simple mechanical construction and other known advantages. Orifice coefficients are empirical because of difficulty in accurately predicting the effects of geometrical complicacy and flow separation from the wall on the flow. In the present paper, Computational Fluid Dynamics (CFD) simulation has been used to predict the orifice flow with better accuracy. CFD simulations have been performed using OpenFOAM-1.6 solver and validated with the published experimental data of and . CFD simulations have been validated with pressure drop and energy balance of our experimental data of water as fluid. The outcomes of the CFD simulations in terms of profiles of velocity, pressure, etc. are discussed in detail. A new scheme has been proposed to track vena-contracta with the help of CFD and with a suitable provision in the hardware of orifice meter. The new scheme maintains the existing advantages of orifice meters and provides better accuracy and sensitivity. [Copyright &y& Elsevier]

Objectives To characterize emergency department ( ED) use by nursing home residents in the United States. Design Analysis of the National Hospital Ambulatory Medical Care Survey. Setting U.S. EDs from 2005 to 2008. Participants Individuals visiting U.S. EDs stratified according to nursing home residency. Measurements All ED visits by nursing home residents were identified. The demographic and clinical characteristics and ED resource utilization, length of stay, and outcomes of nursing home residents and nonresidents were compared. Results During 2005 to 2008, nursing home residents accounted for 9,104,735 of 475,077,828 U.S. ED visits (1.9%; 95% confidence interval ( CI) = 1.8-2.1%). The annualized number of ED visits by nursing home residents was 2,276,184. Most nursing home residents were older (mean age 76.7, 95% CI = 75.8-77.5), female (63.3%), and non-Hispanic white (74.8%). Nursing home residents were more likely to have been discharged from the hospital in the prior 7 days (adjusted odds ratio ( aOR = 1.4, 95% CI = 1.1-1.9), to present with fever ( aOR = 1.9, 95% CI = 1.5-2.4) or hypotension (systolic blood pressure ≤90 mmHg, aOR = 1.8, 95% CI = 1.5-2.2), and to receive diagnostic tests ( OR = 1.9, 95% CI = 1.6-2.2), imaging ( OR = 1.5, 95% CI = 1.3-1.7), or procedures ( OR = 1.6, 95% CI = 1.4-1.7) in the ED. Almost half of nursing home residents visiting the ED were admitted to the hospital. Nursing home residents were more likely to be admitted to the hospital ( aOR = 1.8, 95% CI = 1.6-2.0) and to die ( aOR = 2.3, 95% CI = 1.6-3.3). Conclusion Nursing home residents account for more than 2.2 million ED visits annually in the United States. Nursing home residents have greater medical acuity and complexity. These observations highlight the national challenges of organizing and delivering ED care to nursing home residents in the United States. [ABSTRACT FROM AUTHOR]

One of the most intriguing recent discoveries concerning brain function is that intrinsic neuronal activity manifests as spontaneous fluctuations of the blood oxygen level-dependent (BOLD) functional MRI signal. These BOLD fluctuations exhibit temporal synchrony within widely distributed brain regions known as resting-state networks. Resting-state networks are present in the waking state, during sleep, and under general anesthesia, suggesting that spontaneous neuronal activity plays a fundamental role in brain function. Despite its ubiquitous presence, the physiological role of correlated, spontaneous neuronal activity remains poorly understood. One hypothesis is that this activity is critical for the development of synaptic connections and maintenance of synaptic homeostasis. We had a unique opportunity to test this hypothesis in a 5-y-old boy with severe epileptic encephalopathy. The child developed marked neurologic dysfunction in association with a seizure disorder, resulting in a 1-y period of behavioral regression and progressive loss of developmental milestones. His EEG showed a markedly abnormal pattern of high-amplitude, disorganized slow activity with frequent generalized and multifocal epileptiform discharges. Resting-state functional connectivity MRI showed reduced BOLD fluctuations and a pervasive lack of normal connectivity. The child underwent successful corpus callosotomy surgery for treatment of drop seizures. Postoperatively, the patient's behavior returned to baseline, and he resumed development of new skills. The waking EEG revealed a normal background, and functional connectivity MRI demonstrated restoration of functional connectivity architecture. These results provide evidence that intrinsic, coherent neuronal signaling may be essential to the development and maintenance of the brain's functional organization. [ABSTRACT FROM AUTHOR]

Emergency services constitute crucial and frequently used safety nets for older persons, an emergency visit by a senior very often indicates high vulnerability for functional decline and death, and interventions via the emergency system have significant opportunities to change the clinical course of older patients who require its services. However, the evidence base for widespread employment of emergency system-based interventions is lacking. In this article, we review the evidence and offer crucial research questions to capitalize on the opportunity to optimize health trajectories of older persons seeking emergency care in four areas: prehospital care, delirium, adverse drug events, and falls. [ABSTRACT FROM PUBLISHER]

