Resting state and task-induced deactivation: A methodological comparison in patients with schizophrenia and healthy controls.
Changes in the default mode network (DMN) have been linked to multiple neurological disorders including schizophrenia. The anticorrelated relationship the DMN shares with task-related networks permits the quantification of this network both during task (task-induced deactivations: TID) and during periods of passive mental activity (extended rest). However, the effects of different methodologies (TID vs. extended rest) for quantifying the DMN in the same clinical population are currently not well understood. Moreover, several different analytic techniques, including independent component analyses (ICA) and seed-based correlation analyses, exist for examining functional connectivity during extended resting states. The current study compared both methodologies and analytic techniques in a group of patients with schizophrenia (SP) and matched healthy controls. Results indicated that TID analyses, ICA, and seed-based correlation all consistently identified the midline (anterior and posterior cingulate gyrus) and lateral parietal cortex as core regions of the DMN, as well as more variable involvement of temporal lobe structures. In addition, SP exhibited increased deactivation during task, as well as decreased functional connectivity with frontal regions and increased connectivity with posterior and subcortical areas during periods of extended rest. The increased posterior and reduced anterior connectivity may partially explain some of the cognitive dysfunction and clinical symptoms that are frequently associated with schizophrenia.


Pediatric feeding and swallowing problems: an interdisciplinary team approach.
In 1995, Oshawa General Hospital (now Lakeridge Health Corporation, Oshawa site) developed an interdisciplinary feeding and swallowing clinic to serve children with feeding problems. After four years, a retrospective chart review of 104 subjects was completed to assess the performance of the clinic, which consists of a pediatrician, a speech-language pathologist (S-LP), an occupational therapist (OT), and a registered dietitian (RD). Goals were set at the initial and follow-up visits. These goals were individualized according to client needs and were related to improvements in growth and/or feeding abilities. During this period, 176 of 232, or 75.9% (70-81, 95% confidence interval), of the initial goals were attained by the first follow-up visit. Progress in the clinic, as measured by the number of goals achieved by the first follow-up visit, was further analyzed according to the patient age group/category (i.e., infant, toddler, and child) and by the health care professional (i.e., S-LP, OT, and RD) to ascertain and compare success rates in these groups and professionals. The overall success rates in the patient age groups (p=0.07) and among the different professionals (p=0.92) were not significantly different. In short, the interdisciplinary team approach proved successful in treating feeding problems in patients referred to the clinic.


Patient recognition of and response to symptoms of TIA or stroke.
Campaigns within Australia and internationally have sought to increase awareness of the emergent nature of stroke. For these initiatives to be effective it is important to gather information about delay in seeking treatment and the reasons given for the delay by people with stroke. The purpose of this study was to examine delay in seeking treatment in people with an evolving stroke or TIA and identify clinical, behavioral and demographic factors that contributed to the delay. During a 1-year period 150 participants were given the Response to Stroke Symptoms Questionnaire. The six domains included in the questionnaire were: (1) context in which the stroke occurred; (2) antecedents to symptoms; (3) affective response to symptoms; (4) behavioral response to symptoms; (5) cognitive response to symptoms; (6) the response of others to patient symptoms. The median delay time from symptom onset to admission to hospital was 4.5 h. While 41% of participants delayed less than 3 h, more than 45% delayed greater than 6 h. Independent predictors of delay time included mode of arrival at hospital with those taking an ambulance having a median delay time of 2.7 h vs. 15.4 h for those arriving by private car (p = 0.04). Gender also predicted delay with women delaying longer (p = 0.001). The first response of others was also an independent predictor of delay time (p = 0.003) with those who called the emergency services number or took the patient to hospital resulting in the shortest patient delays. Finally, if the patient appraised their symptoms as serious they had a shorter delay time (p = 0.02). The message about the emergent nature of stroke may be helping to improve delay times. However, there are still many people who delay greater than 3 h after symptom onset. It is important to direct education programs to those with known risk factors for stroke and their families, who often make the decision to call an ambulance.


Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons.
The flotillins/reggie proteins are associated with noncaveolar membrane microdomains and have been implicated in the regulation of a clathrin- and caveolin-independent endocytosis pathway. Endocytosis is required for the amyloidogenic processing of the amyloid precursor protein (APP) and thus to initiate the release of the neurotoxic beta-amyloid peptide (Abeta), the major component of extracellular plaques found in the brains of Alzheimer's disease patients. Here, we report that small interference RNA-mediated downregulation of flotillin-2 impairs the endocytosis of APP, in both neuroblastoma cells and primary cultures of hippocampal neurons, and reduces the production of Abeta. Similar to tetanus neurotoxin endocytosis, but unlike the internalization of transferrin, clathrin-dependent endocytosis of APP requires cholesterol and adaptor protein-2 but is independent of epsin1 function. Moreover, on a nanoscale resolution using stimulated emission depletion microscopy and by Förster resonance energy transfer with fluorescence lifetime imaging microscopy, we provide evidence that flotillin-2 promotes the clustering of APP at the cell surface. We show that the interaction of flotillin-2 with APP is dependent on cholesterol and that clustering of APP enhances its endocytosis rate. Together, our data suggest that cholesterol/flotillin-dependent clustering of APP may stimulate the internalization into a specialized clathrin-dependent endocytosis pathway to promote amyloidogenic processing.


Methodological aspects of SEMG recordings for force estimation--a tutorial and review.
Insight into the magnitude of muscle forces is important in biomechanics research, for example because muscle forces are the main determinants of joint loading. Unfortunately muscle forces cannot be calculated directly and can only be measured using invasive procedures. Therefore, estimates of muscle force based on surface EMG measurements are frequently used. This review discusses the problems associated with surface EMG in muscle force estimation and the solutions that novel methodological developments provide to this problem. First, some basic aspects of muscle activity and EMG are reviewed and related to EMG amplitude estimation. The main methodological issues in EMG amplitude estimation are precision and representativeness. Lack of precision arises directly from the stochastic nature of the EMG signal as the summation of a series of randomly occurring polyphasic motor unit potentials and the resulting random constructive and destructive (phase cancellation) superimpositions. Representativeness is an issue due the structural and functional heterogeneity of muscles. Novel methods, i.e. multi-channel monopolar EMG and high-pass filtering or whitening of conventional bipolar EMG allow substantially less variable estimates of the EMG amplitude and yield better estimates of muscle force by (1) reducing effects of phase cancellation, and (2) adequate representation of the heterogeneous activity of motor units within a muscle. With such methods, highly accurate predictions of force, even of the minute force fluctuations that occur during an isometric and isotonic contraction have been achieved. For dynamic contractions, EMG-based force estimates are confounded by the effects of muscle length and contraction velocity on force producing capacity. These contractions require EMG amplitude estimates to be combined with modeling of muscle contraction dynamics to achieve valid force predictions.


The inevitable pull of the river's current: interpretations derived from a single text using multiple research traditions.
The purpose of this article is to make visible the multiple ways in which doctoral students from various qualitative research traditions learned to think, read, and write interpretively as they completed an assignment requiring the interpretive analysis of a common interview transcript. Students were asked to offer a convincing account of the text and to demonstrate an understanding of what it means to interpret within their selected research tradition. Shared and disputed meanings arising from the interpretive process are presented and discussed. This description of their collective experience might be useful to novice researchers and their mentors.


