Medication therapy management survey of the prescription drug plans.
To evaluate the preliminary development and implementation plans for medication therapy management (MTM) services across plan sponsors for the Medicare Part D Prescription Drug Plans (PDPs) and provide pharmacists with insights for MTM development. Cross-sectional survey. United States. 307 individual contacts from Medicare Advantage or stand-alone PDPs. A survey comprising questions about the PDP demographics, plans and implementation, beneficiary eligibility criteria, scope of services, providers of services, and payment structure for MTM services was e-mailed and mailed in November 2005. Descriptive and bivariate analysis of survey items. A total of 97 usable surveys were completed, a 31.5% response rate. Almost all respondents had a plan in place for MTM services. The majority of PDPs perceived that MTM would have a moderate benefit to their organization. Most PDPs planned to focus efforts on diabetes, heart failure, and other forms of cardiovascular disease. Overwhelmingly, PDPs planned to follow the Centers for Medicare & Medicaid Services (CMS) mandate for criteria regarding beneficiary eligibility. Only 8.2% of respondents planned to use a "traditional" pharmacist, such as a community, long-term care, hospital, or clinic pharmacist. The majority of PDPs (53.6%) planned to employ managed care pharmacists to administer MTM services. Pharmacists are eager to implement MTM services and are looking for PDPs to provide a path of implementation and reimbursement. Many PDPs were planning to deliver MTM services internally using health professional staff, thereby limiting the extent of participation of community, long-term care, hospital and health-system, and clinic-based pharmacists. Further research and advocacy are required to ensure that MTM services accomplish the true intent of the congressional and CMS mandates.


Factors associated with social casino gaming among adolescents across game types.
With the proliferation of social casino games (SCGs) online, which offer the opportunity to gamble without monetary gains and losses, comes a growing concern regarding the effects of these unregulated games on public health, particularly among adolescents. However, given the limited research pertaining to SCG use, little is currently known about the manner in which adolescents engage with this new gambling medium. The present study aims to identify the factors that characterize adolescent social casino gamers, and to determine whether these factors differ by SCG type. Moreover, the study examines the extent to which social casino gaming is associated with monetary gambling and problem gambling in this cohort. Data were obtained from students in Grades 9 to 12 (n = 10,035) residing in the Canadian provinces of Ontario, Saskatchewan, and Newfoundland and Labrador. Participants completed the Youth Gambling Survey (YGS), which is a supplementary instrument administered alongside the Canadian Student Tobacco, Alcohol and Drugs Survey (CSTADS). Logistic regression was used to assess the factors associated with SCG play. Overall, 12.4% of respondents reported having participated in SCGs in the past three months. Compared to adolescents who did not report playing SCGs, SCG players were typically more likely to participate in monetary gambling activities, and were more prevalently classified as problem gamblers of low-to-moderate severity or high severity. Although profiles of SCG players differed across SCG game types, factors significantly associated with the playing of SCGs were gender, weekly spending money, having friends and parents who gamble, and screen time. It was also shown that current smokers were significantly more likely to participate in simulated slots online relative to adolescents who did not play SCGs. Significant associations exist between SCG play, monetary gambling, and problem gambling among adolescents. Gambling intervention efforts directed at this population should aim to identify personal and environmental factors associated with social casino gaming, and should be tailored to different types of SCGs.


An asymmetric solar wind termination shock.
Voyager 2 crossed the solar wind termination shock at 83.7 au in the southern hemisphere, approximately 10 au closer to the Sun than found by Voyager 1 in the north. This asymmetry could indicate an asymmetric pressure from an interstellar magnetic field, from transient-induced shock motion, or from the solar wind dynamic pressure. Here we report that the intensity of 4-5 MeV protons accelerated by the shock near Voyager 2 was three times that observed concurrently by Voyager 1, indicating differences in the shock at the two locations. (Companion papers report on the plasma, magnetic field, plasma-wave and lower energy particle observations at the shock.) Voyager 2 did not find the source of anomalous cosmic rays at the shock, suggesting that the source is elsewhere on the shock or in the heliosheath. The small intensity gradient of Galactic cosmic ray helium indicates that either the gradient is further out in the heliosheath or the local interstellar Galactic cosmic ray intensity is lower than expected.


Maltoheptaose promotes nanoparticle internalization by Escherichia coli.
Nanoparticles conjugated with d-maltoheptaose (G7) showed a striking increase in the internalization by Escherichia coli. This applies to strains with and without the maltodextrin transport channel and particles ranging from a few to a hundred nanometers.


Mxi1-0 regulates the growth of human umbilical vein endothelial cells through extracellular signal-regulated kinase 1/2 (ERK1/2) and interleukin-8 (IL-8)-dependent pathways.
Mxi1 plays an important role in the regulation of cell proliferation. Mxi1-0, a Mxi1 isoform, has a different N-terminal amino acid sequence, intracellular location and expression profile from Mxi1. However, the precise role of Mxi1-0 in cell proliferation and the molecular mechanism underlying its function remain poorly understood. Here, we showed that Mxi1-0 suppression decreased the proliferation of human umbilical vein endothelial cells (HUVECs) along with cell accumulation in the G2/M phase. Mxi1-0 suppression also significantly decreased the expression and secretion of interleukin (IL-8). Neutralizing IL-8 in conditioned medium (CM) from Mxi1-0-overexpressed HUVECs significantly eliminated CM-induced proliferation of HUVECs. In addition, Mxi1-0 suppression significantly decreased the activity of MAP kinase ERK1/2. Treatment of HUVECs with U0126, an ERK1/2 signaling inhibitor, attenuated autocrine production of IL-8 induced by Mxi1-0 overexpression. On the other hand, Mxi1-0 overexpression-induced IL-8 increased the level of phosphorylated ERK1/2 in HUVECs, and such increasing was diminished in cells incubated with CM, which neutralized with anti-IL-8 antibody. Taken together, our results suggest that Mxi1-0 regulates the growth of HUVECs via the IL-8 and ERK1/2 pathways, which apparently reciprocally activate each other.


Protein-Losing Enteropathy as a Complication of the Ketogenic Diet.
The ketogenic diet is an effective treatment for the patients with intractable epilepsy, however, the diet therapy can sometimes be discontinued by complications. Protein-losing enteropathy is a rarely reported serious complication of the ketogenic diet. We present a 16-month-old Down syndrome baby with protein-losing enteropathy during the ketogenic diet as a treatment for West syndrome. He suffered from diarrhea, general edema and hypoalbuminemia which were not controlled by conservative care for over 1 month. Esophagogastroduodenoscopy and stool alpha-1 antitrypsin indicated protein-losing enteropathy. Related symptoms were relieved after cessation of the ketogenic diet. Unexplained hypoalbuminemia combined with edema and diarrhea during ketogenic suggests the possibility of protein-losing enteropathy, and proper evaluation is recommended in order to expeditiously detect it and to act accordingly.


Promoting the conversion of CO2 to CH4via synergistic dual active sites.
Carbon-based single-atom catalysts (SACs) have shown promising applications in the conversion of CO2 into CO. However, the deep reduction process for the production of high-value hydrocarbons is largely limited due to the weak activation of CO. Herein, on the basis of first-principles calculations, a simple coordination regulation method of the active site is proposed to improve the conversion of CO2. Taking NiN4 as an example, by introducing heteroatoms (B, C, O, P, and S atoms), we reveal that NiN3B can effectively capture *CO and further convert to CH4 with an ultralow limiting potential of -0.42 V. The excellent catalytic performance is probably attributed to the formed synergistic dual active sites between non-metal B and metal Ni atoms. Moreover, NiN3B can maintain good stability and the catalytic performance can be further enhanced by increasing the B-doping concentration. This work demonstrates that coordination regulation is an effective strategy to improve the performance of single-atom catalysts and paves a possible way to advance the development of non-Cu-based CO2RR electrocatalysts for high-value hydrocarbon products.


Botulinum toxin A in the treatment of sialorrhea.
To review the efficacy and safety of botulinum toxin A (BTX) in the treatment of sialorrhea. A PubMed search and reference list review was performed to find clinical trials on BTX in the treatment of sialorrhea. The search was limited to English-language trials involving human subjects. Articles from 1965 to October 2006 were searched, using key words botulinum, botulinum toxin, Botox, sialorrhea, saliva, salivary gland, and drooling. Reports of 15 studies were found on BTX in the treatment of sialorrhea in human subjects. Four controlled trials are presented in detail, and 11 uncontrolled studies are summarized. One controlled trial found that BTX caused significant reductions in patients' severity and frequency of drooling compared with placebo. Another found significant saliva reductions in the treatment group receiving the highest dose of BTX but found no subjective improvement compared with the placebo group. A third study comparing BTX with placebo found significant improvements in subjective and objective measures of drooling in the treatment group. A fourth controlled trial found significant reductions from baseline levels of drooling after patients received BTX injections. Similar efficacy was found between the BTX and scopolamine treatment groups. Evidence indicates that BTX is a safe and effective treatment for sialorrhea. More research is needed to determine the ideal dose, injection location, and technique of BTX injections.


Label Distribution Learning by Exploiting Label Distribution Manifold.
Label correlation is helpful to alleviate the overwhelming output space of label distribution learning (LDL). However, existing studies either only consider one of global and local label correlations or exploit label correlation by some prior knowledge (e.g., low-rank assumption, which may not hold sometimes). To efficiently exploit both global and local label correlations in a data-driven way, we propose in this article a new LDL method called label distribution learning by exploiting label distribution manifold (LDL-LDM). Our basic idea is that the underlying manifold structure of label distribution may encode the correlations among labels. LDL-LDM works as follows. First, to exploit global label correlation, we learn the label distribution manifold and encourage the outputs of our model to lie in the same manifold. Second, we learn the label distribution manifold of different clusters of samples to consider local label correlations. Third, to handle incomplete label distribution learning (incomplete LDL), we jointly learn label distribution and label distribution manifold. Theoretical analysis demonstrates the generalization of our method. Finally, experimental results validate the effectiveness of LDL-LDM in both full and incomplete LDL cases.