To evaluate older adult emergency department (ED) patients for depression and cognitive impairment and to re-evaluate those findings 2 weeks later. Prospective cohort study. ED. One thousand two hundred six older community-dwelling ED patients consented to participate; 811 (67%) completed the 2-week follow-up. Screening for depression (9-item Patient Health Questionnaire) and cognitive impairment (Six-Item Screener) was performed. Changes were evaluated through paired comparisons. At 2-week follow-up, for depression, 27 of 97 (28%) with baseline positive tests remained positive, and 22 of 706 (3%) with baseline negative tests were positive. At 2-week follow-up, for cognitive impairment, five of 43 (12%) with baseline positive tests remained positive, and 11 of 765 (1%) with baseline negative tests were positive. Significant variability exists for depression and cognitive impairment testing completed during and after the ED visit, with markedly fewer subjects testing positive at follow-up. The variability may reflect changes in clinical state, confounding from other conditions, or poor validity of the instruments in the ED setting. Further studies are needed to explain these findings before case-finding for these conditions is implemented in the ED setting. [ABSTRACT FROM AUTHOR]

Crystal structures of the xenobiotic metabolizing cytochrome P450 2B4 have demonstrated markedly different conformations in the presence of imidazole inhibitors or in the absence of ligand. However, knowledge of the plasticity of the enzyme in solution has remained scant. Thus, hydrogen-deuterium exchange mass spectrometry (DXMS) was utilized to probe the conformations of ligand-free P450 2B4 and the com- plex with 4-(4-chlorophenyl)imidazole (4-CPI) or 1-biphenyl- 4-methyl-1H-imidazole (1-PBI). The results of DXMS indicate that the binding of 4-CPI slowed the hydrogen-deuterium ex- change rate over the B'- and C-helices and portions of the F-G- helix cassette compared with P450 2B4 in the absence of ligands. In contrast, there was little difference between the ligand-free and 1-PBI-bound exchange sets. In addition, DXMS suggests that the ligand-free P450 2B4 is predomi- nantly open in solution. Interestingly, a new high resolution structure of ligand-free P450 2B4 was obtained in a closed conformation very similar to the 4-CPI complex. Molecular dynamics simulations performed with the closed ligand-free structure as the starting point were used to probe the energetically accessible conformations of P450 2B4. The simulations were found to equilibrate to a conformation resembling the 1-PBI-bound P450 2B4 crystal structure. The results indicate that conformational changes observed in available crystal structures of the promiscuous xenobiotic metabolizing cyto chrome P450 2B4 are consistent with its solution structural behavior. [ABSTRACT FROM AUTHOR]

Rural-dwelling older adults experience unique challenges related to accessing medical and social services. This article describes the development, implementation, and experience of a novel, community-based program to identify rural-dwelling older adults with unmet medical and social needs that leveraged the existing emergency medical services (EMS) system. The program specifically included geriatrics training for EMS providers; screening of older adult EMS patients for falls, depression, and medication management strategies by EMS providers; communication of EMS findings to community-based case managers; in-home evaluation by case managers; and referral to community resources for medical and social interventions. Measures used to evaluate the program included patient needs identified by EMS or the in-home assessment, referrals provided to patients, and patient satisfaction. EMS screened 1,231 of 1,444 visits to older patients (85%). Of those receiving specific screens, 45% had fall-related, 69% medication management-related, and 20% depression-related needs identified. One hundred and seventy-one eligible EMS patients who could be contacted accepted the in-home assessment. Of the 153 individuals completing the assessment, 91% had identified needs and received referrals or interventions. This project demonstrated that screening by EMS during emergency care for common geriatric syndromes and linkage to case managers is feasible in this rural community, although many will refuse the services. Further patient evaluations by case managers, with subsequent interventions by existing service providers as required, can facilitate the needed linkages between vulnerable rural-dwelling older adults and needed community-based social and medical services. [ABSTRACT FROM AUTHOR]

Background: The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors. Design: FOLFIRI + flavopiridol were administered every 2 weeks. Based on sequence-dependent inhibition, flavopiridol was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses were determined, one with flavopiridol administered over 1 h, and one with flavopiridol split as a 30-min bolus followed by a 4-h infusion. Results: A total of 74 patients were enrolled and 63 were evaluable. The MTD with FOLFIRI was flavopiridol 80 mg/m over 1 h or 35 mg/m bolus + 35 mg/m over 4 h. Dose-limiting toxicities were diarrhea, fatigue, neutropenia, and neuropathy. Clinical activity included 2 partial responses in small bowel cancer and bladder cancer and 1 complete response in mucosal melanoma. Stable disease was seen in 22 patients. Pharmacokinetic studies showed increasing C with increasing flavopiridol dose. Clinical benefit was correlated with the presence of wild-type p53. Of 25 patients with colorectal cancer, 11 had as best response SD for >3 m (median 6 m, range 4.2-15.4 m), despite failing ≥1 irinotecan-containing regimen. Conclusions: Treatment with flavopiridol and FOLFIRI is a safe and effective regimen. Concentrations of flavopiridol that enhance the effects of FOLFIRI can be achieved. Clinical activity is encouraging and includes prolonged stable disease in patients with irinotecan-refractory colorectal cancer. [ABSTRACT FROM AUTHOR]