The pediatric nephrotic syndrome spectrum: clinical homogeneity and molecular heterogeneity.
Idiopathic nephrotic syndrome is the most common glomerular disorder of childhood. Recurrence of nephrotic syndrome immediately following renal transplantation is rapid, results in a high rate of graft loss, and represents the most severe form of nephrotic syndrome. This review discusses the molecular heterogeneity of pediatric nephrotic syndrome across the spectrum of disease activity. A schema is offered for a molecular approach to pediatric nephrotic syndrome, including immune-mediated and structural/genetic factors.


Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.
ASXL1 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. De novo ASXL1 mutations cause Bohring-Opitz syndrome characterized by multiple congenital malformations. We show that Asxl1 deletion in mice led to developmental abnormalities including dwarfism, anophthalmia, and 80% embryonic lethality. Surviving Asxl1(-/-) mice lived for up to 42 days and developed features of myelodysplastic syndrome (MDS), including dysplastic neutrophils and multiple lineage cytopenia. Asxl1(-/-) mice had a reduced hematopoietic stem cell (HSC) pool, and Asxl1(-/-) HSCs exhibited decreased hematopoietic repopulating capacity, with skewed cell differentiation favoring granulocytic lineage. Asxl1(+/-) mice also developed mild MDS-like disease, which could progress to MDS/myeloproliferative neoplasm, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1 loss led to an increased apoptosis and mitosis in Lineage(-)c-Kit(+) (Lin(-)c-Kit(+)) cells, consistent with human MDS. Furthermore, Asxl1(-/-) Lin(-)c-Kit(+) cells exhibited decreased global levels of H3K27me3 and H3K4me3 and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12, Bcl2l13). Collectively, we report a novel ASXL1 murine model that recapitulates human myeloid malignancies, implying that Asxl1 functions as a tumor suppressor to maintain hematopoietic cell homeostasis. Future work is necessary to clarify the contribution of microenvironment to the hematopoietic phenotypes observed in the constitutional Asxl1(-/-) mice.


Recursive design of a holographic focusing grating coupler.
A method for designing and recording a holographic optical element that is used as a waveguide focusing grating coupler is presented. It is based on recording the holographic coupler with two predistorted wave fronts, derived from interim holograms, whose readout and recording geometries are different. The corrected holographic coupler has almost aberration-free performance even for couplers with very small f/numbers or with large wavelength shift between recording and readout.


Fatal bovine anaplasmosis in a herd with new genotypes of Anaplasma marginale, Anaplasma ovis and concurrent haemoplasmosis.
Haematological and molecular analysis of blood samples was carried out during an outbreak of bovine anaplasmosis in Hungary. Acute disease was observed in five animals, two of which died. Anaplasma-carrier state was diagnosed in 69 (92%) of cattle. Further evaluation of 24 blood samples revealed concurrent infections with Mycoplasma wenyonii and 'CandidatusM. haemobos' in 22 and 21 animals, respectively. In addition, two cows were identified with rickettsaemia. Regarding molecular investigation of potential hard tick vectors, Haemaphysalis inermis and Dermacentor marginatus males collected from the animals were PCR-negative. However, in one pool (out of 18) of Ixodesricinus males, and in six pools (out of 18) of D. reticulatus males the msp4 gene of Anaplasma marginale was detected. In the same I. ricinus pool Anaplasma ovis was also identified. All ticks were negative for haemoplasmas. Anaplasma sequences yielded 97-99% homology to sequences deposited in the Genbank. This is the first report of fatal bovine anaplasmosis associated with divergent A. marginale genotypes and concurrent 'CandidatusM. haemobos' infection, as well as of an A. ovis strain in ticks collected from cattle.


Influence of molecular structure and plasma hydrolysis on the metabolism of glutamine-containing dipeptides in humans.
Glutamine-containing dipeptides may serve as a source of glutamine in parenteral nutrition solutions. To study the metabolism of glycyl-L-glutamine (gly-gln) and L-alanyl-L-glutamine (ala-gln) bolus injections of both dipeptides (0.1 mmol/kg within 40 seconds) were performed in five healthy male volunteers. Furthermore, plasma hydrolase activity against both peptides was tested by in vitro incubation. Both peptides were rapidly cleared from plasma after injection; however clearance was significantly greater for ala-gln than for gly-gln (1,595 +/- 124 v 507 +/- 14 mL/min). Arterial concentrations of constituent amino acids rose after peptide injection, indicating hydrolysis of the peptides. Glutamine concentration, for example, rose from 573 +/- 29 to a maximum of 718 +/- 34 mumol/L after gly-gln and from 570 +/- 15 to 900 +/- 53 mumol/L after ala-gln injection. Both peptides were hydrolyzed by plasma hydrolases during in vitro incubation. Hydrolysis was greater for ala-gln than for gly-gln. Half-lives of ala-gln and gly-gln were 46 +/- 3 and 553 +/- 160 minutes, respectively. For both peptides, plasma hydrolysis was too low to contribute significantly to in vivo clearance. Our results indicate that gly-gln and ala-gln are suitable sources for glutamine in parenteral nutrition solutions. Furthermore, plasma hydrolases do not play a significant role in peptide metabolism. Both peptides therefore appear to be primarily metabolized via extracellular hydrolysis, presumably by hydrolases on the cell membranes and consecutive uptake of the liberated amino acid residues.


Identification of a new breast cancer-related gene by restriction landmark genomic scanning.
Molecular genetic analyses have demonstrated the importance of the accumulation of genomic changes in the etiology of cancer and, additionally, have identified valuable genetic markers for certain cancers. Although several prognostic markers have already been identified for breast cancer, it is clear that others remain to be identified. Fourteen breast cancer samples and non-cancerous counterparts were applied to restriction landmark genomic scanning (RLGS) and 6 breast cancer cell lines (MCF-7, MDA-MB-435, T-47D, MDA-MB-231, SK-BR-3 and BT-20) and 9 cancer tissue samples were applied to reverse transcnptionalpolymerase chain reaction (RT-PCR) for screening of novel genetic alterations. Two spots were identified on the RLGS profiles of cancerous tissue that differed from those of normal tissue. Nucleotide sequencing and homology search analysis showed that these spots represented the voltage-dependent calcium channel alpha1H subunit gene (CACNA1H gene) and a locus immediately downstream of the growth factor receptor-binding protein 7 (GRB7) gene. Expression of the CACNA1H gene was confirmed by RT-PCR. Two genes, Grb7 and CACNA1H, were identified by RLGS. The expression of CACNA1H in breast cancer was confirmed for the first time.


Addition of a polypeptide stretch at the N-terminus improves the expression, stability and solubility of recombinant protein tyrosine phosphatases from Drosophila melanogaster.
The production of recombinant proteins in Escherichia coli involves substantial optimization in the size of the protein and over-expression strategies to avoid inclusion-body formation. Here we report our observations on this so-called construct dependence using the catalytic domains of five Drosophila melanogaster receptor protein tyrosine phosphatases as a model system. Five strains of E. coli as well as three variations in purification tags viz., poly-histidine peptide attachments at the N- and C-termini and a construct with Glutathione-S-transferase at the N-terminus were examined. In this study we observe that inclusion of a 45 residue stretch at the N-terminus was crucial for over-expression of the enzymes, influencing both the solubility and the stability of these recombinant proteins. While the addition of negatively charged residues in the N-terminal extension could partially rationalize the improvement in the solubility of these constructs, conventional parameters like the proportion of order promoting residues or aliphatic index did not correlate with the improved biochemical characteristics. These findings thus suggest the inclusion of additional parameters apart from rigid domain predictions to obtain domain constructs that are most likely to yield soluble protein upon expression in E. coli.