Chronic alcohol consumption decreases brown adipose tissue mass and disrupts thermoregulation: a possible role for altered retinoid signaling.
Retinoic acid, an active metabolite of dietary vitamin A, acts as a ligand for nuclear receptor transcription factors with more than 500 known target genes. It is becoming increasingly clear that alcohol has a significant impact on cellular retinoic acid metabolism, with resultant effects on its function. Here, we test the hypothesis that chronic alcohol consumption impairs retinoic acid signaling in brown adipose tissue (BAT), leading to impaired BAT function and thermoregulation. All studies were conducted in age-matched, male mice consuming alcohol-containing liquid diets. Alcohol's effect on BAT was assessed by histology, qPCR, HPLC, LC/MS and measures of core body temperature. Our data show that chronic alcohol consumption decreases BAT mass, with a resultant effect on thermoregulation. Follow-up mechanistic studies reveal a decreased triglyceride content in BAT, as well as impaired retinoic acid homeostasis, associated with decreased BAT levels of retinoic acid in alcohol-consuming mice. Our work highlights a hitherto uncharacterized effect of alcohol on BAT function, with possible implications for thermoregulation and energy metabolism in drinkers. Our data indicate that alcohol's effects on brown adipose tissue may be mediated through altered retinoic acid signaling.


An Incidental Myxoma Hidden in Chest Pain.
Chest pain is a very common symptom in an emergency context. Its differential diagnosis is extensive and includes some conditions that require immediate recognition and intervention. It can also be a symptom associated with rarer diagnostic possibilities. Here, we report the case of a 53-year-old woman admitted to the emergency department due to chest pain and initially diagnosed with non-ST elevation acute myocardial infarction. A transthoracic echocardiogram revealed a large hyperechogenic round mass, suggestive of a left atrial cardiac myxoma. Coronary angiography showed no significant lesions. The patient underwent cardiac surgery with excision of the mass, whose histological diagnosis was atrial myxoma. The immediate postoperative period was uneventful, and the patient was discharged asymptomatic and without echocardiographic changes. Cardiac tumors are a rare finding, of which myxomas are the most common. Symptoms can typically result from embolism, obstruction, or constitutional symptoms. A myxoma presenting as acute chest pain and mimicking an acute coronary syndrome is an uncommon finding. This case reminds us of an extremely rare differential diagnosis of chest pain and awakens us to the usefulness and importance of using echocardiography as a diagnostic tool.


The relation between human hair follicle density and touch perception.
Unmyelinated low threshold C-tactile fibers moderate pleasant aspects of touch. These fibers respond optimally to stroking stimulation of the skin with slow velocities (1-10 cm/s). Low threshold mechanoreceptors are arranged around hair follicles in rodent skin. If valid also in humans, hair follicle density (HFD) may relate to the perceived pleasantness of stroking tactile stimulation. We conducted two studies that examined the relation between HFD and affective touch perception in humans. In total, 138 healthy volunteers were stroked on the forearm and rated the pleasantness and intensity. Stimulation was performed by a robotic tactile stimulator delivering C-tactile optimal (1, 3, 10 cm/s) and non-optimal (0.1, 0.3, 30 cm/s) stroking velocities. Additionally, a measure of discriminative touch was applied in study 2. HFD of the same forearm was determined using the Cyanoacrylate Skin Stripping Method (CSSM), which we validated in a pretest. Women had higher HFD than men, which was explained by body size and weight. Furthermore, women rated affective touch stimuli as more pleasant and had higher tactile acuity. Depilation did not affect touch perception. A weak relationship was found between the C-tactile specific aspects of affective touch perception and HFD, and the hypothesis of HFD relating to pleasant aspects of stroking only received weak support.


Investigating a Novel Measure of Brain Networking Following Sports Concussion.
Clinicians managing sports-related concussions are left to their clinical judgment in making diagnoses and return-to-play decisions. This study was designed to evaluate the utility of a novel measure of functional brain networking for concussion management. 24 athletes with acutely diagnosed concussion and 21 control participants were evaluated in a research laboratory. At each of the 4 post-injury time points, participants completed the Axon assessment of neurocognitive function, a self-report symptom inventory, and the auditory oddball and go/no-go tasks while electroencephalogram (EEG) readings were recorded. Brain Network Activation (BNA) scores were calculated from EEG data related to the auditory oddball and go/no-go tasks. BNA scores were unable to differentiate between the concussed and control groups or by self-report symptom severity. These findings conflict with previous work implementing electrophysiological assessments in concussed athletes, suggesting that BNA requires additional investigation and refinement before clinical implementation.


Probing the different life stages of a fluid catalytic cracking particle with integrated laser and electron microscopy.
While cycling through a fluid catalytic cracking (FCC) unit, the structure and performance of FCC catalyst particles are severely affected. In this study, we set out to characterize the damage to commercial equilibrium catalyst particles, further denoted as ECat samples, and map the different pathways involved in their deactivation in a practical unit. The degradation was studied on a structural and a functional level. Transmission electron microscopy (TEM) of ECat samples revealed several structural features; including zeolite crystals that were partly or fully severed, mesoporous, macroporous, and/or amorphous. These defects were then correlated to structural features observed in FCC particles that were treated with different levels of hydrothermal deactivation. This allowed us not only to identify which features observed in ECat samples were a result of hydrothermal deactivation, but also to determine the severity of treatments resulting in these defects. For functional characterization of the ECat sample, the Brønsted acidity within individual FCC particles was studied by a selective fluorescent probe reaction with 4-fluorostyrene. Integrated laser and electron microscopy (iLEM) allowed correlating this Brønsted acidity to structural features by combining a fluorescence and a transmission electron microscope in a single set-up. Together, these analyses allowed us to postulate a plausible model for the degradation of zeolite crystals in FCC particles in the ECat sample. Furthermore, the distribution of the various deactivation processes within particles of different ages was studied. A rim of completely deactivated zeolites surrounding each particle in the ECat sample was identified by using iLEM. These zeolites, which were never observed in fresh or steam-deactivated samples, contained clots of dense structures. The structures are proposed to be carbonaceous deposits formed during the cracking process, and seem resistant towards burning off during catalyst regeneration.


Impact of Muscarinic M3 Receptor Antagonism on the Risk of Type 2 Diabetes in Antidepressant-Treated Patients: A Case-Controlled Study.
M3 muscarinic receptor antagonism has been associated with glucose intolerance and disturbance of insulin secretion. Our objective was to examine the risk of type 2 diabetes mellitus (T2DM) in patients using antidepressants with and without M3 muscarinic receptor antagonism (AD_antaM3 and AD_nonantaM3, respectively). We designed a case-control study using a pharmacy prescription database. We selected a cohort of patients who initiated antidepressant use between the ages of 20 and 40 years and who did not receive any anti-diabetic prescriptions at baseline. Cases were defined as those who developed T2DM [i.e., receiving oral anti-diabetic medication, Anatomical Therapeutic Chemical (ATC) code A10B] during the follow-up period (1994-2014), and ten random controls were picked for each case from the cohort of patients who did not develop T2DM. A total of 530 cases with incident T2DM and 5300 controls were included. Compared with no use of antidepressants during the previous 2 years, recent (within the last 6 months) exposure to AD_antaM3 was associated with a moderately increased risk of T2DM: adjusted odds ratio 1.55 (95% confidence interval 1.18-2.02). In the stratified analyses, this association was dose dependent (>365 defined daily doses) and significant for patients who were in the younger age group (<45 years at the end of follow-up), were female and had no co-morbidity. On the other hand, recent exposure to AD_nonantaM3 was not associated with a risk for T2DM in any of our analyses. Our results suggest that exposure to AD_antaM3 was associated with the development of T2DM among antidepressant users.


Sulfur-containing bis-iridoid glucosides and iridoid glucosides from Saprosmas cortechinii.
Six new sulfur-containing bis-iridoid glucosides, saprosmosides A-F (1-6), were isolated from the leaves of Saprosma scortechinii. From the stems of this same plant, two new iridoid glucosides, 3,4-dihydro-3-methoxypaederoside (8) and 10-O-benzoyldeacetylasperulosidic acid (12), were isolated. Their structures were elucidated by means of chemical, NMR, and mass spectroscopic methods. Additionally, 11 known iridoid glucosides were isolated and characterized as deacetylasperuloside, asperuloside, paederoside (7), deacetylasperulosidic acid (9), scandoside, asperulosidic acid, 10-acetylscandoside, paederosidic acid (10), 6-epi-paederosidic acid (11), methylpaederosidate, and monotropein. The structures of the new bis-iridoid glucosides were formed by intermolecular esterification between the glucose and carboxyl groups of three monomeric iridoid glucosides (7, 9, and 10).


Comparative analyses and implications for antivenom serotherapy of four Moroccan scorpion Buthus occitanus venoms: Subspecies tunetanus, paris, malhommei, and mardochei.
Temporary passive immunity such as serotherapy against venoms requires the full knowledge of all venom's components. Here, four venoms from Moroccan common yellow scorpions belonging to Buthus occitanus, subspecies tunetanus, paris, malhommei, and mardochei, all collected in four different restricted areas, were analysed in deep. They were fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) and their molecular masse profile determined by off-line MALDI-TOF mass spectrometry. Characterisation of their main components was achieved by enzyme-linked immunosorbent assay (ELISA) using specific antisera against the major lethal scorpion toxins identified so far, i.e. voltage-gated sodium channels (Nav) modulators α- and β-toxins, as well as diverse potassium channel pore blocker toxins. For fractions with identical RP-HPLC retention times, we observe that their relative quantities show large differences. Moreover, identical masses present simultaneously in the four venoms are infrequent. ELISAs show that the majority of the RP-HPLC compounds cross-react with the antiserum against the "α-like" toxin Bot I, which has been previously identified in the Algerian Buthus occitanus tunetanus venom. Moreover, minor fractions were recognised by the antiserum against the highly lethal "classical" α-toxin of reference AaH II from the Androctonus australis venom. As such, our results bring new sights for further improving scorpion venom serotherapy in Morocco.


