Role of physiological ClC-1 Cl- ion channel regulation for the excitability and function of working skeletal muscle.
Electrical membrane properties of skeletal muscle fibers have been thoroughly studied over the last five to six decades. This has shown that muscle fibers from a wide range of species, including fish, amphibians, reptiles, birds, and mammals, are all characterized by high resting membrane permeability for Cl(-) ions. Thus, in resting human muscle, ClC-1 Cl(-) ion channels account for ∼80% of the membrane conductance, and because active Cl(-) transport is limited in muscle fibers, the equilibrium potential for Cl(-) lies close to the resting membrane potential. These conditions-high membrane conductance and passive distribution-enable ClC-1 to conduct membrane current that inhibits muscle excitability. This depressing effect of ClC-1 current on muscle excitability has mostly been associated with skeletal muscle hyperexcitability in myotonia congenita, which arises from loss-of-function mutations in the CLCN1 gene. However, given that ClC-1 must be drastically inhibited (∼80%) before myotonia develops, more recent studies have explored whether acute and more subtle ClC-1 regulation contributes to controlling the excitability of working muscle. Methods were developed to measure ClC-1 function with subsecond temporal resolution in action potential firing muscle fibers. These and other techniques have revealed that ClC-1 function is controlled by multiple cellular signals during muscle activity. Thus, onset of muscle activity triggers ClC-1 inhibition via protein kinase C, intracellular acidosis, and lactate ions. This inhibition is important for preserving excitability of working muscle in the face of activity-induced elevation of extracellular K(+) and accumulating inactivation of voltage-gated sodium channels. Furthermore, during prolonged activity, a marked ClC-1 activation can develop that compromises muscle excitability. Data from ClC-1 expression systems suggest that this ClC-1 activation may arise from loss of regulation by adenosine nucleotides and/or oxidation. The present review summarizes the current knowledge of the physiological factors that control ClC-1 function in active muscle.


C/EBPβ promotes angiogenesis through secretion of IL-6, which is inhibited by genistein, in EGFRvIII-positive glioblastoma.
To study the mechanisms underlying the IL-6-promoted angiogenic microenvironment in EGFRvIII-positive glioblastoma, VEGF expression in EGFRvIII-positive/negative tumors was determined by optical molecular imaging. Next, the HUVEC tube formation assay, Western blot, qPCR, RNA silencing, chromatin immunoprecipitation, luciferase reporter and ELISA assays were performed to examine the role of IL-6 and C/EBPβ in the formation of the angiogenic microenvironment in EGFRvIII-positive tumors. Finally, in vitro and in vivo genistein treatment experiments were conducted to challenge the interaction between the IL-6 promoter and C/EBPβ. Optical imaging revealed greater VEGF expression in EGFRvIII-positive tumor-bearing mice, suggesting an angiogenic microenvironment. In vitro experiments demonstrated that C/EBPβ-mediated regulation of IL-6 was indispensable for maintenance of this angiogenic microenvironment. In contrast, genistein-mediated upregulation of CHOP impeded C/EBPβ interaction with the IL-6 promoter, thus disturbing the angiogenic microenvironment. This more malignant microenvironment in EGFRvIII glioblastoma is generated, at least in part, by greater VEGF, IL-6 and C/EBPβ expression. Interaction of C/EBPβ with the IL-6 promoter maintains this angiogenic microenvironment, while disturbance of this dynamically balanced interaction inhibits EGFRvIII tumor proliferation by reducing both VEGF and IL-6 expression.


The clinical effectiveness and cost-effectiveness of telephone triage for managing same-day consultation requests in general practice: a cluster randomised controlled trial comparing general practitioner-led and nurse-led management systems with usual care (the ESTEEM trial).
Telephone triage is proposed as a method of managing increasing demand for primary care. Previous studies have involved small samples in limited settings, and focused on nurse roles. Evidence is limited regarding the impact on primary care workload, costs, and patient safety and experience when triage is used to manage patients requesting same-day consultations in general practice. In comparison with usual care (UC), to assess the impact of GP-led telephone triage (GPT) and nurse-led computer-supported telephone triage (NT) on primary care workload and cost, patient experience of care, and patient safety and health status for patients requesting same-day consultations in general practice. Pragmatic cluster randomised controlled trial, incorporating economic evaluation and qualitative process evaluation. General practices (n = 42) in four regions of England, UK (Devon, Bristol/Somerset, Warwickshire/Coventry, Norfolk/Suffolk). Patients requesting same-day consultations. Practices were randomised to GPT, NT or UC. Data collection was not blinded; however, analysis was conducted by a statistician blinded to practice allocation. Primary - primary care contacts [general practice, out-of-hours primary care, accident and emergency (A&E) and walk-in centre attendances] in the 28 days following the index consultation request. Secondary - resource use and costs, patient safety (deaths and emergency hospital admissions within 7 days of index request, and A&E attendance within 28 days), health status and experience of care. Of 20,990 eligible randomised patients (UC n = 7283; GPT n = 6695; NT n = 7012), primary outcome data were analysed for 16,211 patients (UC n = 5572; GPT n = 5171; NT n = 5468). Compared with UC, GPT and NT increased primary outcome contacts (over 28-day follow-up) by 33% [rate ratio (RR) 1.33, 95% confidence interval (CI) 1.30 to 1.36] and 48% (RR 1.48, 95% CI 1.44 to 1.52), respectively. Compared with GPT, NT was associated with a marginal increase in primary outcome contacts by 4% (RR 1.04, 95% CI 1.01 to 1.08). Triage was associated with a redistribution of primary care contacts. Although GPT, compared with UC, increased the rate of overall GP contacts (face to face and telephone) over the 28 days by 38% (RR 1.38, 95% CI 1.28 to 1.50), GP face-to-face contacts were reduced by 39% (RR 0.61, 95% CI 0.54 to 0.69). NT reduced the rate of overall GP contacts by 16% (RR 0.84, 95% CI 0.78 to 0.91) and GP face-to-face contacts by 20% (RR 0.80, 95% CI 0.71 to 0.90), whereas nurse contacts increased. The increased rate of primary care contacts in triage arms is largely attributable to increased telephone contacts. Estimated overall patient-clinician contact time on the index day increased in triage (GPT = 10.3 minutes; NT = 14.8 minutes; UC = 9.6 minutes), although patterns of clinician use varied between arms. Taking account of both the pattern and duration of primary outcome contacts, overall costs over the 28-day follow-up were similar in all three arms (approximately £75 per patient). Triage appeared safe, and no differences in patient health status were observed. NT was somewhat less acceptable to patients than GPT or UC. The process evaluation identified the complexity associated with introducing triage but found no consistency across practices about what works and what does not work when implementing it. Introducing GPT or NT was associated with a redistribution of primary care workload for patients requesting same-day consultations, and at similar cost to UC. Although triage seemed to be safe, investigation of the circumstances of a larger number of deaths or admissions after triage might be warranted, and monitoring of these events is necessary as triage is implemented. Current Controlled Trials ISRCTN20687662. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 13. See the NIHR Journals Library website for further project information.


Factors associated with self-medication in users of drugstores and pharmacies in Peru: an analysis of the National Survey on User Satisfaction of Health Services, ENSUSALUD 2015.
Background: Irresponsible self-medication is a problem for health systems in developing countries. We aimed to estimate the frequency of self-medication and associated factors in users of drugstores and pharmacies in Peru. Methods: We performed a secondary data analysis of the 2015 National Survey on User Satisfaction of Health Services (ENSUSALUD), a two-stage probabilistic sample of all regions of Peru. Non self-medication (NSM), responsible self-medication (RSM) and irresponsible self-medication (ISM) were defined as the outcome categories. Demographic, social, cultural and health system variables were included as covariates. We calculated relative prevalence ratios (RPR) with their 95% confidence intervals (95%CI) using crude and adjusted multinomial logistic regression models for complex samples with NSM as the referent category. Results: 2582 participants were included. The average age was 41.4 years and the frequencies of NSM, RSM and ISM were 25.2%, 23.8% and 51.0%; respectively. The factors associated with RSM were male gender (RPR: 1.35; 95%CI: 1.06-1.72), being between 40 and 59 years old (RPR: 0.53; 95%IC: 0.39-0.72), being 60 or older (RPR: 0.39; 95%IC: 0.25-0.59), not having health insurance (RPR: 1.89; 95%CI: 1.31-2.71) and living in the Highlands region (RPR: 2.27; 95%CI: 1.23-4.21). The factors associated with ISM were male gender (RPR: 1.41; 95%CI: 1.16-1.72), being between 40 and 59 years old (RPR: 0.68; 95%IC: 0.53-0.88), being 60 or older (RPR: 0.65; 95%IC: 0.48-0.88) and not having health insurance (RPR: 2.03; 95%CI: 1.46-2.83). Conclusion: Around half of the population practiced ISM, which was associated with demographic and health system factors. These outcomes are the preliminary evidence that could contribute to the development of health policies in Peru.