Injection fears and COVID-19 vaccine hesitancy.
When vaccination depends on injection, it is plausible that the blood-injection-injury cluster of fears may contribute to hesitancy. Our primary aim was to estimate in the UK adult population the proportion of COVID-19 vaccine hesitancy explained by blood-injection-injury fears. In total, 15 014 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, took part (19 January-5 February 2021) in a non-probability online survey. The Oxford COVID-19 Vaccine Hesitancy Scale assessed intent to be vaccinated. Two scales (Specific Phobia Scale-blood-injection-injury phobia and Medical Fear Survey-injections and blood subscale) assessed blood-injection-injury fears. Four items from these scales were used to create a factor score specifically for injection fears. In total, 3927 (26.2%) screened positive for blood-injection-injury phobia. Individuals screening positive (22.0%) were more likely to report COVID-19 vaccine hesitancy compared to individuals screening negative (11.5%), odds ratio = 2.18, 95% confidence interval (CI) 1.97-2.40, p < 0.001. The population attributable fraction (PAF) indicated that if blood-injection-injury phobia were absent then this may prevent 11.5% of all instances of vaccine hesitancy, AF = 0.11; 95% CI 0.09-0.14, p < 0.001. COVID-19 vaccine hesitancy was associated with higher scores on the Specific Phobia Scale, r = 0.22, p < 0.001, Medical Fear Survey, r = 0.23, p = <0.001 and injection fears, r = 0.25, p < 0.001. Injection fears were higher in youth and in Black and Asian ethnic groups, and explained a small degree of why vaccine hesitancy is higher in these groups. Across the adult population, blood-injection-injury fears may explain approximately 10% of cases of COVID-19 vaccine hesitancy. Addressing such fears will likely improve the effectiveness of vaccination programmes.


Stokes Shift and Specific Fluorescence as Potential Indicators of Organic Matter Hydrophobicity and Molecular Weight in Membrane Bioreactors.
Hydrophobicity and molecular weight (MW) are two fundamental properties of dissolved organic matter (DOM) in wastewater treatment systems. This study proposes fluorescence Stokes shift and specific fluorescence intensity (SFI) as novel indicators of hydrophobicity and MW. These indicators originate from the energy gap and photon efficiency of the fluorescence process and can be readily extracted from a fluorescence excitation-emission matrix (EEM). The statistical linkages between these indicators and hydrophobicity/MW were explored through investigation of DOM across 10 full-scale membrane bioreactors treating municipal wastewater. Stokes shift was found to exhibit a general rule among the hydrophobicity components in the order of hydrophilic substances (HIS) < hydrophobic acids (HOA) < hydrophobic bases (HOB). The Stokes shift of 1.2 μm-1 is a critical border, above which the relative fluorescence correlated significantly with the HOA-related content (Pearson's r = 0.8). With regard to MW distribution (<1, 1-10, 10-100, and >100 kDa), SFI was found to be the most sensitive to the change of MW of <1 kDa proportion, especially at the excitation/emission wavelengths of 200-320/310-550 nm (r > 0.9). Hydrophobicity-related π conjugation and MW-dependent light exposure might be responsible for the correlations. These fluorescence indicators may be useful for convenient monitoring of DOM in wastewater treatment systems.


Using the "customer service framework" to successfully implement patient- and family-centered care.
Despite the growing momentum toward patient- and family-centered care at the federal policy level, the organizational literature remains divided on its effectiveness, especially in regard to its key dimension of involving patients and families in treatment decisions and safety practices. Although some have argued for the universal adoption of patient involvement, others have questioned both the effectiveness and feasibility of patient involvement. In this article, we apply a well-established theoretical perspective, that is, the Service Quality Model (SQM) (also known as the "customer service framework") to the health care context, to reconcile the debate related to patient involvement. The application helps support the case for universal adoption of patient involvement and also question the arguments against it. A key contribution of the SQM lies in highlighting a set of fundamental service quality determinants emanating from basic consumer service needs. It also provides a simple framework for understanding how gaps between consumer expectations and management perceptions of those expectations can affect the gap between "expected" and "perceived" service quality from a consumer's perspective. Simultaneously, the SQM also outlines "management requirements" for the successful implementation of a customer service strategy. Applying the SQM to the health care context therefore, in addition to reconciling the debate on patient involvement, helps identify specific steps health care managers could take to successfully implement patient- and family-centered care. Correspondingly, the application also provides insights into strategies for the successful implementation of policy recommendations related to patient- and family-centered care in health care organizations.


Leptomeningeal carcinomatosis and sensorineural hearing loss: correlation of labyrinthine enhancement patterns with symptoms.
The purpose of this study was to investigate the correlation between hearing loss and inner ear enhancement in patients suffering from leptomeningeal carcinomatosis (LC) involving the internal acoustic canal (IAC). Previous studies have only reported an association between IAC enhancement and sensorineural deafness. In a prospective study conducted from 2005 to 2007, 14 patients with LC involving the IAC underwent high-resolution MRI and otolaryngology examination. MRI images were analyzed by two experienced radiologists who were blinded to audiologic investigation results. Three (21%) patients had IAC and inner ear enhancement on gadolinium-weighted MRI. All three had a sensorineural hearing loss. Eleven (79%) patients had IAC enhancement without inner ear enhancement. Nine of these 11 patients were free of sensorineural hearing loss. Only two of them had sensorineural deafness. These findings are suggestive of a relation between hearing loss and inner ear enhancement in leptomeningeal carcinomatosis, as previously reported for bacterial meningitis. However, further investigations, including radiopathological correlation and a larger number of patients, are warranted to confirm these preliminary results.


Role of Lymphovascular Invasion in Pattern C Invasive Endocervical Adenocarcinoma.
Lymphovascular invasion (LVI) has been reported as an independent predictor of patient outcome in cervical carcinoma. However, not all studies support independent significance, especially in multivariable analyses. A risk stratification system recently introduced for endocervical adenocarcinoma was reported to better predict risk of lymph node (LN) metastasis. A subset of patients with tumors with pattern C features had LN metastasis and died of disease. In this study, we determined whether LVI had any additional significance in this subset of tumors. A total of 127 patients with pattern C tumors and at least 12-month follow-up were included. Tumors were separated into 3 subgroups. Those with no LVI and negative LNs represented 41 cases; most patients (36, 88%) were alive with no evidence of disease at last follow-up, whereas 4 (10%) died of disease, all after tumor recurrence/metastasis. Tumors with LVI, but negative LNs, represented 55 cases; recurrences were seen in 10 (18%) patients, of which 5 (50%) of them died of disease; remaining 5 patients are alive with persistent disease. Tumors with both LVI and positive LNs represented 31 cases; recurrences were seen in 13 (42%) patients; 11 (85%) patients died of disease and 2 are alive with persistent disease. One additional patient who presented with advanced stage also died of disease. Tumor size, horizontal spread, and LN status were significantly associated with outcome in univariate, but not in multivariable analysis; depth of invasion was not a predictor of outcome. Tumors with no LVI and negative LNs behaved significantly less aggressively than tumors with both LVI and positive LNs (P<0.01). LVI status (independent of LN status) was not significantly associated with patient outcome, although approached significance (P=0.06). In conclusion, LVI is a prerequisite for LN metastasis; however, by itself is not sufficient to predict tumor aggressiveness, whereas over 50% of patients with positive LNs died of disease. Stratifying pattern C tumors into subgroups based on LVI and LN status could further determine treatment in patients with pattern C tumors.


Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis.
Pacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100 000× 10(9)/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a ≥35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a ≥50% reduction in spleen size by physical examination. Median MF symptom improvement was ≥50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT00745550.


Filling the void in geriatric mental health: the Geropsychiatric Nursing Collaborative as a model for change.
Mental health for older adults is a looming public health problem. Yet, geriatric mental health specialists are a scarce commodity, and few generalists have had formal education in either geriatrics or mental health. A multilevel collaboration using a diffusion of innovation model served to achieve change nationally in preparing entry-and advanced practice-level nurses to improve the mental health of older Americans. The John A. Hartford Foundation Geropsychiatric Nursing Collaborative at the American Academy of Nursing is the exemplar described here. The Geropsychiatric Nursing Collaborative developed and infused mental health competency enhancements for generalist and specialist nurses; identified and disseminated teaching-learning strategies to convey related key concepts using the POGOe (Portal of Geriatric Online Education) website; raised awareness through multiple presentations and publications; and notified deans of every school of nursing about these new resources. Fully embracing diffusion of innovation principles, the Geropsychiatric Nursing Collaborative is achieving change in this critical area of nursing practice.


Coping strategies, depression, and anxiety among Ontario family medicine residents.
To assess the current prevalence of depression and anxiety among Ontario family medicine residents, and to describe their coping strategies. Surveys mailed to residents integrated DSM-IV diagnostic criteria and a previously validated Patient Health Questionnaire. Ontario family medicine programs from June to August 2002. Residents entering, advancing in, or graduating from residency programs: approximately 216 yearly for a total of 649 residents. Types and frequency of coping skills used by residents; prevalence of depressive and anxiety disorders. Response rate for residents entering programs was 46% and for graduating residents was 30% (37% response rate overall). Prevalence of depressive disorders was 20% (13% major depressive disorders, 7% other depressive syndromes)(odds ratio [OR] 3.4, confidence interval [CI] 2.7 to 7.5, P < .001). Prevalence of generalized anxiety disorder was 12%, and 2% of residents met criteria for panic syndrome (OR 4.3, CI 1.6 to 11.8, P = .002). Rates were similar for men and women. Medical training was commonly identified as a negative influence on the mental health of troubled residents. Residents most often turned to family and friends when they needed help (43.7% of respondents). About 17.3% saw their family doctors, 15.4% counselors, and 7.9% psychiatrists. Some residents (13.4%) used medication to deal with their affective symptoms, 7.1% underwent cognitive-behavioural therapy, and 8.3% required a leave of absence from their programs. More than half (61.8%) indicated recreational use of alcohol and drugs, 1.2% identified use due to addiction, and 5.9% used drugs to help cope with their problems. Four respondents admitted concern that they might commit suicide during residency; a different three had made previous attempts. Affective disorders (both depression and anxiety syndromes) are three to four times more common among Ontario family practice residents than in the general population; male and female residents are equally affected. Most residents with these problems report negative effects on their function at work. Medical training is the most commonly identified negative influence on mental health. While residents most often obtain help from family members and friends, many seek professional help.


Inducible nitric oxide synthase in monocytes from patients with Graves' disease.
The presence of inducible nitric oxide synthase (iNOS) in fresh monocytes from patients with Graves' disease was demonstrated for the first time. Immunophenotypic analysis showed a profile reflecting a state of activation and differentiation of monocytes. Incubation of lymphomononuclear cells from healthy volunteers in the presence of synthetic peptides with sequences related to thyroid autoantigens (TSH receptor, thyroid peroxidase, or thyroglobulin) led to a stimulation of monocytes manifested by a change in phenotype and expression of iNOS. This expression did not take place on isolated monocytes, unless products associated with Th1 activity were present in the medium. Active peptides contained a characteristic "2-6-11" motif already described [López-Moratalla et al. (1995) Biochim. Biophys. Acta 1265, 181-188]. These results are suggestive of a new role for autoantigens in the pathogenesis of Graves' disease: that of inducing the expression of iNOS and activating the monocyte possibly underlying the autoimmune response.


Mutations in protein-binding hot-spots on the hub protein Smad3 differentially affect its protein interactions and Smad3-regulated gene expression.
Hub proteins are connected through binding interactions to many other proteins. Smad3, a mediator of signal transduction induced by transforming growth factor beta (TGF-β), serves as a hub protein for over 50 protein-protein interactions. Different cellular responses mediated by Smad3 are the product of cell-type and context dependent Smad3-nucleated protein complexes acting in concert. Our hypothesis is that perturbation of this spectrum of protein complexes by mutation of single protein-binding hot-spots on Smad3 will have distinct consequences on Smad3-mediated responses. We mutated 28 amino acids on the surface of the Smad3 MH2 domain and identified 22 Smad3 variants with reduced binding to subsets of 17 Smad3-binding proteins including Smad4, SARA, Ski, Smurf2 and SIP1. Mutations defective in binding to Smad4, e.g., D408H, or defective in nucleocytoplasmic shuttling, e.g., W406A, were compromised in modulating the expression levels of a Smad3-dependent reporter gene or six endogenous Smad3-responsive genes: Mmp9, IL11, Tnfaip6, Fermt1, Olfm2 and Wnt11. However, the Smad3 mutants Y226A, Y297A, W326A, K341A, and E267A had distinct differences on TGF-β signaling. For example, K341A and Y226A both reduced the Smad3-mediated activation of the reporter gene by ∼50% but K341A only reduced the TGF-β inducibilty of Olfm2 in contrast to Y226A which reduced the TGF-β inducibility of all six endogenous genes as severely as the W406A mutation. E267A had increased protein binding but reduced TGF-β inducibility because it caused higher basal levels of expression. Y297A had increased TGF-β inducibility because it caused lower Smad3-induced basal levels of gene expression. Mutations in protein binding hot-spots on Smad3 reduced the binding to different subsets of interacting proteins and caused a range of quantitative changes in the expression of genes induced by Smad3. This approach should be useful for unraveling which Smad3 protein complexes are critical for specific biological responses.


Rhodium-catalyzed synthesis of 1,2-dihydropyridine by a tandem reaction of 4-(1-acetoxyallyl)-1-sulfonyl-1,2,3-triazole.
A tandem reaction of 4-(1-acetoxyallyl)-1-sulfonyl-1,2,3-triazole including formation of α-imino rhodium carbene, 1,2-migration of an acetoxy group and six electron electrocyclic ring closure was reported. The migration of the OAc group with excellent chemoselectivity was the crucial process, leading to the formation of 1,2-dihydropyridine specifically in up to 90% yield. Several transformations of the dihydropyridine product were also achieved illustrating the potential of the protocol in organic synthesis. Based on the observation of the intermediate, a plausible mechanism was proposed.