Knocking on prison's door: a 10-fold rise in the number of psychotic prisoners in Finland during the years 2005-2016.
As in many European countries, Finnish psychiatric services experienced a rapid process of deinstitutionalization in the 1990s. In recent decades, the decrease in numbers of psychiatric hospital beds has in several countries been found to be linked with increasing criminality among severely mentally ill individuals. It has been concluded that deinstitutionalization could be the main reason for this development. To investigate whether the prevalence of severely mentally ill persons to prison is a growing trend also in Finland. We searched for the annual data in electronic case files of all prisoners about the ICD-10 diagnostic group of the most severe psychotic disorders. We also searched for the comorbid substance use disorders. Psychotic disorders due to substance abuse only were excluded from this study. During the years 2005-2016, a rapid 10-fold increase in psychotic disorders has occurred in Finnish prisons. In 2016, 185 prisoners (5.9% of all Finnish prisoners) were diagnosed as having a psychotic disorder that was not induced by substance abuse. The causes of this dramatic change are unclear. Comorbid substance abuse disorders were detected in only 39.5% of these prisoners and therefore substance abuse can only partly explain the increasing criminality of the severely mentally ill persons. 80.5% of psychotic disorders were diagnosed in Psychiatric Hospital for prisoners and 19.5% in prison policlinic services. Trans-institutionalization has become a serious challenge for the Finnish criminal justice and mental health systems. Further studies are needed to detect the causes of this change. More specialized services for severely mentally ill persons are needed both in the community psychiatry and also inside the prison services.


Pulmonary protective and vasodilator effects of a standardized Panax ginseng preparation following artificial gastric digestion.
We have previously demonstrated that purified ginsenosides produce pulmonary vasodilation and prevent effects of free radical injury on the lung. We examined the effect of artificially digested standardized ginseng preparation G115 in perfused rabbit lungs. G115 was incubated in artificial gastric juice (0.03 M NaCl + 0.08 M HCl) 37 degrees C for 1 h, and artificial intestinal juice (0.05 M KH2PO4 + 0.02 M NaOH) 37 degrees C for 5 h, neutralized with NaOH and lyophilized. Pulmonary vasoconstriction was induced with U46619, and cumulative additions of G115 in undigested, gastric digested and gastric and intestinal digested forms were made to the perfusate. In separate experiments, oxygen free radical injury by electrolysis was produced in the presence of G115 in the perfusate and ACh-induced vasodilation assessed before and after injury. Undigested, gastric digested and combined gastric and intestinal digested G115 significantly dilated lungs (44%, undigested; 26%, gastric digested; 45%, gastric and intestinal digested). In addition, both undigested (-27 +/- 5% vs. -24 +/- 5%) as well as gastric and intestinal digested G115 (-23 +/- 3% vs. -16 +/- 2%) preserved ACh-induced vasodilation following injury. Artificially digested G115 is a pulmonary vasodilator which protects against free radical injury, suggesting that oral G115 has the same effects.


pH-Triggered Removal of Nitrogenous Organic Micropollutants from Water by Using Metal-Organic Polyhedra.
Water pollution threatens human and environmental health worldwide. Thus, there is a pressing need for new approaches to water purification. Herein, we report a novel supramolecular strategy based on the use of a metal-organic polyhedron (MOP) as a capture agent to remove nitrogenous organic micropollutants from water, even at very low concentrations (ppm), based exclusively on coordination chemistry at the external surface of the MOP. Specifically, we exploit the exohedral coordination positions of RhII -MOP to coordinatively sequester pollutants bearing N-donor atoms in aqueous solution, and then harness their exposed surface carboxyl groups to control their aqueous solubility through acid/base reactions. We validated this approach for removal of benzotriazole, benzothiazole, isoquinoline, and 1-napthylamine from water.


Hypertension and coronary artery disease: a summary of the American Heart Association scientific statement.
The American Heart Association scientific statement on the treatment of hypertension in the prevention and management of ischemic heart disease was published recently. The main recommendations were as follows: (1) For most adults with hypertension, the blood pressure (BP) goal is <140/90 mm Hg but should be <130/80 [corrected] mm Hg in patients with diabetes mellitus, chronic kidney disease, known coronary artery disease (CAD), CAD equivalents (carotid artery disease, abdominal aortic aneurism, and peripheral vascular disease), or 10-year Framingham risk score of >/=10%. For those with left ventricular dysfunction, the recommended BP target is <120/80 mm Hg. (2) For primary CAD prevention, any effective antihypertensive drug or combination is indicated, but preference is given to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide diuretics. (3) For the management of hypertension in patients with established CAD (stable or unstable angina, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction), beta-blockers and ACE inhibitors (or ARBs) are the basis of treatment. If further BP lowering is needed, a thiazide diuretic and/or a dihydropyridine CCB (not verapamil or diltiazem) can be added. If a beta-blocker is contraindicated or not tolerated, diltiazem or verapamil can be substituted. (4) If there is left ventricular dysfunction, recommended therapy consists of an ACE inhibitor or ARB, a beta-blocker, and either a thiazide or loop diuretic. In patients with more severe heart failure, an aldosterone antagonist and hydralazine/isosorbide dinitrate (in black patients) should be considered.


HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era.
Data describing the incidence and survival of HIV-related central nervous system diseases (CNS-D) in recent years are sparse. Between 1996 and 2007, adult subjects without previous CNS-D within a large UK cohort were included (n=30,954). CNS-D were HIV encephalopathy (HIVe), progressive multifocal leucoencephalopathy (PML), cerebral toxoplasmosis (TOXO) and cryptococcal meningitis (CRYP). Associations between demographic, clinical and laboratory parameters with incidence and survival of CNS-D were evaluated using Poisson regression analysis and Kaplan-Meier techniques. Six hundred and thirteen new CNS-D occurred in 574 subjects (HIVe:187, PML:113, TOXO:184, CRYP:129). Incidence of all CNS-D declined from 13.1 per 1000 PY in 1996/1997 to 1.0 per 1000 PY in 2006/2007 (P=0.0001). Current CD4+ cell count below 200 cells/ul and plasma HIV RNA above 100,000 copies/ml were independently associated with the development of CNS-D. Calendar year 1996/1997, older age, prior AIDS diagnosis and PML diagnosis were significantly associated with shorter survival. An ongoing decline in the incidence of CNS-D has been observed in very recent years. Mortality following such a diagnosis remains high.


Brugada syndrome and neurally mediated susceptibility.
The risk of sudden death in patients with Brugada syndrome (BS) is still unclear. Moreover, particular clinical conditions may have a confounding effect on the diagnostic and therapeutic approach. We report the case of a 27-year-old man with a clinical history of suspected neurally mediated syncope and typical ECG features of BS. The tilt table test showed a type I, mixed, positive response. The electrophysiological study (EPS) disclosed a peculiar ventricular irritability with the induction of a life-threatening arrhythmia. After the implantation of a cardioverter-defibrillator an episode of ventricular fibrillation during sleep at night was correctly identified and treated by the device. The association between neurally mediated susceptibility and the typical ECG abnormalities of BS is not an unexpected event in young subjects. The misjudgment of the pathophysiological mechanism of syncopal episodes may lead, on one hand, to overlook the risk of sudden death and, on the other, to pursue inappropriate therapeutic measures. The application of a tailored diagnostic work-up based on currently available guidelines may be useful to overcome the clinical and therapeutic dilemma.


Effect of community-based nutritional counseling intervention on children's eating habits.
This study aimed to assess the outcome of community-based nutritional counseling interventions on eating habits of rural-dwelling children. A group-randomized trial design was used in this study. A total of 108 rural-dwelling children from a community in the Enugu North agricultural zone, Enugu State, who participated in the study. The children were randomly assigned to 2 groups: the treatment group (n = 54) and the no-treatment control group (n = 54). The child eating behavior questionnaire was used for data collection. Parents of the participating children within each study group completed the child eating behavior questionnaire at 3 time points. The data collected were analyzed using an independent sample t test at a probability level of .05. The outcome of the study showed that the children's eating habits in the treatment group improved positively following the community-based nutritional counseling intervention. The positive gain from exposure to the community-based nutritional counseling intervention program was sustained during follow-up for children in the treatment group compared with the no-treatment group. The community-based nutrition counseling intervention carried out among children in rural communities had a positive adjustment in children's eating habits. The intervention requires the constant collaboration of professional childhood educators, caregivers, home economists, school staff, healthcare specialists, families, and the children themselves. Furthermore, there is a need for future long-term evaluations of the effects of community-based nutritional counseling interventions on children's nutrition and eating habits.


Assembly of actin filaments and microtubules in Nwk F-BAR-induced membrane deformations.
F-BAR domains form crescent-shaped dimers that bind to and deform lipid bilayers, and play a role in many cellular processes requiring membrane remodeling, including endocytosis and cell morphogenesis. Nervous Wreck (NWK) encodes an F-BAR/SH3 protein that regulates synapse growth in Drosophila. Unlike conventional F-BAR proteins that assemble tip-to-tip into filaments and helical arrays around membrane tubules, the Nwk F-BAR domain instead assembles into zigzags, creating ridges and periodic scallops on membranes in vitro. In cells, this membrane deforming activity generates small buds, which can lengthen into extensive protrusions upon actin cytoskeleton polymerization. Here, we show that Nwk-induced cellular protrusions contain dynamic microtubules, distinguishing them from conventional filopodia, and further do not depend on actin filaments or microtubules for their maintenance. Our results indicate new ways in which close cooperation between the membrane remodeling and cytoskeletal machinery underlies large-scale changes in cellular morphology.


The Utility of 3D Ultramicroscopy for Evaluating Cellular Therapies After Spinal Cord Injury.
Cell therapies have shown promise for repairing the injured spinal cord in experimental models and are now being evaluated in clinical trials for the treatment of human spinal cord injury (SCI). To date, experimental evaluation of implanted cell survival, migration, and integration within the injured central nervous system (CNS) of animals has been technically demanding, requiring tissue sectioning, staining, imaging, and manual reconstruction of 2-dimensional (2D) specimens in 3 dimensions (3D). Not only are these histological procedures laborious and fraught with processing artifacts during manual 3D reconstruction, but they are time-intensive. Herein we describe the utility of 3D ultramicroscopy for assessment of cell therapies after SCI, a new state-of-the-art imaging modality in which whole brain and spinal cord samples are optically sectioned to allow evaluation of intact, macroscopic specimens with microscopic resolution.