Patient-centred, self-administered acupressure for Chinese advanced cancer patients experiencing fatigue and co-occurring symptoms: A pilot randomised controlled trial.
To evaluate the feasibility and potential effects of patient-centred self-administered acupressure for alleviating fatigue and co-occurring symptoms among Chinese advanced cancer patients receiving treatment. Thirty advanced cancer patients who screened positive for moderate/severe fatigue with symptoms of insomnia and/or pain were recruited from a hospital in Hong Kong. They were randomly assigned (1:1) to receive a 4-week patient-centred self-administered acupressure intervention or health education. Fatigue (primary outcome) and secondary outcomes (sleep quality, pain, fatigue-sleep disturbance-pain symptom cluster severity, anxiety, depression and quality of life) were measured by questionnaires and actigraphy. Twenty-four participants (80%) completed the study. Adherence to self-administered acupressure practice was satisfactory, with all retained participants attending all sessions and 90.9% practising acupressure daily. All completers rated the class as very enjoyable or quite enjoyable. Fatigue, pain, symptom cluster severity, anxiety, depression and quality of life appeared to improve from baseline to post-intervention in the intervention group. Among these outcomes, only the between-group difference in anxiety post-intervention was significant. The group × time interaction effect was nonsignificant for all outcomes. Patient-centred self-administered acupressure appears to be feasible and acceptable among advanced cancer patients. A fully powered trial is warranted to confirm the intervention effect.


A transgenic mouse model for human neurofibromatosis.
Human T-lymphotropic virus type 1 (HTLV-1) has been associated with the neurologic disorder tropical spastic paraparesis and possibly with multiple sclerosis. The tat gene of HTLV-1 under control of its own long terminal repeat is capable of inducing tumors in transgenic mice. The morphologic and biologic properties of these tumors indicate their close resemblance to human neurofibromatosis (von Recklinghausen's disease), the most common single gene disorder to affect the nervous system. The high spontaneous incidence of this disease, together with the diverse clinical and pathologic features associated with it, suggests that environmental factors may account for some of the observed cases. Multiple tumors developed simultaneously in the transgenic tat mice at approximately 3 months of age, and the phenotype was successfully passed through three generations. The tumors arise from the nerve sheaths of peripheral nerves and are composed of perineural cells and fibroblasts. Tumor cells from these mice adapt easily to propagation in culture and continue to express the tat protein in significant amounts. When transplanted into nude mice, these cultured cells efficiently induce tumors. Evidence of HTLV-1 infection in patients with neural and other soft tissue tumors is needed in order to establish a link between infection by this human retrovirus and von Recklinghausen's disease and other nonlymphoid tumors.


A microbiota-generated bile salt induces biofilm formation in Clostridium difficile.
Clostridium difficile is a major cause of nosocomial infections. Bacterial persistence in the gut is responsible for infection relapse; sporulation and other unidentified mechanisms contribute to this process. Intestinal bile salts cholate and deoxycholate stimulate spore germination, while deoxycholate kills vegetative cells. Here, we report that sub-lethal concentrations of deoxycholate stimulate biofilm formation, which protects C. difficile from antimicrobial compounds. The biofilm matrix is composed of extracellular DNA and proteinaceous factors that promote biofilm stability. Transcriptomic analysis indicates that deoxycholate induces metabolic pathways and cell envelope reorganization, and represses toxin and spore production. In support of the transcriptomic analysis, we show that global metabolic regulators and an uncharacterized lipoprotein contribute to deoxycholate-induced biofilm formation. Finally, Clostridium scindens enhances biofilm formation of C. difficile by converting cholate into deoxycholate. Together, our results suggest that deoxycholate is an intestinal signal that induces C. difficile persistence and may increase the risk of relapse.


Whole genome sequencing and de novo assembly identifies Sydney-like variant noroviruses and recombinants during the winter 2012/2013 outbreak in England.
Norovirus is the commonest cause of epidemic gastroenteritis among people of all ages. Outbreaks frequently occur in hospitals and the community, costing the UK an estimated £110 m per annum. An evolutionary explanation for periodic increases in norovirus cases, despite some host-specific post immunity is currently limited to the identification of obvious recombinants. Our understanding could be significantly enhanced by full length genome sequences for large numbers of intensively sampled viruses, which would also assist control and vaccine design. Our objective is to develop rapid, high-throughput, end-to-end methods yielding complete norovirus genome sequences. We apply these methods to recent English outbreaks, placing them in the wider context of the international norovirus epidemic of winter 2012. Norovirus sequences were generated from 28 unique clinical samples by Illumina RNA sequencing (RNA-Seq) of total faecal RNA. A range of de novo sequence assemblers were attempted. The best assembler was identified by validation against three replicate samples and two norovirus qPCR negative samples, together with an additional 20 sequences determined by PCR and fractional capillary sequencing. Phylogenetic methods were used to reconstruct evolutionary relationships from the whole genome sequences. Full length norovirus genomes were generated from 23/28 samples. 5/28 partial norovirus genomes were associated with low viral copy numbers. The de novo assembled sequences differed from sequences determined by capillary sequencing by <0.003%. Intra-host nucleotide sequence diversity was rare, but detectable by mapping short sequence reads onto its de novo assembled consensus. Genomes similar to the Sydney 2012 strain caused 78% (18/23) of cases, consistent with its previously documented association with the winter 2012 global outbreak. Interestingly, phylogenetic analysis and recombination detection analysis of the consensus sequences identified two related viruses as recombinants, containing sequences in prior circulation to Sydney 2012 in open reading frame (ORF) 2. Our approach facilitates the rapid determination of complete norovirus genomes. This method provides high resolution of full norovirus genomes which, when coupled with detailed epidemiology, may improve the understanding of evolution and control of this important healthcare-associated pathogen.


Comparison between one and two dose SARS-CoV-2 vaccine prioritization for a fixed number of vaccine doses.
The swift development of SARS-CoV-2 vaccines has been met with worldwide commendation. However, in the context of an ongoing pandemic there is an interplay between infection and vaccination. While infection can grow exponentially, vaccination rates are generally limited by supply and logistics. With the first SARS-CoV-2 vaccines receiving medical approval requiring two doses, there has been scrutiny on the spacing between doses; an elongated period between doses allows more of the population to receive a first vaccine dose in the short-term generating wide-spread partial immunity. Focusing on data from England, we investigated prioritization of a one dose or two dose vaccination schedule given a fixed number of vaccine doses and with respect to a measure of maximizing averted deaths. We optimized outcomes for two different estimates of population size and relative risk of mortality for at-risk groups within the Phase 1 vaccine priority order. Vaccines offering relatively high protection from the first dose favour strategies that prioritize giving more people one dose, although with increasing vaccine supply eventually those eligible and accepting vaccination will receive two doses. While optimal dose timing can substantially reduce the overall mortality risk, there needs to be careful consideration of the logistics of vaccine delivery.


Investigation of human cationic antimicrobial protein-18 (hCAP-18), lactoferrin and CD163 as potential biomarkers for ovarian cancer.
Epithelial ovarian cancer is one of the leading causes of gynaecological cancer morbidity and mortality in women. Early stage ovarian cancer is usually asymptomatic, therefore, is often first diagnosed when it is widely disseminated. Currently available diagnostics lack the requisite sensitivity and specificity to be implemented as community-based screening tests. The identification of additional biomarkers may improve the diagnostic efficiency of multivariate index assays. The aims of this study were to characterise and compare the ovarian tissue immunohistochemical localisation and plasma concentrations of three putative ovarian cancer biomarkers: human cationic antimicrobial protein-18 (hCAP-18); lactoferrin; and CD163 in normal healthy women and women with ovarian cancer. In this case-control cohort study, ovarian tissue and blood samples were obtained from 164 women (73 controls, including 28 women with benign pelvic masses; 91 cancer, including 21 women with borderline tumours). Localisation of each antigen within the ovary was assessed by immunohistochemistry and serum concentrations determined by ELISA assays. Immunoreactive (ir) hCAP-18 and lactoferrin were identified in epithelial cells, while CD163 was predominately localised in stromal cells. Tissue ir CD163 increased significantly (P<0.05) with disease grade. Median plasma concentrations of soluble (s)CD163 were significantly greater in the cases (3220 ng/ml) than in controls (2488 ng/ml) (P< 0.01). Median plasma concentrations of hCAP-18 and lactoferrin were not significantly different between cases and controls. The classification efficiency of each biomarker (as determined by the area under the receiver operator characteristic curve; AUC) was: 0.67± 0.04; 0.62 ± 0.08 and 0.51 ± 0.07 for sCD163, hCAP-18 and lactoferrin, respectively. When the 3 biomarkers were modelled using stochastic gradient boosted logistic regression, the AUC increased to 0.95 ± 0.03. The data obtained in this study establishes the localisation and concentrations of CD163, hCAP-18, and lactoferrin in ovarian tumours and peripheral blood. Individually, the 3 biomarkers display only modest diagnostic efficiency as assessed by AUC. When combined in a multivariate index assay, however, diagnostic efficiency increases significantly. As such, the utility of the biomarker panel, as an aid in the diagnosis of cancer in symptomatic women, is worthy of further investigation in a larger phase 2 biomarker trial.


Effect of simple spike firing mode on complex spike firing rate and waveform in cerebellar Purkinje cells in non-anesthetized mice.
Cerebellar Purkinje cells receive two different excitatory inputs from parallel and climbing fibers, causing simple and complex spikes, respectively. Purkinje cells present three modes of simple spike firing, namely tonic, silent and bursting. The influence of complex spike firing on simple spike firing has been extensively studied. However, it is unknown whether and how the simple spike firing mode may influence complex spike waveform and firing rate in vivo. We studied complex spike firing during tonic and silent mode periods in non-anesthetized mice. We found that complex spike firing rate is not influenced by simple spike firing modes, but that the complex spike waveform is altered following high frequency simple spike firing. This alteration is a specific decrement of the second depolarizing component of the complex spike. We demonstrate that the amplitude of the second depolarizing component is inversely proportional to the simple spike firing rate preceding the complex spike and that this amplitude is independent of previous complex spike firing. This waveform modulation is different from previously reported modulation in paired-pulse depression and refractoriness.