Impact of Chemical Structure on Conjunctival Drug Permeability: Adopting Porcine Conjunctiva and Cassette Dosing for Construction of In Silico Model.
Conjunctiva occupies most of the ocular surface area, and conjunctival permeability affects ocular and systemic drug absorption of topical ocular medications. Therefore, the aim of this study was to obtain a computational in silico model for structure-based prediction of conjunctival drug permeability. This was done by employing cassette dosing and quantitative structure-property relationship (QSPR) approach. Permeability studies were performed ex vivo across fresh porcine conjunctiva and simultaneous dosing of a cassette mixture composed of 32 clinically relevant drug molecules with wide chemical space. The apparent permeability values were obtained using drug concentrations that were quantified with liquid chromatography tandem-mass spectrometry. The experimental data were utilized for building a QSPR model for conjunctival permeability predictions. The conjunctival permeability values presented a 17-fold range (0.63-10.74 × 10-6 cm/s). The final QSPR had a Q2 value of 0.62 and predicted the external test set with a mean fold error of 1.34. The polar surface area, hydrogen bond donor, and halogen ratio were the most relevant descriptors for defining conjunctival permeability. This work presents for the first time a predictive QSPR model of conjunctival drug permeability and a comprehensive description on conjunctival isolation from the porcine eye. The model can be used for developing new ocular drugs.


Health and fracking: should the medical profession be concerned?
The use of natural gas that is obtained from high-volume hydraulic fracturing (fracking) may reduce carbon emissions relative to the use of coal and have substantial economic benefits for South Africa. However, concerns have been raised regarding the health and environmental impacts. The drilling and fracking processes use hundreds of chemicals as well as silica sand. Additional elements are either released from or formed in the shale during drilling. These substances can enter the environment in various ways: through failures in the well casing; via alternative underground pathways; as wastewater, spills and leaks on the wellpad; through transportation accidents; and as air pollution. Although many of these chemicals and elements have known adverse health effects, there is little evidence available on the health impacts of fracking. These health concerns have not yet been fully addressed in policy making, and the authors recommend that the voice of health professionals should be part of the public debate on fracking and that a full health impact assessment be required before companies are given the go-ahead to drill.


Lights and shadows of cardiac magnetic resonance imaging in acute myocarditis.
Cardiac magnetic resonance (CMR) is considered a primary tool for the diagnosis of acute myocarditis, due to its unique potential for non-invasive identification of the various hallmarks of the inflammatory response, with relevant impact on patient management and prognosis. Nonetheless, a marked variation in sensitivity and negative predictive value has been reported in the literature, reflecting the intrinsic drawbacks of current diagnostic criteria, which are based mainly on the use of conventional CMR pulse sequences. As a consequence, a negative exam cannot reliably exclude the diagnosis, especially in patients who do not present an infarct-like onset of disease. The introduction of new-generation mapping techniques further widened CMR potentials, allowing quantification of tissue changes and opening new avenues for non-invasive workup of patients with inflammatory myocardial disease. • CMR sensitivity varies in AM, reflecting its clinical polymorphism and the intrinsic drawbacks of LLc. • Semiquantitative approaches such as EGEr or T2 ratio have limited accuracy in diffuse disease forms. • T1 mapping allows objective quantification of inflammation, with no need to normalize measurements. • A revised protocol including T2-STIR, T1 mapping and LGE could be hypothesized to improve sensitivity.


Diagnosis of suspected venous thromboembolic disease in pregnancy.
Venous thromboembolic disease is a leading cause of maternal mortality during pregnancy. Early and accurate radiological diagnosis is essential as anticoagulation is not without risk and clinical diagnosis is unreliable. Although the disorder is potentially treatable, unnecessary treatment should be avoided. Most of the diagnostic imaging techniques involve ionizing radiation which exposes both the mother and fetus to finite radiation risks. There is a relative lack of evidence in the literature to guide clinicians and radiologists on the most appropriate method of assessing this group of patients. This article will review the role of imaging of suspected venous thromboembolic disease in pregnant patients, highlight contentious issues such as radiation risk, intravenous contrast use in pregnancy and discuss the published guidelines, as well as suggesting an appropriate imaging algorithm based on the available evidence.


Tissue plasminogen activator reduces neurological damage after cerebral embolism.
Intravenous administration of tissue plasminogen activator immediately after the injection of numerous small blood clots into the carotid circulation in rabbit embolic stroke model animals caused a significant reduction in neurological damage. In vitro studies indicate that tissue plasminogen activator produced substantial lysis of clots at concentrations comparable to those expected in vivo, suggesting that this may be the mechanism of action of this drug. Drug-induced hemorrhages were not demonstrable. Tissue plasminogen activator may be of value for the immediate treatment of embolic stroke.


Experiences of Fast Queue health care users in primary health care facilities in eThekwini district, South Africa.
Comprehensive Primary Health Care (PHC), based on the principles of accessibility, availability, affordability, equity and acceptability, was introduced in South Africa to address inequalities in health service provision. Whilst the Fast Queue was instrumental in the promotion of access to health care, a major goal of the PHC approach, facilities were not prepared for the sudden influx of clients. Increased access resulted in long waiting times and queues contributing to dissatisfaction with the service which could lead to missed appointments and non-compliance with established treatment plans. Firstly to describe the experiences of clients using the Fast Queue strategy to access routine healthcare services and secondly, to determine how the clients' experiences led to satisfaction or dissatisfaction with the Fast Queue service. A descriptive qualitative survey using content analysis explored the experiences of the Fast Queue users in a PHC setting. Setting was first identified based on greatest number using the Fast Queue and geographic diversity and then a convenience sample of health care users of the Fast Queue were sampled individually along with one focus group of users who accessed the Queue monthly for medication refills. The same interview guide questions were used for both individual interviews and the one focus group discussion. Five clinics with the highest number of attendees during a three month period and a total of 83 health care users of the Fast Queue were interviewed. The average participant was female, 31 years old, single and unemployed. Two themes with sub-themes emerged: health care user flow and communication, which highlights both satisfaction and dissatisfaction with the fast queue and queue marshals, could assist in directing users to the respective queues, reduce waiting time and keep users satisfied with the use of sign posts where there is a lack of human resources. Effective health communication strategies contribute to positive experiences by health care users and these can be effected by: (1) involvement of health care providers in planning the construction of health facilities to give input about patient flow, infection prevention and control and provision of privacy, (2) effective complaints mechanisms for users to ensure that complaints are followed up and (3)encouraging users to arrive at the facility throughout the day, rather than the present practice where all users arrive at the clinic early in the morning.