Effective Management of Femur Fracture Using Damage Control Orthopedics Following Fat Embolism Syndrome.
Fat embolism syndrome (FES) is a rare event following a traumatic injury, and its pathophysiologic mechanism continues to be elusive. Fat embolism syndrome generally occurs when a bone marrow fat enters the bloodstream resulting in a cascade of inflammatory response, hyper-coagulation, and an array of symptoms that generally begin within 24-48 hours. FES early symptoms include petechial rash, shortness of breath, altered mental status, seizures, fever, and may result in decreased urine output. The common etiologies of a fat embolism include long bone fractures, mainly femoral and pelvic fractures. There are multiple management methods described in the literature to help prevent FES and other long bone fracture complications from occurring. Although not universally adopted, the damage control orthopedics (DCO) has been the major management option for patients with a long bone fracture. DCO is entertained by provisional immobilization of patients with long bone fractures and those who are considered severely traumatized patients (STP). Thus, immobilization can help minimize the traumatic effect and the subsequent second hit by performing non-life saving surgical procedures. In this case, a patient with a transverse femur fracture suffered disconcerting symptoms of fat embolism prior to definitive femur repair. Hence, damage control orthopedics was entertained with a postponement of his femur repair to facilitate stabilization. The use of damage control orthopedics was successful in this patient with no long term complications.


A novel computer system for the evaluation of nasolabial morphology, symmetry and aesthetics after cleft lip and palate treatment. Part 2: Comparative anthropometric analysis of patients with repaired unilateral complete cleft lip and palate and healthy individuals.
The aim of this study was to use a novel system, 'Analyse It Doc' (A.I.D.) for a complex anthropometric analysis of the nasolabial region in patients with repaired unilateral complete cleft lip and palate and in healthy individuals. A set of standardized facial photographs in frontal, lateral and submental view have been taken in 50 non-cleft controls (mean age 20.6 years) and 42 patients with repaired unilateral complete cleft and palate (mean age 19.57 years). Then, based on linear, angular and area measurements taken from the digital photographs with the aid of the A.I.D. system, a photogrammetric analysis of intergroup differences in nasolabial morphology and symmetry was conducted. Patients with cleft lip and palate differed from the controls in terms of more than half of analysed angular measurements and proportion indices derived from linear and area measurements of the nasolabial region. The findings presented herein imply that despite primary surgical repair, patients with unilateral complete cleft lip and palate still show some degree of nasolabial dysmorphology. Furthermore, the study demonstrated that the novel computer system is suitable for a reliable, simple and time-efficient anthropometric analysis in a clinical setting.


Three-dimensional laser combined with C-arm computed tomography-assisted puncture of intracerebral hemorrhage.
Intracerebral hemorrhage (ICH) is the deadliest subtype of stroke, with a 30-day case fatality rate of approximately 40%. Timely and accurate treatment is essential to facilitate recovery. The introduction of stereotactic instruments and navigation systems has greatly improved the accuracy of surgical treatment. In this study, we explored the application and effects of a three-dimensional (3D) laser combined with C-arm computed tomography (CT) on ICH puncture. According to the principle of randomness, 118 patients with ICH were divided into control and experimental groups. The control group was treated with CT-guided puncture, and the experimental group was treated with 3D laser combined with C-arm CT puncture. The hematoma clearance rates at 3, 5, and 7 days after surgery and the prognosis at 1, 3, and 6 months after surgery were compared between the two groups. The hematoma clearance rates of the group using 3D laser combined with C-arm CT at 3, 5, and 7 days after surgery were significantly higher than those of the control group, and the difference was statistically significant (p < 0.05). One month postoperatively, the daily living ability (ADL) grading and recovery of the patients in the test group was significantly better than those of the control group (p < 0.05), but there was no statistically significant difference in ADL 3 and 6 months after surgery (p > 0.05). 3D laser combined with C-arm CT puncture has the advantages of real-time guidance, accurate positioning, and simple operation. It is an effective minimally invasive surgical method that is easy to master.


An interdisciplinary approach to controlling chikungunya outbreaks on French islands in the south-west Indian ocean.
The outbreak of chikungunya that occurred on French Island territories in the southwest Indian Ocean in 2005 and 2006 caused severe morbidity and mortality. In the aftermath, French authorities set up a scientific task force including experts in epidemiology, public health, entomology, virology, immunology, sociology, animal health, community and hospital medicine. The mission of the task force was to conceive and propose research programs needed to increase understanding of the disease and epidemic and to help public health officials in improving epidemic response measures. The purpose of this article is to describe the findings of the task force at the end of its two-year existence and initial outcomes in the the areas studied. Discussion emphasizes topics requiring further study.


Improved Location Estimation in Wireless Sensor Networks Using a Vector-Based Swarm Optimized Connected Dominating Set.
Location estimation in wireless sensor networks (WSNs) has received tremendous attention in recent times. Improved technology and efficient algorithms systematically empower WSNs with precise location identification. However, while algorithms are efficient in improving the location estimation error, the factor of the network lifetime has not been researched thoroughly. In addition, algorithms are not optimized in balancing the load among nodes, which reduces the overall network lifetime. In this paper, we have proposed an algorithm that balances the load of computation for location estimation among the anchor nodes. We have used vector-based swarm optimization on the connected dominating set (CDS), consisting of anchor nodes for that purpose. In this algorithm, major tasks are performed by the base station with a minimum number of messages exchanged by anchor nodes and unknown nodes. The simulation results showed that the proposed algorithm significantly improves the network lifetime and reduces the location estimation error. Furthermore, the proposed optimized CDS is capable of providing a global optimum solution with a minimum number of iterations.


Should we freeze it? Agreement on fate of borderline blastocysts is poor and does not improve with a modified blastocyst grading system.
What is the inter-observer agreement among embryologists for decision to freeze blastocysts of borderline morphology and can it be improved with a modified grading system? The inter-observer agreement among embryologists deciding whether to freeze blastocysts of marginal morphology was low and was not improved by a modified grading system. While previous research on inter-observer variability on the decision of which embryo to transfer from a cohort of blastocysts is good, the impact of grading variability regarding decision to freeze borderline blastocysts has not been investigated. Agreement for inner cell mass (ICM) and trophectoderm (TE) grade is only fair, factors which contribute to the grade that influences decision to freeze. This was a prospective study involving 18 embryologists working at four different IVF clinics within a single organisation between January 2019 and July 2019. All embryologists currently practicing blastocyst grading at a multi-site organisation were invited to participate. The survey was comprised of blastocyst images in three planes and asked (i) the likelihood of freezing and (ii) whether the blastocyst would be frozen based on visual assessment. Blastocysts varied by quality and were categorised as either top (n = 20), borderline (n = 60) or non-viable/degenerate quality (n = 20). A total of 1800 freeze decisions were assessed. To assess the impact of grading criteria on inter-observer agreement for decision to freeze, the survey was taken once when the embryologists used the Gardner criteria and again 6 months after transitioning to a modified Gardner criterion with four grades for ICM and TE. The fourth grade was introduced with the aim to promote higher levels of agreement for the clinical usability decision when the blastocyst was of marginal quality. The inter-observer agreement for decision to freeze was near perfect (kappa 1.0) for top and non-viable/degenerate quality blastocysts, and this was not affected by the blastocysts grading criteria used (top quality; P = 0.330 and non-viable/degenerate quality; P = 0.18). In contrast, the cohort of borderline blastocysts received a mixed freeze rate (average 52.7%) during the first survey, indicative of blastocysts that showed uncertain viability and promoting significant disagreement for decision to freeze among the embryologists (kappa 0.304). After transitioning to a modified Gardner criteria with an additional grading tier, the average freeze rate increased (64.8%; P < 0.0001); however, the inter-observer agreement for decision to freeze was unchanged (kappa 0.301). Therefore, significant disagreement for decision to freeze among embryologists is an ongoing issue not resolved by the two grading criteria assessed here. Blastocyst assessment was performed from time-lapse images in three planes, rather than with a microscope in the laboratory. The inter-observer agreement for decision to freeze may be lower for embryologists working in different clinics with different grading protocols. The decision to freeze a blastocyst with borderline morphology is a common clinical issue that has the potential to arise for any patient during blastocyst culture. Disagreement for decision to freeze these blastocysts, and therefore clinical usability in frozen embryo transfer cycles, affects consistency in patient care due to a potential impact on cumulative live birth rates, as well as financial, emotional and time costs associated with the frozen embryo transfer cycles. We demonstrate significant disagreement for decision to freeze borderline blastocysts among embryologists using the same grading scheme within a large multisite organisation, a phenomenon which was not improved with a modified grading system. Decision-making around borderline embryos is an area requiring further research, especially as studies continue to demonstrate the reduced but modest live birth rates for low quality blastocysts (Grade C). These results provide support for emerging technology for embryo assessment, such as artificial intelligence. None declared. Not applicable.


Availability and Accessibility of Student-Specific Weight Loss Programs and Other Risk Prevention Health Services on College Campuses.
More than one third of college students who are overweight or obese are in need of weight loss programs tailored to college students. However, the availability and accessibility of these programs is unknown. The aim of this study is to examine the availability and ease of access to weight loss programs for students at 10 universities with the largest undergraduate enrollment. The 10 public universities with the largest student bodies with a mean (SD) undergraduate enrollment of 41,122 (7657) students were examined. The websites of the universities were assessed to determine the availability of weight loss programs. Services for high-risk health needs common to university campuses (ie, alcohol and other drugs, victim services, sexual health, and eating disorders) were searched. Of the universities searched, 3 (30%, 3/10) offered weight loss programming, however, none met the predetermined criteria. Comparatively, all schools (100%, 10/10) offered no-cost and continual enrollment programming for the other high-risk health needs. There are limited weight loss services available to undergraduate students compared with other university services. Collaboration between existing college health service providers is suggested for the delivery of appropriate programming for overweight and obese undergraduates wanting to lose weight.