Stimulation of Leydig and Sertoli Cellular Secretory Function by Anti-Oestrogens: Tamoxifen.
Tamoxifen is a selective oestrogen receptor modulator (SERM). SERMs act on oestrogen receptors to inhibit oestradiol mediated negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, thereby upregulating gonadotrophin secretion and release from the pituitary. Hence, Tamoxifen is used to upregulate activation of the HPG axis in the treatment of male-factor infertility. However, due to a lack of robust evidence, Tamoxifen has not been FDA approved for use in male-factor infertility and so its use is currently off-label. In this study, we performed a literature search of the OVID medline database and identified 37 studies describing the effects of tamoxifen which we then reviewed. Evidence suggests Tamoxifen effectively increases androgen levels and sperm concentrations in males with idiopathic oligozoospermia. Evidence for increased motility and pregnancy rates in these patients is less conclusive. Further randomised control trials are needed to elucidate the safety of Tamoxifen combination therapies and their efficacy in improving pregnancy rates.


Simultaneous chromatography and electrophoresis: two-dimensional planar separations.
Single-dimension separations are routinely coupled in series to achieve two-dimensional separations, yet little has been done to simultaneously exploit multiple dimensions during separation. In this work, simultaneous chromatography and electrophoresis is introduced and evaluated for its potential to achieve two-dimensional separations. In simultaneous chromatography and electrophoresis, chromatography occurs via capillary action while an orthogonal electric field concurrently promotes electrophoresis in a second dimension. A novel apparatus with a dual solvent reservoir was designed to apply the concurrent electric field. Various compounds were used to characterize the apparatus and technique, i.e., vitamins, amino acids, and dyes. Improved separation is reported with equivalent analysis times in comparison to planar chromatography alone. The feasibility of simultaneously employing chromatography and electrophoresis in two dimensions is discussed.


Immunogenicity of hepatitis A vaccination in decompensated cirrhotic patients.
Hepatitis A virus (HAV) vaccination is recommended in chronic liver disease because of an increased morbidity and mortality associated with HAV superinfection. However, data regarding the efficacy of HAV vaccination in patients with advanced chronic liver disease is limited. We assessed the efficacy of a standard HAV vaccination schedule in decompensated chronic liver disease in comparison with compensated disease and defined clinical predictors associated with seroconversion. Eighty-four anti-HAV antibody-negative patients, 49 with compensated liver disease, and 35 with decompensated disease were enrolled. Seroconversion was measured by qualitative and quantitative anti-HAV antibody measurements 1 month after each vaccine dose, and univariate/multivariate analysis was performed to define clinical predictors associated with seroconversion. One month after the primary dose, 71.4% of patients with compensated liver disease had detectable anti-HAV antibody compared with 37.1% with decompensated liver disease (P <.05). One month after the booster dose, 98% of compensated patients seroconverted compared with 65.7% with decompensated disease (P <.05). The median serum antibody concentration in compensated liver disease was 76.4 mIU/mL at month 1 and 327.91 mIU/mL at month 7 compared with 20.0 mIU/mL and 102.57 mIU/mL, respectively, in decompensated disease. On multivariate analysis, Child-Pugh class was the only factor predicting response to vaccination. Seroconversion after HAV vaccination was significantly less common in decompensated liver disease and the presence of advanced disease (Child-Pugh class B/C) predicted a lower response rate. These findings indicate that the response to HAV vaccination in chronic liver disease is optimal when targeted to patients before the development of hepatic decompensation.


Isoproterenol causes hyperpolarization through opening of ATP-sensitive potassium channels in vascular smooth muscle of the canine saphenous vein.
Experiments were designed to determine how isoproterenol affects the cell membrane potential of smooth muscle cells of the canine saphenous vein. Measurements of membrane potential were performed using glass microelectrodes. Isoproterenol (10(-9) to 10(-6) M) caused sustained, concentration-dependent membrane hyperpolarizations in tissues with and without endothelium. ICI 118,551 (a selective beta 2-adrenoceptor antagonist), but not atenolol (a selective beta 1-adrenoceptor antagonist), abolished the hyperpolarization to isoproterenol. Forskolin, an activator of adenylate cyclase, produced sustained hyperpolarizations, which were not mimicked by 1,9-dideoxyforskolin. Incubation with either ouabain or extracellular K(+)-free solution did not inhibit the electrical response to isoproterenol. Glibenclamide (a selective ATP-sensitive K+ channel antagonist) attenuated the hyperpolarizations induced by either isoproterenol or forskolin, whereas charybdotoxin (an inhibitor of large conductance Ca(++)-activated K+ channels) did not. These findings suggest that isoproterenol opens ATP-sensitive K+ channels indirectly through activation of adenylate cyclase in the smooth muscle of the canine saphenous vein. The adrenergic receptor involved belongs to the beta 2-adrenoceptor subtype.


Health Literacy Is Associated With Health Behaviors and Social Factors Among Older Adults: Results from the LifeLines Cohort Study.
This study assesses the associations between health literacy and various health behaviors and social factors among older adults, and whether social factors moderate the other associations. Data from 3,241 participants in the LifeLines Cohort Study were analyzed (mean baseline age = 68.9 years). Data on health literacy, health behaviors (physical activity, fruit and vegetable consumption, smoking, breakfast consumption, alcohol consumption, and body mass index (BMI), and social factors (loneliness, social support, social activities, social contacts, and living situation) were collected in three waves. Logistic regression analyses were used, adjusted for age and gender. Low health literacy was associated with insufficient physical activity, insufficient fruit and vegetable consumption, lack of regular breakfast consumption, obesity (odds ratios (ORs) > 1.31, p-values < .005) and low alcohol use (OR = 0.81, p = .013), but not with smoking. Low health literacy was also associated with greater loneliness, engaging in fewer social activities, and having fewer social contacts (ORs > 1.48, p-values < .005), but not with social support or living situation. Only the association between health literacy and smoking was moderated by social contacts, but this finding needs confirmation in future studies. In conclusion, low health literacy is negatively associated with health behaviors and social factors in older adults, but social factors seldom moderate the associations between health literacy and health behaviors.


Risk Factors of Infectious Complications After Endobronchial Ultrasound-Guided Transbronchial Biopsy.
Infectious complications after endobronchial ultrasound-guided transbronchial biopsy with a guide sheath (EBUS-GS-TBB) are serious in that they may delay or change scheduled subsequent therapy. The aim of this study was to identify risk factors for infection after EBUS-GS-TBB. What are the risk factors for infection after EBUS-GS-TBB? We retrospectively reviewed the medical records of 1,045 consecutive patients who had undergone EBUS-GS-TBB for peripheral lung lesions between January 2013 and December 2017 at Fujita Health University Hospital. We evaluated the following risk factors for infectious complications after EBUS-GS-TBB: relevant patient characteristics (age and comorbidities), lesion size, CT scan features of target lesion (intratumoral low-density areas [LDAs] and cavitation), stenosis of responsible bronchus observed by bronchoscopy, and laboratory data before EBUS-GS-TBB (WBC count and C-reactive protein concentration). Forty-seven of the study patients developed infectious complications (24 with pneumonia, 14 with intratumoral infection, three with lung abscess, three with pleuritis, and three with empyema), among whom the complication caused a delay in cancer treatment in 13 patients, cancellation of cancer treatment in seven patients, and death in three patients. Multivariate analysis showed that cavitation (P = .007), intratumoral LDAs (P < .001), and stenosis of responsible bronchus observed by bronchoscopy (P < .001) were significantly associated with infectious complications after EBUS-GS-TBB. Prophylactic antibiotics had been administered to 13 patients in the infection group. Propensity matched analysis could not show significant benefit of prophylactic antibiotics in preventing post-EBUS-GS-TBB infections. Cavitation, LDAs for CT scan features of target lesions, and stenosis of responsible bronchus observed by bronchoscopy are risk factors of post-EBUS-GS-TBB infection. In the cohort, prophylactic antibiotics failed to prevent infectious complications.


In vivo mechanism by which leflunomide controls lymphoproliferative and autoimmune disease in MRL/MpJ-lpr/lpr mice.
Two activities have been identified for the immunosuppressive metabolite of leflunomide, A77 1726: inhibition of dihydroorotate dehydrogenase (DHO-DHase), an enzyme involved in the biosynthesis of pyrimidine nucleotides (PyN); and inhibition of protein tyrosine kinases. The in vitro potency of A77 1726 as a DHO-DHase inhibitor is reported to be 10- to 500-fold greater than as a tyrosine kinase inhibitor. These observations suggested that the immunosuppressive efficacy of leflunomide in vivo is related to inhibition of DHO-DHase. However, observations that patients with disorders in the PyN synthetic pathway are not overtly immunodeficient militate against this hypothesis. We investigated the effects of leflunomide in vivo and report that amelioration of lymphoproliferative and autoimmune diseases in MRL/MpJ-lpr/lpr (lpr/lpr) mice by leflunomide is not accompanied by reduced PyN concentrations in lymph node cells. Our hypothesis that lymphocytes could salvage serum uridine to counter the effects of reduced PyN synthesis in vivo was supported by in vitro studies. Finally, we observed that amelioration of disease correlated with a reduction of tyrosine phosphorylated proteins in lymph node cells of lpr/lpr mice. These observations suggest that the primary mechanism by which leflunomide prevents autoimmune and lymphoproliferative diseases in lpr/lpr mice is not depletion of PyN, but correlates with reduced tyrosine phosphorylation concentrations in lymph node cells.