Joint Associations Between Body Mass Index and Waist Circumference With Atrial Fibrillation in Men and Women.
Background Associations between adiposity and atrial fibrillation (AF) might differ between sexes. We aimed to determine precise estimates of the risk of AF by body mass index (BMI) and waist circumference (WC) in men and women. Methods and Results Between 2008 and 2013, over 3.2 million adults attended commercial screening clinics. Participants completed health questionnaires and underwent physical examination along with cardiovascular investigations, including an ECG. We excluded those with cardiovascular and cardiac disease. We used multivariable logistic regression and determined joint associations of BMI and WC and the risk of AF in men and women by comparing likelihood ratio χ2 statistics. Among 2.1 million included participants 12 067 (0.6%) had AF. A positive association between BMI per 5 kg/m2 increment and AF was observed, with an odds ratio of 1.65 (95% CI, 1.57-1.73) for men and 1.36 (95% CI, 1.30-1.42) for women among those with a BMI above 20 kg/m2. We found a positive association between AF and WC per 10 cm increment, with an odds ratio of 1.47 (95% CI, 1.36-1.60) for men and 1.37 (95% CI, 1.26-1.49) for women. Improvement of likelihood ratio χ2 was equal after adding BMI and WC to models with all participants. In men, WC showed stronger improvement of likelihood ratio χ2 than BMI (30% versus 23%). In women, BMI showed stronger improvement of likelihood ratio χ2 than WC (23% versus 12%). Conclusions We found a positive association between BMI (above 20 kg/m2) and AF and between WC and AF in both men and women. BMI seems a more informative measure about risk of AF in women and WC seems more informative in men.


Interactions between traditional Chinese medicine and western drugs in Taiwan: A population-based study.
Drug-drug interactions have long been an active research area in clinical medicine. In Taiwan, however, the widespread use of traditional Chinese medicines (TCM) presents additional complexity to the topic. Therefore, it is important to see the interaction between traditional Chinese and western medicine. (1) To create a comprehensive database of multi-herb/western drug interactions indexed according to the ways in which physicians actually practice and (2) to measure this database's impact on the detection of adverse effects between traditional Chinese medicine compounds and western medicines. First, a multi-herb/western medicine drug interactions database was created by separating each TCM compound into its constituent herbs. Each individual herb was then checked against an existing single-herb/western drug interactions database. The data source comes from the National Health Insurance research database, which spans the years 1998-2011. This study estimated the interaction prevalence rate and further separated the rates according to patient characteristics, distribution by county, and hospital accreditation levels. Finally, this new database was integrated into a computer order entry module of the electronic medical records system of a regional teaching hospital. The effects it had were measured for two months. The most commonly interacting Chinese herbs were Ephedrae Herba and Angelicae Sinensis Radix/Angelicae Dahuricae Radix. Ephedrae Herba contains active ingredients similar to in ephedrine. 15 kinds of traditional Chinese medicine compounds contain Ephedrae Herba. Angelicae Sinensis Radix and Angelicae Dahuricae Radix contain ingredients similar to coumarin, a blood thinner. 9 kinds of traditional Chinese medicine compounds contained Angelicae Sinensis Radix/Angelicae Dahuricae Radix. In the period from 1998 to 2011, the prevalence of herb-drug interactions related to Ephedrae Herba was 0.18%. The most commonly prescribed traditional Chinese compounds were MA SHING GAN SHYR TANG (23.1%), followed by SHEAU CHING LONG TANG (15.5%) and DINQ CHUAN TANG (13.2%). The prevalence of herb-drug interactions related to Angelicae Sinensis Radix, Angelicae Dahuricae Radix was 4.59%. The most common traditional Chinese compound formula were TSANG EEL SAAN (32%), followed by HUOH SHIANG JENQ CHIH SAAN (31.4%) and SHY WUH TANG (10.7%). Once the multi-herb drug interaction database was deployed in a hospital system, there were 480 prescriptions that indicated a TCM-western drug interaction. Physicians were alerted 24 times during two months. These alerts resulted in a prescription change four times (16.7%). Due to the unique cultural factors that have resulted in widespread acceptance of both western and traditional Chinese medicine, Taiwan stands well positioned to report on the prevalence of interactions between western drugs and traditional Chinese medicine and devise ways to reduce their incidence. This study built a multi-herb/western drug interactions database, embedded inside a hospital clinical information system, and then examined the effects that drug interaction alerts had on clinician prescribing behaviour. The results demonstrated that western drug/traditional Chinese medicine interactions are prevalent and that western-trained physicians tend to change their prescribing behaviour more than traditional Chinese medicine physicians in their response to medication interaction alerts.


First Record of Rhizoctonia solani AG 1-IB on Mucuna pruriens in India.
Mucuna is the source of L-Dopa (L 3,4 dihydroxyphenylalanine), a precursor of a dopamine used to treat Parkinson's disease. Leaf blight symptoms were observed on Mucuna pruriens plants in October to November 2010 in a field at the Indian Council of Agricultural Research Complex for the Northeastern Hill Region, Umiam, Meghalaya, India. Symptoms included black necrotic areas on leaves, collapsed leaf tissue and, occasionally, fungal growth visible on the leaf. In advanced infections, dead leaves were attached to the stem, followed by defoliation with only infected pods still attached. Approximately 10% of plants were infected in ~0.5 ha surveyed. Symptomatic leaf pieces were washed with sterile water, surface-sterilized using 4% NaOCl for 30 s, washed again, blotted dry, and plated on PDA amended with streptomycin (100 ppm). Characteristics of three fungal isolates were typical of Rhizoctonia solani J.G. Kühn [teleomorph = Thanatephorus cucumeris (A. B. Frank) Donk], i.e., hyphal branching at 90° angles, basal constriction at the hyphal branching point with a septum close to the lateral hyphum (3), and presence of multinucleate hyphal cells confirmed using DAPI (2-(4-amidinophenyl)-1H-indole-6-carboxamidine) staining (1). A culture was deposited at the Agharkar Research Institute, Pune, India (NFCCI No. 2602). The ITS1-5.8S-ITS2 region of nuclear rDNA of one isolate was sequenced after amplification with primers ITS1 and ITS4 (4), (GenBank Accession No. JQ675536). A BLAST search revealed 99% similarity of the sequence with that of 2 R. solani AG 1-IB isolates (AB122137 and AB000039). Sequences were aligned using MAFT Version 6. Maximum parsimony analysis using MEGA 5 placed the test isolate in AG 1-IB with 99% bootstrap support. PCR assays with primers for R. solani AG 1-IB produced a DNA band of ~300 bp (2). Koch's postulates were completed by inoculating 5-mm colonized plugs of PDA at the soil line of each of 5 potted, 40-day-old plants of M. pruriens, and covering the base of each plant with moistened cheesecloth. In addition, 3 plants were inoculated with colonized plugs at the junction of the lamina and petiole of 9 leaves/plant, spraying the plants with sterilized water, and covering the plants with polythene for 3 days. In addition, 10 detached leaves were inoculated with colonized PDA plugs and incubated in a moist chamber. Three non-inoculated plants served as a control treatment for the first 2 methods, and 10 leaves as a control treatment for the third method with sterilized PDA plugs. Symptoms of leaf blight (necrosis from base to leaf tip, with abundant fungal growth) developed in 6 to 7 days on plants inoculated at the soil line, 4 days on leaves inoculated at the junction of the lamina and petiole, and 2 to 3 days on detached leaves. Control plants and leaves remained asymptomatic for all 3 methods. R. solani was reisolated from inoculated plants as described above, and confirmed to be AG 1-IB. The fungus was not reisolated from control plants or leaves. To our knowledge, this is the first record of R. solani AG 1-IB causing leaf blight on M. pruriens in India. References: (1) M. M. Kulik and P. D. Dery. Biotech. Histochem. 70:95, 1995. (2) M. Matsumoto. Mycoscience 43:185, 2002. (3) B. Sneh et al. Identification of Rhizoctonia Species. The American Phytopathological Society Press, St Paul, MN, 1991. (4) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, CA, 1990.