Pharmacokinetics of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1- piperazinyl)-1,4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride (DW-116), a new quinolone antibiotic in rats.
The objectives of this study were to characterize the pharmacokinetics of 1-5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1- piperazinyl)-1,4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride (DW-116), a newly developed quinolone antibiotic, and to compare these kinetics with those of ciprofloxacin and rufloxacin, representative quinolone antibiotics, in rats. Rats were subjected to surgery involving catheterization of the femoral vein and artery. DW-116 (4, 20, or 200 mg/kg), ciprofloxacin (20 mg/kg), or rufloxacin (20 mg/kg) was administered either intravenously (iv) or orally. Blood samples were collected at various times and subjected to an HPLC assay for the quinolones. Temporal profiles of plasma concentration after iv administrations of DW-116 at doses of 4, 20, and 200 mg/kg exhibited an apparent multiexponential decline. In the three doses examined, systemic clearance and steady-state volume of distribution of DW-116, calculated by model-independent methods, were in the range 0.17 approximately 0.23 L/h/kg and 2.90 approximately 4.44 L/kg, respectively. When DW-116 was given orally at doses of 4, 20, or 200 mg/kg, the AUC values were nearly identical to those following iv administration, indicating an almost complete absorption (i.e., the percent bioavailability was 90.0 for 4 mg/kg, 99.0 for 20 mg/kg, and 98.3 for 200 mg/kg) in the dose range examined. The absorption of DW-116 appears to be extremely rapid because the mean residence time calculated from the oral administration data was not significantly different from that for the iv administration. At a dose of 20 mg/kg, the mean residence time for iv administered ciprofloxacin and rufloxacin was smaller than that of DW-116, indicating that DW-116 remains in the body longer than the other quinolones. Absolute percent bioavailabilities of ciprofloxacin (69.9%) and rufloxacin (84.9%) were smaller than that obtained for DW-116 (99.0%). Because it has been reported that the in vivo antibacterial activity of DW-116 is comparable or superior to that of rufloxacin and ciprofloxacin, despite the fact that the in vitro activity is significantly lower, the pharmacokinetics of this antibiotic may be responsible, at least in part, for the enhanced in vivo antibacterial activity of DW-116.


Nonlinear propagation of ultrasound through microbubble contrast agents and implications for imaging.
Microbubble contrast agents produce nonlinear echoes under ultrasound insonation, and current imaging techniques detect these nonlinear echoes to generate contrast agent images accordingly. For these techniques, there is a potential problem in that bubbles along the ultrasound transmission path between transducer and target can alter the ultrasound transmission nonlinearly and contribute to the nonlinear echoes. This can lead to imaging artefacts, especially in regions at depth. In this paper we provide insight, through both simulation and experimental measurement, into the nonlinear propagation caused by microbubbles and the implications for current imaging techniques. A series of investigations at frequencies below, at, and above the resonance frequency of microbubbles were performed. Three specific effects on the pulse propagation (i.e., amplitude attenuation, phase changes, and harmonic generation) were studied. It was found that all these effects are dependent on the initial pulse amplitude, and their dependence on the initial phase of the pulse is shown to be insignificant. Two types of imaging errors are shown to result from this nonlinear propagation: first, that tissue can be misclassified as microbubbles; second, the concentration of microbubbles in the image can be misrepresented. It is found that these imaging errors are significant for all three pulse frequencies when the pulses transmit through a microbubble suspension of 6 cm in path length. It also is found that the first type of error is larger at the bubble resonance frequency.


18-year recurrence-free survival after extensive surgery for kidney cancer with atrial tumor thrombi.
Tumor thrombus formation is a unique aspect of renal cell carcinoma with significant therapeutic and prognostic implications. The prognostic significance of cephalad extent of tumor thrombi to the right atrium remains controversial. Extended surgical removal, however, is the only way to expect survival. In 1989, a 40-year-old man was diagnosed with an advanced renal cell carcinoma (T(3C)N(2)M(0)) involving perinephric fat, hilar and para-aortic lymph nodes and a tumor thrombus extending to the right atrium. He was treated with extensive surgical resection of the tumor and its lymphatic and vascular extensions. Interferon-alpha injections were given for 2.5 years as an adjuvant immunotherapy. The patient was annually checked with abdominal ultrasound, chest X-ray and computed tomography, but has manifested no local or distant metastasis for 18 years. To our knowledge, this is the first reported case of extensive surgery on advanced renal cell carcinoma with no evidence of recurrence for 18 years.


The immunogenicity of the tumor-associated antigen Lewis(y) may be suppressed by a bifunctional cross-linker required for coupling to a carrier protein.
A Lewis(y) (Le(y)) tetrasaccharide modified by an artificial aminopropyl spacer was synthesized by a highly convergent approach that employed a levulinoyl ester and a 9-fluorenylmethoxycarbonate for temporary protection of the hydroxy groups and a trichloroethyloxycarbonyl as an amino protecting group. The artificial aminopropyl moiety was modified by a thioacetyl group, which allowed efficient conjugation to keyhole limpet hemocyanin (KLH) modified by electrophilic 4-(maleimidomethyl)cyclohexane-1-carboxylate (MI). Mice were immunized with the KLH-MI-Le(y) antigen. A detailed analysis of sera by ELISA established that a strong immunoglobulin G (IgG) antibody response was elicited against the linker region. The use of a smaller and more flexible 3-(bromoacetamido)propionate for the attachment of Le(y) to KLH not only reduced the IgG antibody response against the linker but also led to a significantly improved immune response against the Le(y) antigen. This study shows that highly antigenic linkers suppress antibody responses to weak antigens such as self-antigens.


Predicting the functional and structural consequences of nsSNPs in human methionine synthase gene using computational tools.
Methionine synthase encoded by the MTR gene is one of the key enzymes involved in the SAM (S- Adenosyl Methionine) cycle catalyzing the conversion of homocysteine to methionine. Methionine plays an important role in the DNA, RNA, protein, phospholipids, and neurotransmitters methylation. It also maintains serum homocysteine level and indirectly regulates de novo nucleotide synthesis and repair. The current study predicted the functional consequences of nsSNPs in human MTR gene using SIFT, PolyPhen2, PROVEAN, SNAP2, PMut, nsSNPAnalyzer, PhD-SNP, SNPs&GO, I-Mutant, MuPro, and iPTREE-STAB. The PTM sites within the protein were predicted using ModPred and the phylogenetic conservations of amino acids & conserved domains of protein were predicted using ConSurf and NCBI conserved domain search tool respectively. The protein 3D structure was generated using SPARKS-X and analyzed using RAMPAGE. Structural deviation was analyzed using TM-Score. STRING analysis was preformed to predict protein-protein interactions. D621G, G682D, V744L, V766E, and R1027W were predicted to be the most deleterious nsSNPs in MTR. R1027 was predicted to having the three PTM sites and G682 & V744 were predicted as highly conserved residues. D621G, G682D, V744L, V776E, and R1027W were predicted to be within conserved domains of methionine synthase. The G682D, V744L, V776E, and R1027W were predicted to alter protein 3D structure. STRING predicted that methionine synthase interacting with 10 different proteins. The present study predicted D621G, G682D, V744L, V766E, and R1027W as functionally and structurally significant nsSNPs in human MTR gene. The present study can provide the significant information for further experimental analysis. Abbreviations: cblG: methylcobalamin deficiency G; MTR: 5-methyl tetrahydrofolate-homocysteine methyl transferase; MS: methionine synthase; SAM: S-adenosyl methionine; nsSNPs: non-synonymous single nucleotide polymorphisms; OMIM: online mendelian inheritance in man; NCBI: national center for biological information; SIFT: sorting intolerant from tolerant; PolyPhen2: polymorphism phenotyping 2; PROVEAN: protein variation effect analyzer; SNPs&GO: single nucleotide polymorphisms and gene ontology; PhD-SNP: predictor of human deleterious single nucleotide polymorphisms; RI: reliability index; PTM: post translational modification; SPDBV: Swiss PDB viewer; PDB: protein data bank; RMSD: root mean square deviation; STRING: search tool for the retrieval of interacting proteins.


Antigen-specific T-helper cells abrogate suppression in Trypanosoma cruzi-infected mice.
The ability of antigen-specific T-helper (Th) cells to enhance direct plaque-forming cell responses in spleen cells from Trypanosoma cruzi-infected C57BL/6 mice was investigated at various times during the course of infection from day 7 to day 230. The injection of antigen-specific Th cells in vivo or the addition of antigen-specific Th cells in vitro was effective in enhancing direct plaque-forming cell responses, except at the time of the most intense suppression during the acute phase of infection (i.e., day 28). The ability of antigen-specific Th cells to overcome nonspecific immunosuppression was due not only to the activity of antigen-specific Th cells added to Mishel-Dutton cultures but also to activation of resident T cells. Thus, antigen-specific Th cells and resident T cells act in concert to produce enhanced direct plaque-forming cell responses. The effect of plastic-adherent spleen cells from infected mice on the ability of antigen-specific Th cells to stimulate anti-sheep erythrocyte responses of normal spleen cells was examined because macrophages have been shown to have an immunoregulatory role during the course of experimental American trypanosomiasis. Increasing numbers of macrophages from infected mice caused increased immunosuppression of normal spleen cells that could not be overcome with the addition of primed Th cells. It can be concluded from these data that antigen-specific Th cells can potentiate immune responses in mice infected with T. cruzi but that highly active suppressor macrophages can inhibit the expression of these primed Th cells.


Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model.
Osteogenesis imperfecta (OI) is a genetic disorder characterized by altered bone quality and imbalanced bone remodeling, leading to skeletal fractures that are most prominent during childhood. Treatments for OI have focused on restoring pediatric bone density and architecture to recover functional strength and consequently reduce fragility. Though antiresorptive agents like bisphosphonates (BPs) are currently the most common intervention for the treatment of OI, a number of studies have shown efficacy of sclerostin antibody (SclAb) in inducing gains in bone mass and reducing fragility in OI mouse models. In this study, the effects of the concurrent use of BP and SclAb were evaluated during bone growth in a mouse harboring an OI-causing Gly→Cys mutation on col1a1. A single dose of antiresorptive BP facilitated the anabolic action of SclAb by increasing availability of surfaces for new bone formation via retention of primary trabeculae that would otherwise be remodeled. Chronic effects of concurrent administration of BP and SclAb revealed that accumulating cycles conferred synergistic gains in trabecular mass and vertebral stiffness, suggesting a distinct advantage of both therapies combined. Cortical gains in mass and strength occurred through SclAb alone, independent of presence of BP. In conclusion, these preclinical results support the scientific hypothesis that minimal antiresorptive treatment can amplify the effects of SclAb during early stages of skeletal growth to further improve bone structure and rigidity, a beneficial outcome for children with OI. © 2018 American Society for Bone and Mineral Research.


Sequence Factorization with Multiple References.
The success of high-throughput sequencing has lead to an increasing number of projects which sequence large populations of a species. Storage and analysis of sequence data is a key challenge in these projects, because of the sheer size of the datasets. Compression is one simple technology to deal with this challenge. Referential factorization and compression schemes, which store only the differences between input sequence and a reference sequence, gained lots of interest in this field. Highly-similar sequences, e.g., Human genomes, can be compressed with a compression ratio of 1,000:1 and more, up to two orders of magnitude better than with standard compression techniques. Recently, it was shown that the compression against multiple references from the same species can boost the compression ratio up to 4,000:1. However, a detailed analysis of using multiple references is lacking, e.g., for main memory consumption and optimality. In this paper, we describe one key technique for the referential compression against multiple references: The factorization of sequences. Based on the notion of an optimal factorization, we propose optimization heuristics and identify parameter settings which greatly influence 1) the size of the factorization, 2) the time for factorization, and 3) the required amount of main memory. We evaluate a total of 30 setups with a varying number of references on data from three different species. Our results show a wide range of factorization sizes (optimal to an overhead of up to 300%), factorization speed (0.01 MB/s to more than 600 MB/s), and main memory usage (few dozen MB to dozens of GB). Based on our evaluation, we identify the best configurations for common use cases. Our evaluation shows that multi-reference factorization is much better than single-reference factorization.


With or without spikes: localization of focal epileptic activity by simultaneous electroencephalography and functional magnetic resonance imaging.
In patients with medically refractory focal epilepsy who are candidates for epilepsy surgery, concordant non-invasive neuroimaging data are useful to guide invasive electroencephalographic recordings or surgical resection. Simultaneous electroencephalography and functional magnetic resonance imaging recordings can reveal regions of haemodynamic fluctuations related to epileptic activity and help localize its generators. However, many of these studies (40-70%) remain inconclusive, principally due to the absence of interictal epileptiform discharges during simultaneous recordings, or lack of haemodynamic changes correlated to interictal epileptiform discharges. We investigated whether the presence of epilepsy-specific voltage maps on scalp electroencephalography correlated with haemodynamic changes and could help localize the epileptic focus. In 23 patients with focal epilepsy, we built epilepsy-specific electroencephalographic voltage maps using averaged interictal epileptiform discharges recorded during long-term clinical monitoring outside the scanner and computed the correlation of this map with the electroencephalographic recordings in the scanner for each time frame. The time course of this correlation coefficient was used as a regressor for functional magnetic resonance imaging analysis to map haemodynamic changes related to these epilepsy-specific maps (topography-related haemodynamic changes). The method was first validated in five patients with significant haemodynamic changes correlated to interictal epileptiform discharges on conventional analysis. We then applied the method to 18 patients who had inconclusive simultaneous electroencephalography and functional magnetic resonance imaging studies due to the absence of interictal epileptiform discharges or absence of significant correlated haemodynamic changes. The concordance of the results with subsequent intracranial electroencephalography and/or resection area in patients who were seizure free after surgery was assessed. In the validation group, haemodynamic changes correlated to voltage maps were similar to those obtained with conventional analysis in 5/5 patients. In 14/18 patients (78%) with previously inconclusive studies, scalp maps related to epileptic activity had haemodynamic correlates even when no interictal epileptiform discharges were detected during simultaneous recordings. Haemodynamic changes correlated to voltage maps were spatially concordant with intracranial electroencephalography or with the resection area. We found better concordance in patients with lateral temporal and extratemporal neocortical epilepsy compared to medial/polar temporal lobe epilepsy, probably due to the fact that electroencephalographic voltage maps specific to lateral temporal and extratemporal epileptic activity are more dissimilar to maps of physiological activity. Our approach significantly increases the yield of simultaneous electroencephalography and functional magnetic resonance imaging to localize the epileptic focus non-invasively, allowing better targeting for surgical resection or implantation of intracranial electrode arrays.


Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer's disease mouse model 5xFAD.
Alzheimer's disease (AD) is the most common form of dementia characterized by the formation of amyloid plaques (Aβ). Over the last decade, the important role of the innate immune system for the disease development has been established. Chronic activation of microglial cells creates a proinflammatory environment, which is believed to be central for the development of the disease as well as its progression. We used the AD mouse model 5xFAD to investigate if inflammatory alterations are present in microglial cells before plaque deposition. We applied mass spectrometry and bioinformation analysis to elucidate early microglial alterations. Interestingly, we found the cytokines IL1β and IL10 to be elevated in the 5xFAD brain after the formation of Aβ plaque at 10 weeks only. Using mass spectrometry analysis of microglial cells with bioinformation analysis, we found JAK/STAT, p38 MAPK and Interleukin pathways affected in microglial cells before plaque deposition at 6 weeks. At 10 weeks, GO analysis showed affected pathways related to interferon-gamma regulation and MAPK pathways. Our study points toward early inflammatory changes in microglial cells even before the accumulation of Aβ.


Conclusions and future directions for periodic reporting on the use of adult clinical preventive services of public health priority--United States.
The findings described in this supplement can help improve collaboration among public health and other stakeholders who influence population health, including employers, health plans, health professionals, and voluntary associations, to increase the use of a set of clinical preventive services that, with improved use, can substantially reduce morbidity and mortality in the U.S. adult population. This supplement highlighted that the use of the clinical preventive services in the U.S. adult population is not optimal and is quite variable, ranging from approximately 10% to 85%, depending on the particular service. Use was particularly low for tobacco cessation, aspirin use to reduce risk of cardiovascular disease, and influenza vaccination; however, ample opportunity exists to improve use of all of these services. Among the specific populations least likely to have used the recommended services, persons with no insurance, no usual source of care, or no recent use of the health-care system (if included in the analysis) were the groups least likely to have used the services. Use among the uninsured was generally 10 to 30 percentage points below the general population averages, suggesting that improvements in insurance coverage are likely to increase use of these clinical preventive services. A randomized, controlled trial of an expansion of Medicaid coverage by Oregon in 2008 supports this hypothesis by demonstrating improved use of clinical services with increased health insurance coverage. A recent survey among the uninsured found a low level of awareness of the provisions of the Patient Protection and Affordable Care Act of 2010 as amended by the Healthcare and Education Reconciliation Act of 2010 (referred to collectively as the Affordable Care Act [ACA]). Therefore, improving opportunities for coverage might be insufficient, and focused efforts by governmental health agencies and other stakeholders are likely to be needed to enroll uninsured persons in health plans. In addition, although use of the preventive services in insured populations was greater than among the uninsured, use among the insured was generally <75%, and often much less. Therefore, having health insurance coverage might not itself be sufficient to optimize use of clinical preventive services, and additional measures to improve use are likely to be necessary.


Panobinostat: a review of trial results and future prospects in multiple myeloma.
Multiple myeloma is an incurable often devastating disease that is responsible for 1-2% of all cancers. Multiple myeloma is the second most common hematologic malignancy. Over the past two decades, advances in therapy have doubled life expectancy. Unfortunately, all patients ultimately relapse. Novel agents (immunomodulatory drugs and proteasome inhibitors) have changed the outlook for patients, but further breakthroughs are needed. Epigenetic treatments offer potential for advancing therapy by modifying oncogene responses. The acetylation status of various proteins can affect the availability of chromatin for transcription. This response may be modulated epigenetically to advantage using histone deacetylase inhibitors like panobinostat.


The vulnerability of middle-aged and older adults in a multiethnic, low-income area: contributions of age, ethnicity, and health insurance.
This community-partnered study was developed and fielded in partnership with key community stakeholders and describes age- and race-related variation in delays in care and preventive service utilization between middle-aged and older adults living in South Los Angeles. The survey sample included adults aged 50 and older who self-identified as African American or Latino and lived in ZIP codes of South Los Angeles (N=708). Dependent variables were self-reported delays in care and use of preventive services. Insured participants aged 50 to 64 were more likely to report any delay in care (adjusted predicted percentage (APP)=18%, 95% confidence interval (CI)=14-23) and problems obtaining needed medical care (APP=15%, 95% CI=12-20) than those aged 65 and older. Uninsured participants aged 50 to 64 reported even greater delays in care (APP=45%, 95% CI=33-56) and problems obtaining needed medical (APP=33%, 95% CI=22-45) and specialty care (APP=26%, 95% CI=16-39) than those aged 65 and older. Participants aged 50 to 64 were generally less likely to receive preventive services, including influenza and pneumococcal vaccines and colonoscopy than older participants, but women were more likely to receive mammograms. Participants aged 50 to 64 had more problems obtaining recommended preventive care and faced more delays in care than those aged 65 and older, particularly if they were uninsured. Providing insurance coverage for this group may improve access to preventive care and promote wellness.