How do artistic creative activities regulate our emotions? Validation of the Emotion Regulation Strategies for Artistic Creative Activities Scale (ERS-ACA).
There is a rich literature exploring emotional responses to engaging in artistic creative activities such as making music, writing, dancing and crafts. However, it remains unclear how such activities affect our emotions; specifically which mental processes ('strategies') are used to regulate our emotional responses. This paper therefore describes the design and validation of a novel instrument measuring types of emotional regulation strategies (ERSs) used when engaging in artistic creative activities: the Emotion Regulation Strategies for Artistic Creative Activities Scale (ERS-ACA). Using data from an initial pilot study (n = 740 adults, 80.4% female, median age 25-34) and a follow-up large internet sample (n = 47,924, 56.7% female, average age 47.3 ± 14.6 years), we followed a theory-driven iterative factor analysis process. Our analyses converged on a final 18-item scale comprising an overall 'general' factor of ERSs alongside three subscales: a 7-item factor comprising 'avoidance strategies' (such as distraction, suppression and detachment), a 6-item factor comprising 'approach strategies' (such as acceptance, reappraisal and problem solving), and a 5-item factor comprising 'self-development strategies' (such as enhanced self-identify, improved self-esteem and increased agency). All factors showed strong internal reliability (Cronbach's alpha: General Factor = 0.93, Factor 1 = 0.9, Factor 2 = 0.88, Factor 3 = 0.88). We confirmed strong convergent and divergent validity, construct validity, consistency of internal reliability and test-retest reliability of the scale in a third study (n = 165, 82.2% female, average age 46.3 ± 12.2 years). In conclusion, artistic creative activities appear to affect our emotions via a number of ERSs that can be broadly classified into three categories: avoidance, approach and self-development. The ERS-ACA scale presented and validated here should support further research into the use of ERSs when engaging in artistic creative activities and enhance our understanding about how these activities affect mental health.


Regular versus as-needed budesonide and formoterol combination treatment for moderate asthma: a non-inferiority, randomised, double-blind clinical trial.
Treatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting β2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma. In this non-inferiority randomised clinical trial, we recruited adult patients (18-65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 μg budesonide and 4·5 μg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 μg budesonide and 4·5 μg formoterol combination plus symptom-driven 500 μg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00849095. Between April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2-17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated. In patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small. Italian Medicines Agency.


Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: implications for wild-type, V30M, and L55P amyloid fibril formation.
Analytical ultracentrifugation methods were utilized to further characterize the acid denaturation pathways of wild-type, V30M, and L55P transthyretin (TTR) that generate intermediates leading to amyloid fibril formation and possibly the diseases senile systemic amyloidosis and familial amyloid polyneuropathy. Equilibrium and velocity methods were employed herein to characterize the TTR quaternary structural requirements for amyloid fibril formation. From neutral to slightly acidic conditions (pH 7.5-5.1), wild-type transthyretin (0.2-0.3 mg/mL, 100 mM KCl, 37 degrees C) exists as a tetramer and is incapable of fibril formation. Under more acidic conditions (pH 5 to 3.9), tetrameric wild-type TTR slowly dissociates to a monomer having an alternatively folded tertiary structure(s) that self-assembles at physiological concentration (0.2 mg/mL) into a ladder of quaternary structural intermediates of increasing molecular weight. These intermediates appear to be on the pathway of amyloid fibril formation, since they ultimately disappear when amyloid fibrils are observed. The V30M and L55P TTR variants exhibit similar acid denaturation pathways, with the exception that dissociation of the tetramer to the monomeric amyloidogenic intermediate occurs at a higher pH and to a much greater extent, allowing the quaternary structural intermediates to be readily observed by velocity methods. Partial denaturation and assembly of the monomeric amyloidogenic intermediate(s) occur at pH 5.4 for V30M and L55P TTR over a 72 h period, during which wild-type TTR maintains its normal tetrameric three-dimensional structure. Interestingly, the L55P and V30M familial amyloid polyneuropathy (FAP) associated variants form amyloid protofilaments at pH 7.5 (37 degrees C) after several weeks of incubation, suggesting that the activation barriers for TTR tetramer dissociation to the monomeric amyloidogenic intermediate are much lower for the FAP variants relative to wild-type TTR, which does not form amyloid or amyloid protofilaments under these conditions. This study establishes the key role of the monomeric amyloidogenic intermediate and its self-assembly into a ladder of quaternary structural intermediates for the formation of wild-type, V30M, and L55P transthyretin amyloid fibrils.


Porphyromonas gingivalis as putative pathogen in ovine periodontitis.
Ovine periodontitis has clinical features similar to early onset periodontitis in man. Porphyromonas gingivalis has been implicated as a putative pathogen in this disease and its role in periodontitis in 107 sheep was investigated. The organism was recovered from most diseased sites at a significant percentage level of the total bacterial count. Antibody assays of 107 animals using an ELISA did not distinguish between diseased (46) and control adult (33) sheep for either P. gingivalis or any of the other putative periodontopathogens tested, but did differentiate adult sheep from healthy lambs (28) for all bacteria except one. It is suggested that sheep rather than human bacterial strains should be used in antibody studies of ovine periodontitis.


Snake fangs: 3D morphological and mechanical analysis by microCT, simulation, and physical compression testing.
This Data Note provides data from an experimental campaign to analyse the detailed internal and external morphology and mechanical properties of venomous snake fangs. The aim of the experimental campaign was to investigate the evolutionary development of 3 fang phenotypes and investigate their mechanical behaviour. The study involved the use of load simulations to compare maximum Von Mises stress values when a load is applied to the tip of the fang. The conclusions of this study have been published elsewhere, but in this data note we extend the analysis, providing morphological comparisons including details such as curvature comparisons, thickness, etc. Physical compression results of individual fangs, though reported in the original paper, were also extended here by calculating the effective elastic modulus of the entire snake fang structure including internal cavities for the first time. This elastic modulus of the entire fang is significantly lower than the locally measured values previously reported from indentation experiments, highlighting the possibility that the elastic modulus is higher on the surface than in the rest of the material. The micro-computed tomography (microCT) data are presented both in image stacks and in the form of STL files, which simplifies the handling of the data and allows its re-use for future morphological studies. These fangs might also serve as bio-inspiration for future hypodermic needles.


Elderly patients in the emergency department.
Emergency department nursing care of the older individual requires a specific knowledge base to ensure optimal outcomes. Health-care resource utilization specific to elderly patients in the emergency department and selected common health problems that bring older people to the emergency department are described. Distinctions between normal age-related changes and disease signs and symptoms are explained to provide emergency department nurses with the requisite information to care for the elderly appropriately.


Changing pattern of AIDS: a bone marrow study.
We compared bone marrow findings in 2 groups of patients with AIDS during 2 different periods: group 1, n = 20; male/female ratio, 19/1; and group 2, n = 120; male/female ratio, 6/1. Bone marrow iron stores were decreased significantly in group 2 (P < .01), and the incidence of AIDS-related lymphomas was higher, with frequent bone marrow involvement. Two group 1 patients had Kaposi sarcoma, and a 21-month-old girl with transfusion-transmitted AIDS had Burkitt-like lymphoma. In group 2, 44 patients had a history of malignant neoplasms, including Kaposi sarcoma (10 cases), hematologic neoplasms (33 cases), and metastatic leiomyosarcoma (1 case). Of the 120 patients, 15 (12.5%) had bone marrow involvement by malignant neoplasms. The majority of the non-Hodgkin lymphomas were high-grade lymphomas. Patients with AIDS-related malignant neoplasms had higher CD4+ cell counts and viral loads than patients without malignant neoplasms (P < .01, P < .05, respectively). The finding of decreased iron stores in patients with AIDS might aid clinical management of their anemia. The increased incidence of malignant neoplasms, especially lymphomas, in recent years might be related to prolonged survival but with incomplete reconstitution of immune function after antiretroviral therapy.


Differences in the effects of alpha-1 adrenergic blockade with prazosin and indoramin on coronary blood flow during exercise.
This study compared the effects of two selective alpha-1 adrenergic blockers, prazosin and indoramin, on the response of coronary blood flow and myocardial oxygen consumption during treadmill exercise in chronically instrumented dogs. Left circumflex coronary artery blood flow was measured with an electromagnetic flowmeter, whereas myocardial arteriovenous oxygen difference was determined with indwelling aortic and coronary sinus catheters. During control conditions, coronary blood flow, arteriovenous oxygen extraction and myocardial oxygen consumption increased regularly with exercise. Both prazosin and indoramin decreased arterial pressure at rest and during exercise, but during heavier levels of exercise blood pressure was lower and heart rates were higher after prazosin. Prazosin did not alter myocardial oxygen consumption, whereas indoramin tended to decrease oxygen consumption; myocardial oxygen consumption was significantly less after indoramin than after prazosin during the heaviest levels of exercise. Prazosin, but not indoramin, significantly decreased coronary vascular resistance both at rest and during exercise, and blunted the decrease in coronary sinus oxygen tension which occurred during exercise. In comparison with prazosin, during heavy exercise coronary blood flow was significantly decreased, myocardial oxygen extraction significantly increased and myocardial oxygen consumption significantly decreased after indoramin.


A Stroke Recovery Trial Development Framework: Consensus-Based Core Recommendations from the Second Stroke Recovery and Rehabilitation Roundtable.
A major goal of the Stroke Recovery and Rehabilitation Roundtable (SRRR) is to accelerate development of effective treatments to enhance stroke recovery beyond that expected to occur spontaneously or with current approaches. In this paper, we describe key issues for the next generation of stroke recovery treatment trials and present the Stroke Recovery and Rehabilitation Roundtable Trials Development Framework (SRRR-TDF). An exemplar (an upper limb recovery trial) is presented to demonstrate the utility of this framework to guide the GO, NO-GO decision-making process in trial development.