A pilot randomised controlled trial of the feasibility of using body scan and isometric exercises for reducing urge to smoke in a smoking cessation clinic.
The main cause of relapse in smokers attempting to quit is inability to resist urges to smoke. Pharmacotherapy ameliorates but does not entirely prevent urges to smoke when abstinent, so other methods to resist urges to smoke might be helpful. Exercise is effective, but aerobic exercise is often impractical when urges strike. Two techniques, body scan and isometric exercise, have been shown to reduce urge intensity and nicotine withdrawal symptoms in temporarily abstinent smokers. It is unclear whether they would be used or effective in typical smokers attempting to quit. In a pilot trial set in a UK smoking cessation clinic, 20 smokers were randomised to receive emails containing .mp3 files and .pdf illustrations of the instructions for doing the body scan and isometric exercises. Twenty smokers received no other intervention, although all 40 were receiving weekly behavioural support and nicotine replacement therapy. Carbon monoxide confirmed abstinence, nicotine withdrawal symptoms, urges to smoke, and use of the techniques to resist urges were recorded weekly for four weeks after quit day. 60-80% of quitters reported using the isometric exercises each week and 40-70% reported using the body scan to deal with urges. On average, these techniques were rated as 'slightly helpful' for controlling the urges. There were no large or significant differences in withdrawal symptoms or urge intensity between the two groups. The risk ratio and 95% confidence interval for exercises compared with controls for prolonged confirmed abstinence at four weeks was 0.82 (0.44-1.53). 81% of quitters intended to continue using isometric exercises and 25% body scan, while 81% and 50% respectively would recommend using these techniques to others trying to stop. Isometric exercises, and to a lesser extent body scan, were popular and perceived as somewhat helpful by quitters. The trial showed that these techniques were used and a larger trial could now be developed to examine the influence of the methods on reducing urges to smoke and increasing abstinence.


A model for transgenerational imprinting variation in complex traits.
Despite the fact that genetic imprinting, i.e., differential expression of the same allele due to its different parental origins, plays a pivotal role in controlling complex traits or diseases, the origin, action and transmission mode of imprinted genes have still remained largely unexplored. We present a new strategy for studying these properties of genetic imprinting with a two-stage reciprocal F mating design, initiated with two contrasting inbred lines. This strategy maps quantitative trait loci that are imprinted (i.e., iQTLs) based on their segregation and transmission across different generations. By incorporating the allelic configuration of an iQTL genotype into a mixture model framework, this strategy provides a path to trace the parental origin of alleles from previous generations. The imprinting effects of iQTLs and their interactions with other traditionally defined genetic effects, expressed in different generations, are estimated and tested by implementing the EM algorithm. The strategy was used to map iQTLs responsible for survival time with four reciprocal F populations and test whether and how the detected iQTLs inherit their imprinting effects into the next generation. The new strategy will provide a tool for quantifying the role of imprinting effects in the creation and maintenance of phenotypic diversity and elucidating a comprehensive picture of the genetic architecture of complex traits and diseases.


Alcohol and Road Traffic Injuries in Latin America and the Caribbean: A Case-Crossover Study.
This study reports dose-response estimates for the odds ratio (OR) and population attributable risk of acute alcohol use and road traffic injury (RTI). Data were analyzed on 1,119 RTI patients arriving at 16 emergency departments (EDs) in Argentina, Brazil, Costa Rica, Dominican Republic, Guatemala, Guyana, Mexico, Nicaragua, Panama, and Trinidad and Tobago. Case-crossover analysis, pair-matching the number of standard drinks consumed within the 6 hours prior to the RTI with 2 control periods (prior d/wk), was performed using fractional polynomial analysis for dose-response. About 1 in 6 RTI patients in EDs were positive for self-reported alcohol 6 hours prior to the injury (country range 8.6 to 24.1%). The likelihood of an RTI with any drinking prior (compared to not drinking) was 5 times higher (country range OR 2.50 to 15.00) and the more a person drinks the higher the risk. Every drink (12.8 g alcohol) increased the risk of an RTI by 13%, even 1 to 2 drinks were associated with a sizable increase in risk of an RTI and a dose-response was found. Differences in ORs for drivers (OR = 3.51; 95% CI = 2.25 to 5.45), passengers (OR = 8.12; 95% CI = 4.22 to 15.61), and pedestrians (OR = 6.30; 95% CI = 3.14 to 12.64) and attributable fractions were noted. Acute use of alcohol was attributable to 14% of all RTIs, varying from 7% for females to 19% for being injured as a passenger. The finding that the presence of alcohol increases risk among drivers and nondrivers alike may further help to urge interventions targeting passengers and pedestrians. Routine screening and brief interventions in all health services could also have a beneficial impact in decreasing rates of RTIs. Higher priority should be given to alcohol as a risk factor for RTIs, particularly in Latin America and the Caribbean.


[Clinico-electrocardiographic variants of combined lesions of the sinoatrial and atrioventricular nodes].
A study of 71 patients with atrioventricular blocks and 57 patients with the sick-sinus syndrome (SSS) revealed electrophysiologic evidence of sinus dysfunction in 38 (53.5%) patients with atrioventricular blocks. Sinus dysfunction was due to pathologic vegetative effects in 15 (21.1%) patients with AV blocks, and a pathology of the sinus node itself in 23 (32.4%). Impaired atrioventricular conductivity, was registered in 29 (38.7%) patients with the SSS. A disorder of atrioventricular automatism was detected in 38 patients, and was combined with impaired AV conductivity in 19 of those. Five clinico-electrocardiographic variants of binodal heart disease have been identified, and possible therapies are discussed for each of those.


Pulmonary embolism in surgical patients: 1959-79.
The Edinburgh surgical statistics (audit) have been analysed for the years 1959, 1964, 1969, 1974, and 1979 to determine the trends in pulmonary embolism in surgical patients who died. There was a total of 61,038 operations, 1528 postoperative deaths, 804 necropsies, and 158 reported pulmonary emboli. The incidence of embolism diagnosed clinically and at necropsy fell throughout the period. This fall held good after corrections for necropsy rates, prognosis, and proportions of major operations. Although the overall necropsy rate fell from 58% to 40%, in patients expected to have a good prognosis the rate rose from 68% to 75%. Necropsy-proved embolism in "good prognosis" patients fell from 0.5% to 0.15% per 100 major operations. The main reduction has taken place since most surgeons in the area adopted methods of prophylaxis against venous thrombosis, but a direct relationship is not proved by this study.