Myxedema Crisis Presenting with Seizures: A Rare Life-Threatening Presentation-A Case Report and Review of the Literature.
Myxedema crisis is a life-threatening extreme form of hypothyroidism with a high mortality rate if left untreated. Myxedema crisis is commonly seen in older patients, especially in women, and is associated with signs of hypothyroidism, hypothermia, hyponatraemia, hypercarbia, and hypoxemia. Patients might present with different organ specific symptoms. Seizures are a recognized but rare manifestation of myxedema with a very high mortality rate. Prompt diagnosis and appropriate management may improve the prognosis. Many contributory factors may involve development of seizures in a patient with myxedema. Hyponatraemia is one such cause, which is seen in moderate-severe form in the background of myxedema. We report an elderly male who presented with generalized tonic clonic seizure preceded by memory impairment and drowsiness. He had moderate hyponatraemia and very high thyroid stimulatory hormone levels in association with low free thyroxin levels. Diagnosis of myxedema crisis was made and patient was successfully treated with sodium correction and thyroid hormone replacement.


MiR-339 depresses cell proliferation via directly targeting S-phase kinase-associated protein 2 mRNA in lung cancer.
S-phase kinase-associated protein 2 (Skp2) takes great part in the development of multiple tumors. However, the post-transcriptional modulation mechanism of Skp2 remains unclear. Here, we present a new regulatory microRNA of Skp2, miR-339, which directly targets Skp2 to inhibit cell proliferation in lung cancer. The expression of miR-339 or Skp2 in lung cancer samples was tested by real time-PCR. The correlation between miR-339 and Skp2 in lung cancer samples was analyzed by Pearson's correlation coefficient. The effect of miR-339 or anti-miR-339 on Skp2 was evaluated by immunoblotting. The luciferase reporter gene assay was used to test the targeting of miR-339 on Skp2. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and colony formation analysis were applied to examine the function of miR-339 targeting Skp2 in lung cancer cells. The negative correlation of miR-339 with Skp2 was found in clinical human lung cancer tissues. Furthermore, Skp2 expression was obviously abated by miR-339 in lung cancer A549 cells. Mechanistically, we used bioinformatics to predict that miR-339 could target the 3'-untranslated region of Skp2 mRNA. Luciferase reporter gene assay demonstrated that miR-339 could decrease the luciferase activities of the 3'-untranslated region vector of Skp2. In terms of function, ectopic miR-339 expression significantly suppressed cell proliferation in lung cancer. Overexpressed Skp2 accelerated miR-339-bated proliferation of lung cancer cells. MiR-339 inhibitor promoted cell proliferation in lung cancer, but Skp2 RNA interference reversed miR-339 inhibitor-driven cell proliferation. MiR-339 targets the 3'-untranslated region of Skp2 mRNA to depress the proliferation of lung cancer cells.


Minimal motor for powering particle motion from spin imbalance.
We introduce a minimalistic quantum motor for coupled energy and particle transport. The system is composed of two spins, each coupled to a different bath and to a particle which can move on a ring consisting of three sites. We show that the energy flowing from the baths to the system can be partially converted to perform work against an external driving, even in the presence of moderate dissipation. We also analytically demonstrate the necessity of coupling between the spins. We suggest an experimental realization of our model using trapped ions or quantum dots.


Infertility treatment for postmenopausal patients: an equity-based approach.
This article examines two questions pertaining to the extension of infertility treatment to postmenopausal women. First, what concepts and principles of infertility practice apply to assisted reproduction for the postmenopausal patient? Second, what role should these concepts play in the development of an ethical justification for extending women's reproductive lives past the menopausal boundary? The argument offered here supports their claim to infertility services on the basis of the formal principle of justice, which requires that similar cases be treated similarly. The cases of many postmenopausal patients are argued to be relevantly similar to classes of patients who already receive assistance in reproduction.


Misdiagnosis of conversion disorders.
Five cases are presented describing the clinical features for which they were referred and admitted to a rehabilitation unit and later identified as having been misdiagnosed as having a conversion disorder. The diagnoses were sarcoma-induced osteomalacia, cerebellar medulloblastoma, Huntington's chorea, transverse myelitis, and lower extremity dystonia. A perceived history of psychological difficulties, an unusual neurologic presentation, and normal initial diagnostic testing in a female patient were associated with a misdiagnosis of conversion disorders; unfortunately, these factors also characterize actual conversion disorders.


Evaluation of shading algorithms for surface display: depth information, surface orientation, colour and transparency.
When interpreting a shaded surface image the observer must infer a three-dimensional shape from a two-dimensional image. The principal monocular cues used in this process are surface orientation and apparent depth. Four shading algorithms were compared, ranging from pure depth to pure surface orientation with two intermediates. Eight observers assessed these algorithms using 40 sets of images showing test objects derived from emission computed axial tomograms, X-ray computed tomograms and simulated data. The results demonstrated a highly significant preference (p less than 0.01) for surface orientation over depth information for all observers and both imaging modalities. The coefficient of concordance showed that the observers were in good agreement as to the rank order of the algorithms, with significant agreement (p less than 0.05) for 37 of the 40 sets of images. The overall preferred algorithm was based on a local polynomial fitting procedure and contained primarily surface information. This shading algorithm was extended to include colour, which was used both as an arbitrary surface property to identify parts of a complex object and as a means of conveying temporal information. Further extension of the algorithm to the display of transparent surfaces was facilitated by an illumination model based on purely isotropic light. This enabled even irregular surfaces to be displayed as transparent objects, and was combined with opaque shading for displaying nested surfaces in nuclear magnetic resonance data.


Large negative differential resistance in a molecular junction of carbon nanotube and anthracene.
We propose a novel molecular junction with single walled carbon nanotube (SWNT) as electrodes bridged by an anthracene molecule. It is found that when the coupling between the molecule and the SWNT is noncovalent, the current-voltage (I-V) curve shows a striking nonlinear feature and a large negative differential resistance (NDR) at small bias. While in covalent adsorption site, the I-V curve behaves nearly linear. Theoretical studies based on the nonequilibrium Green's function method demonstrate that mechanism of the NDR is due to the narrow features of the local density of states (LDOS) of the SWNT as well as the alignment between the peak of LDOS of the electrodes and the molecular energy levels.


[Carotid endarterectomy].
Carotid endarterectomy has been a controversial matter since its introduction more than 40 years ago. In the last decade several clinical trials were performed to determine the efficacy of this operation in patients with carotid estenosis and hemispheric or ocular ischemic symptoms. In 1991 the interim results of the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial were reported, both trials demonstrating the beneficial effects of surgery in symptomatic patients with stenosis of greater than 70%. In 1994 the Asymptomatic Carotid Atherosclerosis Study reported their interim results in patients who have stenosis of greater than 60% in favor of endarterectomy, in centers with documented perioperative mortality and morbidity of less than 3%. The Asymptomatic Carotid Surgery Trial is still in progress. All this trials have restored the confidence on carotid endarterectomy.


Hospital Variation and Associated Organizational Factors of Pregnancy-Related Venous Thromboembolism in China.
Identifying organizational factors affecting venous thromboembolism (VTE) incidence and variations between hospitals. From a 2019 survey of VTE and live births in 113 hospitals, organizational factors: (hospital type, characteristics, live birth number), resource availability: (D-dimer, B-scan ultrasonography of lower extremity veins, computed tomographic pulmonary angiography [CTPA], and competency: [risk assessment, use of anticoagulants and patient education], data were collected and the associations, weighted by live birth number, analyzed. Of 113 hospitals in China, 770,828 live births and 526 cases of VTE (68.2 per 100,000 live births) were reported. Nine hospitals lacked B-scan ultrasonography of lower extremity veins and 22 lacked CTPA. Prevalence rates of VTE rates were higher in general hospitals (Odds ratio [OR] = 4.251, 95% CI: 3.373-5.357), hospitals with live births < 10,000 (OR = 1.650-2.193), and hospitals without B-scan ultrasonography (OR = 1.661, 95% CI: 1.096-2.518). Hospitals implementing patient education, had a lower risk of VTE (OR = 0.296-0.374), and VTE rate decreased with the annual increase in live births. Improved hospital resource availability and competency, especially patient education, is vital for reducing VTE-related maternal mortality and morbidity risk.


Cryptococcus paraflavus sp. nov. (Tremellales), isolated from steppe plants in Russia.
Three strains related to Cryptococcus flavus were isolated from plants collected in the Prioksko-terrasny biosphere reserve (Russia). Physiological characterization, mycocinotyping, sequencing of the D1/D2 domain of the 26S rDNA and the ITS region revealed their separate taxonomic position. The name Cryptococcus paraflavus is proposed to accommodate these isolates (type strain VKM Y-2923).


Role of oxidative stress in pathophysiology of rheumatoid arthritis: insights into NRF2-KEAP1 signalling.
Rheumatoid arthritis is one of the most prevalent, chronic, inflammatory disorders involving multiple articular and extra-articular complications. Immune deregulation owing to a combinatorial network of cells, inflammatory components, degrading enzymes, angiogenetic factors, exhibiting pleiotropy, synergy, or redundancy, is a critical hallmark for synovial inflammatory milieu reasoning clinical heterogeneity and variability of the disease. As a prototype of autoimmune disease, the pathophysiology of rheumatoid arthritis has been linked to oxidative stress. However, the exact mechanism for these potential driving factors contributing to disease inception and perpetuation is yet elusive. Nuclear factor erythroid 2-related factor 2 - Kelch ECH associating protein 1 (Nrf2-Keap1) pathway, controlled via multifactorial regulation, functions as a ubiquitous, evolutionarily conserved intracellular defense mechanism. Nrf2-Keap1 signalling maintains homeostatic responses against a plethora of environmental or endogenous deviations in cellular growth, death, redox metabolism, inflammation, bone remodelling, detoxification, etc. Administration of antioxidants as an add-on pharmacotherapy along with conventional drugs has been elucidated as a better measure for disease management. Some of the most promising natural and synthetic redox-based therapeutic compounds function as either scavengers of reactive species, or inhibitors of their sources, or activators of an endogenous antioxidant system (Nrf2-Keap1). The present review focuses on the binomial "rheumatoid arthritis-oxidative stress", bringing insights into their pathophysiological interrelationships and Nrf2 signalling, as well as the implications of potential diagnostic oxidative stress biomarkers and therapeutic interventions directed for disease management in patients with rheumatoid arthritis.Highlights:RA has complex etiopathogenesis, evolving from multiple endogenous and exogenous factors with oxidative stress as a critical pathogenic signature.Oxidative damage and damaged compounds could serve as potent biomarkers for disease diagnosis, therapeutic response, and prognosis.One of the supreme cytoprotective signalling cascades, the Nrf2-Keap1 pathway has been known to elicit a protective effect against RA and various other autoimmune, inflammatory, degenerative disorders.Inclusion of natural and synthetic antioxidants has been encouraged by various studies for additional therapy to conventional drugs for better management of the disease.