[Did Mozart Suffer from Gilles de la Tourette Syndrome?]
The personal and private lives of great men and women in history, like writers, painters and musicians, have been the subject of great interest for many years. A clear example of this is the vast scrutiny is cast over the famous composer, Wolfgang Amadeus Mozart. What may have started as curiosity, rapidly evolved into extensive research, as the answers about the musician's legendary talent may lie in the details of his life (his childhood, his relationships, his quirks and his mannerisms). It is usually up to historians, anthropologists or philosophers to delve into the pages of old books, trying to grasp answers and clues. However, for some time, Physicians have sought their own part in solving the puzzle. The long told hypothesis regarding Mozart's diagnosis of Gilles de la Tourette syndrome will be examined. Could all of the peculiarities and oddities of the genius be caused by a neurological disorder? Or was this musical genius just an eccentric brilliant man?.


Lexicon of disease spread modelling terms.
Over the past decade there has been a notable increase in the magnitude and variety of modelling work in the realm of animal health. Similarly, there has been an increase in the extent to which modelling is used as a component in the development of animal health policy. The increased dependency on modelling creates a need to enhance understanding and linkages between policy-makers (those that pose the policy or scientific questions, commission modelling work and use model outputs in the development of policy), intermediaries (those that are responsible for working with modellers and communicating model results to policy-makers), and modellers. Development of a lexicon of disease spread modelling terms can help support clear communication and collaboration between all players.


The Green Prescription and older adults: what do general practitioners see as barriers?
Limited research exists that has examined the barriers that older adults (those aged 65 years and older) can encounter when given a Green Prescription (GRx). This study aimed to identify what general practitioners (GPs) perceived their older-aged patients' barriers were with regard to carrying out a GRx. This study also identified the strategies that GPs used to assist their older-aged patients in overcoming barriers to physical activity engagement. Fifteen GPs from the Auckland region of New Zealand were interviewed individually. An inductive thematic approach was used to analyse data. GPs identified chronic health conditions, fear of injury, transportation constraints, set routines and lack of confidence as being barriers that some of their older-aged patients have encountered when considering whether to become more physically active and, also, when engaging in actual physical activity. Physical activity interventions, such as the GRx programme, can have an important role in helping confer health-related gain for low-active older adults. To ensure that such interventions are successful on a long-term basis, practitioners need to be aware of the barriers that their older-aged patients can encounter when given a prescription for physical activity.


Properties and limitations of hologram recording materials.
The role of the recording material in holographic imaging is reviewed. Following a general classification of holograms into four basic types, the thick and thin amplitude and phase holograms, a discussion is given of the diffraction efficiency and other intrinsic characteristics of each of these types. The effects of zero spread nonlinearities in hologram recording are examined, and the limitations they impose on the usable diffraction efficiency of the various hologram types are discussed. The effect of the recording material modulation transfer function is treated by means of a fictitious mask model which facilitates prediction of the recordable object field and resolution. The noise characteristics of recording media are discussed in terms of their effect on holographic recording. Some examples of noise limitations on holographic information recording by silver halide emulsions are examined, as are the effects of such limitations on the dynamic range of holography. The effects of silver halide grain noise in conventional and holographic recording are compared, showing the conditions under which better performance can be achieved in the latter by a given emulsion. The characteristics of several nonsilver halide hologram recording materials are briefly summarized.


A shift in anterior-posterior positional information underlies the fin-to-limb evolution.
The pectoral fins of ancestral fishes had multiple proximal elements connected to their pectoral girdles. During the fin-to-limb transition, anterior proximal elements were lost and only the most posterior one remained as the humerus. Thus, we hypothesised that an evolutionary alteration occurred in the anterior-posterior (AP) patterning system of limb buds. In this study, we examined the pectoral fin development of catshark (Scyliorhinus canicula) and revealed that the AP positional values in fin buds are shifted more posteriorly than mouse limb buds. Furthermore, examination of Gli3 function and regulation shows that catshark fins lack a specific AP patterning mechanism, which restricts its expression to an anterior domain in tetrapods. Finally, experimental perturbation of AP patterning in catshark fin buds results in an expansion of posterior values and loss of anterior skeletal elements. Together, these results suggest that a key genetic event of the fin-to-limb transformation was alteration of the AP patterning network.


Duration of red blood cell storage and survival of transfused patients (CME).
Disquieting reports of increased complication and death rates after transfusions of red blood cells (RBCs) stored for more than 14 days prompted us to perform an observational retrospective cohort study of mortality in relation to storage time. We conducted a cohort study utilizing data on all recipients of at least one RBC transfusion in Sweden and Denmark between 1995 and 2002, as recorded in the Scandinavian Donations and Transfusions (SCANDAT) database. Relative risks of death in relation to storage time were estimated using Cox regression, adjusted for several possible confounding factors. After various exclusions, 404,959 transfusion episodes remained for analysis. The 7-day risk of death was similar in all exposure groups, but a tendency for a higher risk emerged among recipients of blood stored for 30 to 42 days (hazard ratio, 1.05; 95% confidence interval [CI], 0.97-1.12), compared to recipients of blood stored for 10 to 19 days. With 2-year follow-up, this excess remained at the same level (hazard ratio, 1.05; 95% CI, 1.02-1.08). No dose-response pattern was revealed and no differential effect was seen when the analyses were restricted to recipients of leukoreduced units only. Although a small excess mortality was noted in recipients of the oldest RBCs, the risk pattern was more consistent with weak confounding than with an effect of the momentary exposure to stored RBCs. It seems, thus, that any excess mortality conferred by older RBCs in the combined Swedish and Danish transfusion recipient population is likely less than 5%, which is considerably smaller than in the hitherto largest investigation.


Cardiovascular disease incidence rates: a study using routinely collected health data.
There is substantial evidence that systemic anticancer therapies and radiotherapy can increase the long-term risk of cardiovascular disease (CVD). Optimal management decisions for cancer patients therefore need to take into account the likely risks from a proposed treatment option, as well as its likely benefits. For CVD, the magnitude of the risk depends on the incidence of the disease in the general population to which the patient belongs, including variation with age and sex, as well as on the treatment option under consideration. The aim of this paper is to provide estimates of CVD incidence rates in the general population of England for use in cardio-oncology and in other relevant clinical, research and health policy contexts. We studied a population-based representative cohort, consisting of 2,633,472 individuals, derived by electronic linkage of records from primary care with those of admitted-patient care in England during April 1, 2010, to April 1, 2015. From 38 individual CVDs available via the linked dataset we identified five relevant categories of CVD whose risk may be increased by cancer treatments: four of heart disease and one of stroke. We calculated incidence rates by age-group and sex for all relevant CVD categories combined, for the four relevant categories of heart disease combined, and for the five relevant CVD categories separately. We present separate incidence rates for all 38 individual CVDs available via the linked dataset. We also illustrate how our data can be used to estimate absolute CVD risks in a range of people with Hodgkin lymphoma treated with chemotherapy and radiotherapy. Our results provide population-based CVD incidence rates for a variety of uses, including the estimation of absolute risks of CVD from cancer treatments, thus helping patients and clinicians to make appropriate individualized cancer treatment decisions. Graphical Abstract: Cardiovascular incidence rates for use in cardio-oncology and elsewhere: A presentation of age- and sex-specific cardiovascular disease (CVD) incidence rates for use in calculation of absolute cardiovascular risks of cancer treatments, and in other clinical, research and health policy contexts. Abbreviations - CVD: cardiovascular disease; y: years.


Determination of hydrogen cyanide concentration in mainstream smoke of tobacco products by polarography.
There has been a worldwide concern for the health risks of cigarette smoking and hydrogen cyanide (HCN) considered as one of the hazardous tobacco compounds which is needed to be determined in order to reduce the dose related to smoke disease risk. In this study, we prepare the experimental procedure to entrap the HCN from mainstream smoke of different brands of Tehran cigarette, through simulating human inhalation and determine its concentration applying polarography. The HCN level of the 50 commonly consumed tobacco products (47 cigarettes and 3 cigars) obtained from local store is ranged between 17.56 ± 1.02 and 1553.98 ± 0.56 μg per stick, this acquired amount is more than FDA approval (10 μg per stick), so the harmful effects of smoking is indicative. The comparative study of the results shows that the price and the weight of each product do not indicate HCN level. As can be seen, R(2) value which is a statistical measure of how close the data are to the fitted regression line is low (R(2) < 0.2). So it should not be deceived by names such as ultra light or infinite gravity to suck, because this names or the price haven(')t effect on the amount of HCN and its destructive effects.


Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia.
Blockade of N-methyl-D-aspartate receptors (NMDARs) produces behavior in healthy people that is similar to the psychotic symptoms and cognitive deficits of schizophrenia and can exacerbate symptoms in people with schizophrenia. However, an endogenous brain disruption of NMDARs has not been clearly established in schizophrenia. We measured mRNA transcripts for five NMDAR subunit mRNAs and protein for the NR1 subunit in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control (n=74) brains. Five NMDAR single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia were tested for association with NMDAR mRNAs in postmortem brain and for association with cognitive ability in an antemortem cohort of 101 healthy controls and 48 people with schizophrenia. The NR1 subunit (mRNA and protein) and NR2C mRNA were decreased in postmortem brain from people with schizophrenia (P=0.004, P=0.01 and P=0.01, respectively). In the antemortem cohort, the minor allele of NR2B rs1805502 (T5988C) was associated with significantly lower reasoning ability in schizophrenia. In the postmortem brain, the NR2B rs1805502 (T5988C) C allele was associated with reduced expression of NR1 mRNA and protein in schizophrenia. Reduction in NR1 and NR2C in the DLPFC of people with schizophrenia may lead to altered NMDAR stoichiometry and provides compelling evidence for an endogenous NMDAR deficit in schizophrenia. Genetic variation in the NR2B gene predicts reduced levels of the obligatory NR1 subunit, suggesting a novel mechanism by which the NR2B SNP may negatively influence other NMDAR subunit expression and reasoning ability in schizophrenia.


Physical activity and cardiovascular morbidity.
Habitual physical activity may appear as a determinant of cardiovascular morbidity because of (i) noncausal associations with other risk factors, (ii) an influence on known risk factors, and/or (iii) some, as yet, not defined mechanisms. The associations of physical activity with other life-style variables, such as smoking and plasma low-density lipoproteins, vary both in direction and strength with population, time, and type of physical activity (eg, work versus leisure time). On the other hand physical activity has been shown to cause an increase in plasma high-density lipoproteins and a decrease in plasma triglycerides and insulin and to predict a lower incidence of hypertension. In some multivariate analyses-of the incidence of coronary heart disease and strokes, physical activity has evolved as an independent predictor of reduced risk. On the type, intensity, and frequency of physical activity as needed for risk reduction, the results are not fully consistent. For delineating the mechanisms for the independent reduction of risk by physical activity, major investments of further research are still necessary.


[Opinions about disease among members of the social network of patients with Hansen's disease in Recife].
This article describes a study done in Recife, Brazil, between November 1993 and July 1994 to explore the opinions of the members of the social network (for example, family members, friends, and neighbors) of carriers of Hansen's disease regarding their estimation, interpretation, and management of physical manifestations of the disease in the time leading up to diagnosis. The sample consisted of 93 members of the social network, ranging in age between 20 and 70 years, who supported the course of action of 83 patients diagnosed in the study period. The analysis sought to detect differing capacities among the members of the patients' social network to discriminate between persons classified as cases (presence of disabilities or precursor lesions) or controls. The study found a lack of information about transmission of Hansen's disease and revealed a transitional phase in which there was expectation of cure along with a stigmatizing view of the consequences of the disease. Only one-quarter of the study subjects suspected prior to diagnosis that the patient had Hansen's disease, which suggests low perception of the risk represented by the disease and reinforces the idea that its physical manifestations can be invisible. The results reveal a profile of perception and management of Hansen's disease that favors its propagation and the development or worsening of its physical and social consequences.


Toward an ecoregion scale evaluation of eDNA metabarcoding primers: A case study for the freshwater fish biodiversity of the Murray-Darling Basin (Australia).
High-throughput sequencing of environmental DNA (i.e., eDNA metabarcoding) has become an increasingly popular method for monitoring aquatic biodiversity. At present, such analyses require target-specific primers to amplify DNA barcodes from co-occurring species, and this initial amplification can introduce biases. Understanding the performance of different primers is thus recommended prior to undertaking any metabarcoding initiative. While multiple software programs are available to evaluate metabarcoding primers, all programs have their own strengths and weaknesses. Therefore, a robust in silico workflow for the evaluation of metabarcoding primers will benefit from the use of multiple programs. Furthermore, geographic differences in species biodiversity are likely to influence the performance of metabarcoding primers and further complicate the evaluation process. Here, an in silico workflow is presented that can be used to evaluate the performance of metabarcoding primers on an ecoregion scale. This workflow was used to evaluate the performance of published and newly developed eDNA metabarcoding primers for the freshwater fish biodiversity of the Murray-Darling Basin (Australia). To validate the in silico workflow, a subset of the primers, including one newly designed primer pair, were used in metabarcoding analyses of an artificial DNA community and eDNA samples. The results show that the in silico workflow allows for a robust evaluation of metabarcoding primers and can reveal important trade-offs that need to be considered when selecting the most suitable primer. Additionally, a new primer pair was described and validated that allows for more robust taxonomic assignments and is less influenced by primer biases compared to commonly used fish metabarcoding primers.


Milk and meat in our diet: good or bad for health?
Foods derived from animals are an important source of nutrients in the diet but there is considerable uncertainty about whether or not these foods contribute to increased risk of various chronic diseases. For milk in particular there appears to be an enormous mismatch between both the advice given on milk/dairy foods items by various authorities and public perceptions of harm from the consumption of milk and dairy products, and the evidence from long-term prospective cohort studies. Such studies provide convincing evidence that increased consumption of milk can lead to reductions in the risk of vascular disease and possibly some cancers and of an overall survival advantage from the consumption of milk, although the relative effect of milk products is unclear. Accordingly, simply reducing milk consumption in order to reduce saturated fatty acid (SFA) intake is not likely to produce benefits overall though the production of dairy products with reduced SFA contents is likely to be helpful. For red meat there is no evidence of increased risk of vascular diseases though processed meat appears to increase the risk substantially. There is still conflicting and inconsistent evidence on the relationship between consumption of red meat and the development of colorectal cancer, but this topic should not be ignored. Likewise, the role of poultry meat and its products as sources of dietary fat and fatty acids is not fully clear. There is concern about the likely increase in the prevalence of dementia but there are few data on the possible benefits or risks from milk and meat consumption. The future role of animal nutrition in creating foods closer to the optimum composition for long-term human health will be increasingly important. Overall, the case for increased milk consumption seems convincing, although the case for high-fat dairy products and red meat is not. Processed meat products do seem to have negative effects on long-term health and although more research is required, these effects do need to be put into the context of other risk factors to long-term health such as obesity, smoking and alcohol consumption.


Talking about walking: biomechanics and the language of locomotion.
What drives humans around the world to converge in certain ways in their naming while diverging dramatically in others? We studied how naming patterns are constrained by investigating whether labeling of human locomotion reflects the biomechanical discontinuity between walking and running gaits. Similarity judgments of a student locomoting on a treadmill at different slopes and speeds revealed perception of this discontinuity. Naming judgments of the same clips by speakers of English, Japanese, Spanish, and Dutch showed lexical distinctions between walking and running consistent with the perceived discontinuity. Typicality judgments showed that major gait terms of the four languages share goodness-of-example gradients. These data demonstrate that naming reflects the biomechanical discontinuity between walking and running and that shared elements of naming can arise from correlations among stimulus properties that are dynamic and fleeting. The results support the proposal that converging naming patterns reflect structure in the world, not only acts of construction by observers.


New formula for evaluation of the QT interval in patients with left bundle branch block.
Left bundle branch block (LBBB) and QT prolongation both are associated with a worse prognosis. LBBB lengthens the QT interval. To date it is not known whether QT prolongation during LBBB differs in repolarization from QT prolongation during narrow QRS. The purpose of the present proof-of-concept-study was to develop a formula that allows comparison of the adjusted QT interval during LBBB with reference values and thereby allows interpretation of the QT interval irrespective of QRS widening. Sixty consecutive patients with sinus rhythm (SR) and narrow QRS underwent electrophysiologic study for ablation. In all patients, the intrinsic QRS ,QT, and JT times were measured during SR, and ventricular pacing from both the right ventricular apex (RVA) and the right ventricular outflow tract (RVOT) caused LBBB. We determined prolongation of the QT during as compared to SR (ΔQT). ΔQT was then divided by the QRS length during pacing QRS (QRSb). This describes the percentage of the QRS duration at LBBB, which must be subtracted from the measured QT (QTb) to determine the modified QT interval (QTm). The ratio of ΔQT to paced QRS was calculated as 48.3% (RVA) and 48.8% (RVOT) (mean 48.5%). The ratio intrinsic of JTi to paced JT was 1.0055 (RVA) and 1.0087 (RVOT). There was no significant difference in intrinsic JT vs paced JT (P = .2). Right ventricular pacing causes prolongation of the QT due to a paced LBBB without prolongation of the JT time. In our study, we showed that QT prolongation caused by LBBB constitutes 48.5% of the QRS width. This is the value that must be subtracted from the measured QT in LBBB in order to estimate the modified QT. Thus, the resulting formula for "modified QT" estimation in LBBB is QTm = QTb - 48.5% * (QRSb).


Functional analysis of the 5' flanking region of the human G6PC3 gene: regulation of promoter activity by glucose, pyruvate, AMP kinase and the pentose phosphate pathway.
G6PC3 is a widely expressed isoform of glucose-6-phosphatase, found in many foetal and adult tissues. Mutations in this gene cause developmental abnormalities and severe neutropenia due to abolition of glucose recycling between the cytoplasm and endoplasmic reticulum. Low G6PC3 expression as a result of promoter polymorphisms or dysregulation could produce similar outcomes. Here we investigated the regulation of human G6PC3 promoter activity. HeLa and H4IIE cells were transiently transfected with G6PC3 promoter coupled to the firefly luciferase gene, and promoter activity was measured by dual luciferase assay. Activity was highest in a 453 bp segment of the G6PC3 promoter, from -455 to -3 relative to the transcriptional start site. This promoter was unresponsive to glucostatic hormones. Its activity increased significantly between 1 and 5.5 mM glucose, and was not elevated further by glucose concentrations up to 25 mM. Pyruvate increased its activity, but β-hydroxybutyrate and sodium acetate did not. Promoter activity was reduced by inhibitors of hexokinase, glyceraldehyde phosphate dehydrogenase and the oxidative branch of the pentose phosphate pathway, but not by a transketolase inhibitor. Deletion of two adjacent Enhancer-boxes (-274 to -279 and -299 to -304) reduced promoter activity and abolished the glucose effect, suggesting they could function as a glucose response element. Deletion of an additional downstream 140 bp (-140 to -306) restored activity, but not the glucose response, suggesting the presence of repressor elements in this region. 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) reduced promoter activity, showing dependence on AMP-kinase. Regulation of the G6PC3 promoter is thus radically different to that of the hepatic isoform, G6PC. It is sensitive to carbohydrate, but not to fatty acid metabolites, and at much lower physiological concentrations. Based on these findings, we speculate that reduced G6PC3 expression could occur during hypoglycemic episodes in vivo, which are common in utero and in the postnatal period. If such episodes lower G6PC3 expression they could place the foetus or infant at risk of impaired immune function and development, and this possibility requires further examination both in vitro and in vivo.