Through-focus visual performance measurements and predictions with multifocal contact lenses.
We measured high-contrast visual acuity (VA) and 12c/deg contrast sensitivity (CS) through-focus functions (TFF) of four eyes of four cyclopleged subjects in three conditions: naked eye, with a center-distance and center-near Proclear(R) multifocal addition 2D contact lens. In all conditions, an adaptive optics system statically compensated the astigmatism of the subject's eye alone. Multifocal contact lenses enlarged the width of the curve of through-focus visual performance but reduced the peak performance. We investigated the ability of image quality metrics based on wave-aberration measurements to predict VA and CS TFF. CS(12) metric through-focus and measured through-focus contrast sensitivities were well correlated (r(2)=0.74). Even if visual acuity metrics were often poorer than measured ones, the shapes of the measured through-focus curves and rMTFa(5-15) through-focus were quite comparable (r(2)=0.67).


Molecular analysis of a leprosy immunotherapeutic bacillus provides insights into Mycobacterium evolution.
Evolutionary dynamics plays a central role in facilitating the mechanisms of species divergence among pathogenic and saprophytic mycobacteria. The ability of mycobacteria to colonize hosts, to proliferate and to cause diseases has evolved due to its predisposition to various evolutionary forces acting over a period of time. Mycobacterium indicus pranii (MIP), a taxonomically unknown 'generalist' mycobacterium, acts as an immunotherapeutic against leprosy and is approved for use as a vaccine against it. The large-scale field trials of this MIP based leprosy vaccine coupled with its demonstrated immunomodulatory and adjuvant property has led to human clinical evaluations of MIP in interventions against HIV-AIDS, psoriasis and bladder cancer. MIP, commercially available as 'Immuvac', is currently the focus of advanced phase III clinical trials for its antituberculosis efficacy. Thus a comprehensive analysis of MIP vis-à-vis evolutionary path, underpinning its immanent immunomodulating properties is of the highest desiderata. Genome wide comparisons together with molecular phylogenetic analyses by fluorescent amplified fragment length polymorphism (FAFLP), enterobacterial repetitive intergenic consensus (ERIC) based genotyping and candidate orthologues sequencing revealed that MIP has been the predecessor of highly pathogenic Mycobacterium avium intracellulare complex (MAIC) that did not resort to parasitic adaptation by reductional gene evolution and therefore, preferred a free living life-style. Further analysis suggested a shared aquatic phase of MAIC bacilli with the early pathogenic forms of Mycobacterium, well before the latter diverged as 'specialists'. This evolutionary paradigm possibly affirms to marshall our understanding about the acquisition and optimization of virulence in mycobacteria and determinants of boundaries therein.


Dose response relationships of insulin hypoglycaemia and gastric acid in man.
Fourteen studies of gastric acid secretion in a basal hour and in the two hours after a single intravenous injection of soluble insulin (0.01 to 0.40 units/kg) were performed in a healthy man. The peak acid output after insulin (measured as the two consecutive 15-minute samples giving the highest acid output) was significantly correlated with the lowest concentration of blood glucose, the fall in blood glucose, the rate of fall of blood glucose, and the maximum fall of blood glucose in any 15 minutes. Peak acid outputs after insulin were similar over the range 0.1 to 0.2 units/kg, and greater than at lower or higher doses. These results are contrary to the accepted assumption that insulin-stimulated acid secretion is an ;all-or-none' phenomenon. They support instead the hypothesis that insulin hypoglycaemia provides a quantitative glycopenic stimulus producing quantitative vagal acid response. Extreme hypoglycaemia, below about 15 mg/100 ml of blood glucose, inhibits insulin-stimulated acid secretion.


Prognostication and Goals of Care Decisions in Severe Traumatic Brain Injury: A Survey of The Seattle International Severe Traumatic Brain Injury Consensus Conference Working Group.
Abstract Best practice guidelines have advanced severe traumatic brain injury (TBI) care; however, there is little that currently informs goals of care decisions and processes despite their importance and frequency. Panelists from the Seattle International severe traumatic Brain Injury Consensus Conference (SIBICC) participated in a survey consisting of 24 questions. Questions queried use of prognostic calculators, variability in and responsibility for goals of care decisions, and acceptability of neurological outcomes, as well as putative means of improving decisions that might limit care. A total of 97.6% of the 42 SIBICC panelists completed the survey. Responses to most questions were highly variable. Overall, panelists reported infrequent use of prognostic calculators, and observed variability in patient prognostication and goals of care decisions. They felt that it would be beneficial for physicians to improve consensus on what constitutes an acceptable neurological outcome as well as what chance of achieving that outcome is acceptable. Panelists felt that the public should help to define what constitutes a good outcome and expressed some support for a "nihilism guard." More than 50% of panelists felt that if it was certain to be permanent, a vegetative state or lower severe disability would justify a withdrawal of care decision, whereas 15% felt that upper severe disability justified such a decision. Whether conceptualizing an ideal or existing prognostic calculator to predict death or an unacceptable outcome, on average a 64-69% chance of a poor outcome was felt to justify treatment withdrawal. These results demonstrate important variability in goals of care decision making and a desire to reduce this variability. Our panel of recognized TBI experts opined on the neurological outcomes and chances of those outcomes that might prompt consideration of care withdrawal; however, imprecision of prognostication and existing prognostication tools is a significant impediment to standardizing the approach to care-limiting decisions.


Medical interpreter-mediated genetic counseling for Spanish preferring adults at risk for a hereditary cancer syndrome.
The objective of this study was to identify interpretation challenges specific to exome sequencing and errors of potential clinical significance in the context of genetic counseling for adults at risk for a hereditary cancer syndrome. Thirty transcripts of interpreter-mediated telephone results disclosure genetic counseling appointments were coded for errors by bilingual researchers, and the coders applied an overall rating to denote the degree to which the errors interfered with communication overall. Genetic counselors reviewed a subset of errors flagged for potential clinical significance to identify those likely to have clinical impact. Qualitative interviews with 19 interpreters were analyzed to elucidate the challenges they face in interpreting for genetic counseling appointments. Our analysis identified common interpretation errors such as raising the register, omissions, and additions. Further, we found errors specific to genetic counseling concepts and content that appeared to impact the ability of the genetic counselor to accurately assess risk. These errors also may have impacted the patient's ability to understand their results, access appropriate follow-up care, and communicate with family members. Among interpreters' strengths was the use of requests for clarification; in fact, even more use of clarification would have been beneficial in these encounters. Qualitative interviews surfaced challenges stemming from the structure of interpreter work, such as switching from medical and nonmedical interpretations without substantial breaks. Importantly, while errors were frequent, most did not impede communication overall, and most were not likely to impact clinical care. Nevertheless, potentially clinically impactful errors in communication of genetics concepts may contribute to inequitable care for limited English proficient patients and suggest that additional training in genetics and specialization in healthcare may be warranted. In addition, training for genetic counselors and guidance for patients in working effectively with interpreters could enhance interpreters' transmission of complex genetic concepts.


Current results on the use of imatinib mesylate in patients with relapsed Philadelphia chromosome positive leukemia after allogeneic or syngeneic hematopoietic stem cell transplantation.
Here, we describe a patient diagnosed with chronic myelogenous leukemia who relapsed after matched unrelated donor SCT. The patient was treated with imatinib mesylate and donor lymphocyte infusions, and achieved a complete molecular remission. Additionally, safety and efficacy of imatinib mesylate in a total of 134 patients from 8 centers who underwent allogeneic or syngeneic stem cell transplantation (SCT) and had a relapse of Philadelphia chromosome positive leukemia was reviewed. Data was compiled from abstracts accepted as oral or poster presentations at the ASH (American Society of Hematology) 2001 and EBMT (European Group for Blood and Marrow Transplantation) 2001 & 2002 meetings and additionally literature published on this patient group. Efficacy of imatinib therapy was assessed by morphology, cytogenetic analysis, and determination of donor chimerism. In the evaluable population, hematologic and cytogenetic responses were observed in 66% and 60% of the patients, respectively. Fifty-one of 114 (45%) patients achieved a complete cytogenetic response. No response or progress of disease was noted in 22 out of evaluable 91 patients. The observation period was limited to a maximum of 28 months. A significant improvement in donor chimerism was frequently observed. Only five cases of significant GVHD were reported. Preliminary results show that imatinib mesylate has the potential to positively influence the ratio of donor and recipient cells without inducing a high incidence of severe GVHD. The data suggest that earlier start of imatinib mesylate prior to hematologic relapse in minimum residual disease (MRD) positive patients is a promising treatment concept.


The future of risk factor research in understanding the etiology of eating disorders.
This article explores whether particular risk factors are best seen as precursors or as symptoms. Psychological, cultural, family, developmental, and biological risk domains that may be important in the etiology of eating disorders are briefly reviewed. We describe a 4-year prospective study assessing a wide range of risk factors for development of eating disorders in a large school-based sample of adolescents. For subjects who were relatively asymptomatic, a personality or temperamental characteristic of negative affect/esteem measured at study entrance was the only significant predictor of later risk score for both girls and boys. The significant comorbidity demonstrated in a separate group that had high risk for eating disorders suggests that negative affectivity may be a vulnerability factor for overall psychopathology rather than a predisposition specifically for eating disorders. Following subjects through the young-adult years and later may further clarify the range of influences affecting disordered eating. Primary prevention and early intervention programs in the schools are also recommended.