Stereotactic radiosurgery does not appear to impact cochlear implant performance in patients with neurofibromatosis type II.
Neurofibromatosis Type 2 (NF2) is a genetic condition associated with the presence of bilateral vestibular schwannoma and progressive sensorineural hearing loss. Treatment options include observation, stereotactic radiosurgery (SRS) or surgical resection. Historically, retrocochlear pathology was a contraindication to cochlear implantation (CI). However it is now recognized as viable, in an attempt to restore hearing and improve communication.Thus, the aim of this study was to contrast auditory function in CI recipients with NF2 whose tumors were either observed versus initially treated with SRS. A local review of hearing outcomes in 2 CI patients (3 ears total) with NF2 was undertaken and then pooled with the existing medical literature. Comparative post-implant outcome data, including pure-tone average and aided speech perception measurements was analyzed and compared between 8 subjects whose tumors were observed and 11 subjects who received pre-implantation SRS. Mean tumor size in the observation cohort was 0.81cm (.13cm to 1.50cm), and 2.34cm in the SRS group (0.10cm to 3.7cm). The mean reported duration of deafness was 22 months as compared to 71 months in the SRS cohort. Both groups demonstrated similar pre-implant candidacy criteria, average age and open-set speech recognition. Although disparate outcome measurements were utilized across studies, an analysis of post-implant open-set speech perception found no significant differences between groups. Despite a small sample size and highly variable post implantation testing methods, patients who undergo SRS for NF2 associated Schwannoma prior to CI have similar hearing performance and benefit by having already completed definitive tumor management.


Conjuring cognition: a review of educational magic-based interventions.
For hundreds of years, magic tricks have been employed within a variety of pedagogic contexts, including promoting science and mathematics, delivering educational messaging, enhancing scepticism about the paranormal, and boosting creative thinking for product design. This review examines this diverse body of work, focusing on studies that have assessed the impact of such interventions. Although the studies tended to yield positive outcomes, much of the work suffered from methodological shortcomings, including measuring the impact of interventions over a relatively short period of time, focusing on self-report measures and failing to employ control groups. The paper makes several recommendations for future study in the area, including assessing the longer-term impact of magic-based interventions, comparing these interventions to other types of pedagogic techniques, focussing on knowledge retention and behavioural outcomes, and collaborating with magicians to develop more impactful interventions.


A matrix model for valuing anesthesia service with the resource-based relative value system.
The purpose of this study was to propose a new crosswalk using the resource-based relative value system (RBRVS) that preserves the time unit component of the anesthesia service and disaggregates anesthesia billing into component parts (preoperative evaluation, intraoperative management, and postoperative evaluation). The study was designed as an observational chart and billing data review of current and proposed payments, in the setting of a preoperative holing area, intraoperative suite, and post anesthesia care unit. In total, 1,195 charts of American Society of Anesthesiology (ASA) physical status 1 through 5 patients were reviewed. No direct patient interventions were undertaken. Spearman correlations between the proposed RBRVS billing matrix payments and the current ASA relative value guide methodology payments were strong (r=0.94-0.96, P<0.001 for training, test, and overall). The proposed RBRVS-based billing matrix yielded payments that were 3.0%±1.34% less than would have been expected from commercial insurers, using standard rates for commercial ASA relative value units and RBRVS relative value units. Compared with current Medicare reimbursement under the ASA relative value guide, reimbursement would almost double when converting to an RBRVS billing model. The greatest increases in Medicare reimbursement between the current system and proposed billing model occurred as anesthetic management complexity increased. The new crosswalk correlates with existing evaluation and management and intensive care medicine codes in an essentially revenue neutral manner when applied to the market-based rates of commercial insurers. The new system more highly values delivery of care to more complex patients undergoing more complex surgery and better represents the true value of anesthetic case management.


Assessment of individual fracture risk: FRAX and beyond.
The World Health Organization fracture risk assessment tool (FRAX) and the Garvan fracture risk calculator are both widely available tools for individualized fracture risk prediction in daily practice. The FRAX model is implemented in several guidelines and most widely used at present. However, clinicians should take into account the differences between the models, especially with regard to the effect of the number of falls, number and clustering of previous fractures, and the number of clinical risk factors on the outcome of predicted fracture risk. Further development will be needed for optimal integration of bone- and fall-related risks, clustering of fractures, and dosing of risk factors to validate the models in different populations and to validate the ability to select patients who will achieve fracture risk reduction with anti-osteoporosis therapy. FRAX may be used as the primary model, and in patients with recurrent fractures and falls the use of the Garvan model may be of additional value.


Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.
Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.


Statistical Inference with M-Estimators on Adaptively Collected Data.
Bandit algorithms are increasingly used in real-world sequential decision-making problems. Associated with this is an increased desire to be able to use the resulting datasets to answer scientific questions like: Did one type of ad lead to more purchases? In which contexts is a mobile health intervention effective? However, classical statistical approaches fail to provide valid confidence intervals when used with data collected with bandit algorithms. Alternative methods have recently been developed for simple models (e.g., comparison of means). Yet there is a lack of general methods for conducting statistical inference using more complex models on data collected with (contextual) bandit algorithms; for example, current methods cannot be used for valid inference on parameters in a logistic regression model for a binary reward. In this work, we develop theory justifying the use of M-estimators-which includes estimators based on empirical risk minimization as well as maximum likelihood-on data collected with adaptive algorithms, including (contextual) bandit algorithms. Specifically, we show that M-estimators, modified with particular adaptive weights, can be used to construct asymptotically valid confidence regions for a variety of inferential targets.


Employment is maintained and sick days decreased in psoriasis/psoriatic arthritis patients with etanercept treatment.
Psoriasis and psoriatic arthritis (PsA) impair quality of life, including reduction in employment or job duties. The PRESTA (Psoriasis Randomized Etanercept STudy in Patients with Psoriatic Arthritis) study, a randomized, double-blind, two-dose trial, examined the efficacy of etanercept treatment in patients with moderate-to-severe plaque psoriasis and PsA and the main results have been presented previously. This analysis examined employment status, job duties and sick days, pre-defined endpoints in PRESTA, among this patient population. Participants (N=752) were randomized to receive etanercept 50 mg twice weekly (BIW; n=379) or 50 mg once weekly (QW; n=373) for 12 weeks by subcutaneous injection. All participants then received open-label etanercept 50 mg QW for 12 additional weeks, while remaining blinded to the randomization. A pharmacoeconomic questionnaire was administered at baseline, week 12 and week 24 of treatment. The questionnaire included employment status and changing job responsibilities and sick time taken due to psoriasis or PsA. The statistical methods included analysis of covariance, t-test, Fisher's exact test and McNemar's test. Last-observation-carried-forward imputation was used for missing data. Employment was at least maintained from baseline to week 24 in both dose groups (56% [BIW/QW] and 60% [QW/QW] at baseline, 61% and 60%, respectively, at week 24). Among employed participants, the proportion of patients whose job responsibilities changed due to PsA decreased significantly from baseline to week 24 (17-23% to 5-8%; p<0.01). Similar results were seen with job responsibility changes due to psoriasis (11-14% to 4%; p<0.01). The number of monthly sick days also decreased from baseline to week 24 (2.4 days for both treatment groups to 0.7 (BIW/QW) and 1.1 (QW/QW); p≤0.03 for each). No significant differences between the treatment groups were observed for any economic endpoint at any time point. For patients with moderate-to-severe plaque psoriasis and PsA, etanercept treatment resulted in reducing job responsibility changes due to disease and in reducing sick time. Effective treatment of psoriasis and PsA may reduce missed work days.


Streptomyces iconiensis sp. nov. and Streptomyces smyrnaeus sp. nov., two halotolerant actinomycetes isolated from a salt lake and saltern.
The taxonomic positions of two novel actinomycetes, designated strains BNT558(T) and SM3501(T), were established by using a polyphasic approach. The organisms had chemical and morphological features that were consistent with their classification in the genus Streptomyces. The whole-cell hydrolysates of the two strains contained ll-diaminopimelic acid as the diagnostic diamino acid. The predominant menaquinones were MK-9(H6) and MK-9(H8) for strain BNT558(T) and MK-9(H8) and MK-9(H6) for strain SM3501(T). Major fatty acids of the strains were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The polar lipid profile of strain BNT558(T) contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, one unidentified glycolipid and one unidentified aminophospholipid, while that of strain SM3501(T) consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, three unidentified atypical aminolipids, one unidentified aminolipid and two unidentified glycolipids. The G+C contents of the genomic DNA were 70.2 and 69.6 mol% for strains BNT558(T) and SM3501(T), respectively. 16S rRNA gene sequence data supported the classification of the isolates in the genus Streptomyces and showed that they formed two distinct branches within the genus. Based on almost-complete 16S rRNA gene sequences, strain BNT558(T) was related most closely to Streptomyces albiaxialis NRRL B-24327(T) and strain SM3501(T) was related most closely to Streptomyces cacaoi subsp. cacaoi NBRC 12748(T). DNA-DNA relatedness between each of the isolates and its closest phylogenetic neighbours showed that they belonged to distinct species. The two isolates were readily distinguished from one another and from the type strains of the other species classified in the genus Streptomyces based on a combination of phenotypic and genotypic properties. Based on the genotypic and phenotypic evidence, strains BNT558(T) and SM3501(T) belong to two novel species in the genus Streptomyces, for which the names Streptomyces iconiensis sp. nov. (type strain BNT558(T) = KCTC 29198(T) = DSM 42109(T)) and Streptomyces smyrnaeus sp. nov. (type strain SM3501(T) = KCTC 29214(T) = DSM 42105(T)) are proposed, respectively.


A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55).
Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy. The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control. We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV. This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.


Posttreatment variables improve outcome prediction after intra-arterial therapy for acute ischemic stroke.
There are multiple clinical and radiographic factors that influence outcomes after endovascular reperfusion therapy (ERT) in acute ischemic stroke (AIS). We sought to derive and validate an outcome prediction score for AIS patients undergoing ERT based on readily available pretreatment and posttreatment factors. The derivation cohort included 511 patients with anterior circulation AIS treated with ERT at 10 centers between September 2009 and July 2011. The prospective validation cohort included 223 patients with anterior circulation AIS treated in the North American Solitaire Acute Stroke registry. Multivariable logistic regression identified predictors of good outcome (modified Rankin score ≤2 at 3 months) in the derivation cohort; model β coefficients were used to assign points and calculate a risk score. Discrimination was tested using C statistics with 95% confidence intervals (CIs) in the derivation and validation cohorts. Calibration was assessed using the Hosmer-Lemeshow test and plots of observed to expected outcomes. We assessed the net reclassification improvement for the derived score compared to the Totaled Health Risks in Vascular Events (THRIVE) score. Subgroup analysis in patients with pretreatment Alberta Stroke Program Early CT Score (ASPECTS) and posttreatment final infarct volume measurements was also performed to identify whether these radiographic predictors improved the model compared to simpler models. Good outcome was noted in 186 (36.4%) and 100 patients (44.8%) in the derivation and validation cohorts, respectively. Combining readily available pretreatment and posttreatment variables, we created a score (acronym: SNARL) based on the following parameters: symptomatic hemorrhage [2 points: none, hemorrhagic infarction (HI)1-2 or parenchymal hematoma (PH) type 1; 0 points: PH2], baseline National Institutes of Health Stroke Scale score (3 points: 0-10; 1 point: 11-20; 0 points: >20), age (2 points: <60 years; 1 point: 60-79 years; 0 points: >79 years), reperfusion (3 points: Thrombolysis In Cerebral Ischemia score 2b or 3) and location of clot (1 point: M2; 0 points: M1 or internal carotid artery). The SNARL score demonstrated good discrimination in the derivation (C statistic 0.79, 95% CI 0.75-0.83) and validation cohorts (C statistic 0.74, 95% CI 0.68-0.81) and was superior to the THRIVE score (derivation cohort: C statistic 0.65, 95% CI 0.60-0.70; validation cohort: C-statistic 0.59, 95% CI 0.52-0.67; p < 0.01 in both cohorts) but was inferior to a score that included age, ASPECTS, reperfusion status and final infarct volume (C statistic 0.86, 95% CI 0.82-0.91; p = 0.04). Compared with the THRIVE score, the SNARL score resulted in a net reclassification improvement of 34.8%. Among AIS patients treated with ERT, pretreatment scores such as the THRIVE score provide only fair prognostic information. Inclusion of posttreatment variables such as reperfusion and symptomatic hemorrhage greatly influences outcome and results in improved outcome prediction.


Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents.
Attention deficit hyperactivity disorder (ADHD) is a major problem in children and adolescents, characterised by age-inappropriate levels of inattention, hyperactivity and impulsivity, and is associated with long-term social, academic and mental health problems. The stimulant medications methylphenidate and amphetamine are the most frequently used treatments for ADHD, but these are not always effective and can be associated with side effects. Clinical and biochemical evidence suggests that deficiencies of polyunsaturated fatty acids (PUFA) could be related to ADHD. Children and adolescents with ADHD have been shown to have significantly lower plasma and blood concentrations of PUFA and, in particular, lower levels of omega-3 PUFA. These findings suggest that PUFA supplementation may reduce the attention and behaviour problems associated with ADHD. To compare the efficacy of PUFA to other forms of treatment or placebo in treating the symptoms of ADHD in children and adolescents. We searched the following databases in August 2011: CENTRAL (The Cochrane Library 2011, Issue 2), MEDLINE (1948 to July Week 3, 2011), EMBASE (1980 to 2011 Week 29), PsycINFO (1806 to current), CINAHL (1937 to current), BIOSIS (1969 to 30 July 2011), Science Citation Index (1970 to 30 July 2011), Social Science Citation Index (1970 to 30 July 2011), Conference Proceedings Citation Index - Science (1990 to 30 July 2011), Conference Proceedings Citation Index - Social Science and Humanities (1990 to 30 July 2011), Cochrane Database of Systematic Reviews (2011, Issue 7), DARE (2011 Issue 2), Dissertation Abstracts (via Dissertation Express) and the metaRegister of Controlled Trials (mRCT). In addition, we searched the following repositories for theses on 2 August 2011: DART, NTLTD and TROVE. We also checked reference lists of relevant studies and reviews for additional references. Two review authors independently assessed the results of the database searches. We resolved any disagreements regarding the selection of studies through consensus or, if necessary, by consultation with a third member of the review team. Two members of the review team independently extracted details of participants and setting, interventions, methodology and outcome data. If differences were identified, we resolved them by consensus or referral to a third member of the team. We made all reasonable attempts to contact the authors where further clarification or missing data were needed. We included 13 trials with 1011 participants in the review. After screening 366 references, we considered 23 relevant and obtained the full text for consideration. We excluded five papers and included 18 papers describing the 13 trials. Eight of the included trials had a parallel design: five compared an omega-3 PUFA supplement to placebo; two compared a combined omega-3 and omega-6 supplement to placebo, and one compared an omega-3 PUFA to a dietary supplement. Five of the included trials had a cross-over design: two compared combined omega-3/6 PUFA to placebo; two compared omega-6 PUFA with placebo; one compared omega-3 to omega-6 PUFA, and one compared omega-6 PUFA to dexamphetamine. Supplements were given for a period of between four and 16 weeks.There was a significantly higher likelihood of improvement in the group receiving omega-3/6 PUFA compared to placebo (two trials, 97 participants; risk ratio (RR) 2.19, 95% confidence interval (CI) 1.04 to 4.62). However, there were no statistically significant differences in parent-rated ADHD symptoms (five trials, 413 participants; standardised mean difference (SMD) -0.17, 95% CI -0.38 to 0.03); inattention (six trials, 469 participants; SMD -0.04, 95% CI -0.29 to 0.21) or hyperactivity/impulsivity (five trials, 416 participants; SMD -0.04, 95% CI -0.25 to 0.16) when all participants receiving PUFA supplements were compared to those receiving placebo.There were no statistically significant differences in teacher ratings of overall ADHD symptoms (four trials, 324 participants; SMD 0.05, 95% CI -0.18 to 0.27); inattention (three trials, 260 participants; SMD 0.26, 95% CI -0.22 to 0.74) or hyperactivity/impulsivity (three trials, 259 participants; SMD 0.10, 95% CI -0.16 to 0.35).There were also no differences between groups in behaviour, side effects or loss to follow-up.Overall, there were no other differences between groups for any other comparison. Overall, there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children and adolescents. The majority of data showed no benefit of PUFA supplementation, although there were some limited data that did show an improvement with combined omega-3 and omega-6 supplementation.It is important that future research addresses current weaknesses in this area, which include small sample sizes, variability of selection criteria, variability of the type and dosage of supplementation, short follow-up times and other methodological weaknesses.


A Pilot Study of Cardiorespiratory Fitness, Adiposity, and Cardiometabolic Health in Youth With Overweight and Obesity.
To conduct a preliminary assessment of the relationships between cardiorespiratory fitness, adiposity, and cardiometabolic health using gold standard measures in diverse youth ranging from overweight to severe obesity. Twenty of 30 participants (mean [SD]; age 13.2 [1.8] y, 55% female, 45% African American) met the criteria for VO2peak during a graded cycle ergometer test to volitional fatigue. The body composition was measured by dual-energy X-ray absorptiometry (percentage of body fat, fat mass index, and fat-free mass) and magnetic resonance imaging (abdominal visceral and subcutaneous [SAT] adipose tissue). The VO2peak was expressed relative to fat-free mass. Fasting lipid levels, glycemic biomarkers, and vital signs were examined individually and used in a composite cardiometabolic risk score. Accelerometer-measured physical activity and sedentary time were included as covariates. VO2peak was negatively associated with abdominal SAT (r = -.49, P < .05), but not visceral adipose tissue or markers of cardiometabolic health. The association between SAT and VO2peak was partly explained by habitual sedentary time. We demonstrated a significant negative association between cardiorespiratory fitness and SAT in a diverse group of high-risk youth. The inclusion of rigorous, laboratory-based measures and youth with severe obesity extends the previous work in pediatric populations.