Trigeminal neuralgia occurs and recurs in the absence of neurovascular compression.
Vascular compression of the trigeminal nerve is the most common factor associated with the etiology of trigeminal neuralgia (TN). Microvascular decompression (MVD) has proven to be the most successful and durable surgical approach for this disorder. However, not all patients with TN manifest unequivocal neurovascular compression (NVC). Furthermore, over time patients with an initially successful MVD manifest a relentless rate of TN recurrence. The authors performed a retrospective review of cases of TN Type 1 (TN1) or Type 2 (TN2) involving patients 18 years or older who underwent evaluation (and surgery when indicated) at Oregon Health & Science University between July 2006 and February 2013. Surgical and imaging findings were correlated. The review identified a total of 257 patients with TN (219 with TN1 and 38 with TN2) who underwent high-resolution MRI and MR angiography with 3D reconstruction of combined images using OsiriX. Imaging data revealed that the occurrence of TN1 and TN2 without NVC was 28.8% and 18.4%, respectively. A subgroup of 184 patients underwent surgical exploration. Imaging findings were highly correlated with surgical findings, with a sensitivity of 96% for TN1 and TN2 and a specificity of 90% for TN1 and 66% for TN2. Magnetic resonance imaging detects NVC with a high degree of sensitivity. However, despite a diagnosis of TN1 or TN2, a significant number of patients have no NVC. Trigeminal neuralgia clearly occurs and recurs in the absence of NVC.


Triticale Bran Alkylresorcinols Enhance Resistance to Oxidative Stress in Mice Fed a High-Fat Diet.
Triticale (× Triticosecale Whitm.) is a cereal grain with high levels of alkyresorcinols (AR) concentrated in the bran. These phenolic lipids have been shown to reduce or inhibit triglyceride accumulation and protect against oxidation; however, their biological effects have yet to be evaluated in vivo. The purpose of this study was to determine the effects of ARs extracted from triticale bran (TB) added to a high-fat diet on the development of obesity and oxidative stress. CF-1 mice were fed a standard low-fat (LF) diet, a 60% high-fat diet (HF) and HF diets containing either 0.5% AR extract (HF-AR), 10% TB (HF-TB), or 0.5% vitamin E (HF-VE). Energy intake, weight gain, glucose tolerance, fasting blood glucose (FBG) levels, and body composition were determined. Oxygen radical absorbance capacity (ORAC), superoxide dismutase (SOD) activity, and glutathione (GSH) assays were performed on mice liver and heart tissues. The findings suggest that ARs may serve as a preventative measure against risks of oxidative damage associated with high-fat diets and obesity through their application as functional foods and neutraceuticals. Future studies aim to identify the in vivo mechanisms of action of ARs and the individual homologs involved in their favorable biological effects.


Possible molecular targets for therapeutic applications of caffeic acid phenethyl ester in inflammation and cancer.
Of the various derivatives of caffeic acid, caffeic acid phenethyl ester (CAPE) is a hydrophobic, bioactive polyphenolic ester obtained from propolis extract. The objective in writing this review article was to summarize all published studies on therapeutics of CAPE in inflammation and cancer to extract direction for future research. The possible molecular targets for the action of CAPE, include various transcription factors such as nuclear factor-κB, tissue necrosis factor-α, interleukin-6, cyclooxygenase-2, Nrf2, inducible nitric oxide synthase, nuclear factor of activated T cells, hypoxia-inducible factor-1α, and signal transducers and activators of transcription. Based on the valuable data on its therapeutics in inflammation and cancer, clinical studies of CAPE should also be conducted to explore its toxicities, if any.


Teaching professionalism in medical education: a Best Evidence Medical Education (BEME) systematic review. BEME Guide No. 25.
We undertook a systematic review to identify the best evidence for how professionalism in medicine should be taught. Eligible studies included any articles published between 1999 and 2009 inclusive. We reviewed papers presenting viewpoints and opinions as well as empirical research. We performed a comparative and thematic synthesis on all papers meeting inclusion criteria in order to capture the best available evidence on how to teach professionalism. We identified 217 papers on how to teach professionalism. Of these, we determined 43 to be best evidence. Few studies provided comprehensive evaluation or assessment data demonstrating success. As yet, there has not emerged a unifying theoretical or practical model to integrate the teaching of professionalism into the medical curriculum. Evident themes in the literature are that role modelling and personal reflections, ideally guided by faculty, are the important elements in current teaching programmes, and are widely held to be the most effective techniques for developing professionalism. While it is generally held that professionalism should be part of the whole of a medical curriculum, the specifics of sequence, depth, detail, and the nature of how to integrate professionalism with other curriculum elements remain matters of evolving theory.


Community seroprevalence of SARS-CoV-2 in children and adolescents in England, 2019-2021.
To understand community seroprevalence of SARS-CoV-2 in children and adolescents. This is vital to understanding the susceptibility of this cohort to COVID-19 and to inform public health policy for disease control such as immunisation. We conducted a community-based cross-sectional seroprevalence study in participants aged 0-18 years old recruiting from seven regions in England between October 2019 and June 2021 and collecting extensive demographic and symptom data. Serum samples were tested for antibodies against SARS-CoV-2 spike and nucleocapsid proteins using Roche assays processed at UK Health Security Agency laboratories. Prevalence estimates were calculated for six time periods and were standardised by age group, ethnicity and National Health Service region. Post-first wave (June-August 2020), the (anti-spike IgG) adjusted seroprevalence was 5.2%, varying from 0.9% (participants 10-14 years old) to 9.5% (participants 5-9 years old). By April-June 2021, this had increased to 19.9%, varying from 13.9% (participants 0-4 years old) to 32.7% (participants 15-18 years old). Minority ethnic groups had higher risk of SARS-CoV-2 seropositivity than white participants (OR 1.4, 95% CI 1.0 to 2.0), after adjusting for sex, age, region, time period, deprivation and urban/rural geography. In children <10 years, there were no symptoms or symptom clusters that reliably predicted seropositivity. Overall, 48% of seropositive participants with complete questionnaire data recalled no symptoms between February 2020 and their study visit. Approximately one-third of participants aged 15-18 years old had evidence of antibodies against SARS-CoV-2 prior to the introduction of widespread vaccination. These data demonstrate that ethnic background is independently associated with risk of SARS-CoV-2 infection in children. NCT04061382.


Accurate emotion prediction in dyads and groups and its potential social benefits.
Emotion dynamics vary considerably from individual to individual and from group to group. Successful social interactions require people to track this moving target in order to anticipate the thoughts, feelings, and actions of others. In two studies, we test whether people track others' emotional idiosyncrasies to make accurate, target-specific emotion predictions. In both studies, participants predicted the emotion transitions of a specific target-either a close friend (Study 1) or a first-year college roommate (Study 2)-as well as an average group member. Results demonstrate that people can make highly accurate predictions both for specific individuals and specific groups. Accurate predictions rely on target-specific knowledge; new community members were able to make accurate predictions at zero-acquaintance, but accuracy increased over time as individuals accrued specialized knowledge. Results also suggest that accurate emotion prediction is associated with social success in both individual and communal relationships and that such a relation might emerge over time. Overall, our studies suggest that people accurately make individualized predictions of others' emotion transitions and that doing so fulfills a meaningful function in the social world. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Incidence, aetiology and prevention of musculoskeletal injuries in volleyball: A systematic review of the literature.
Currently, there is no overview of the incidence and (volleyball-specific) risk factors of musculoskeletal injuries among volleyball players, nor any insight into the effect of preventive measures on the incidence of injuries in volleyball. This study aimed to review systematically the scientific evidence on the incidence, prevalence, aetiology and preventive measures of volleyball injuries. To this end, a highly sensitive search strategy was built based on two groups of keywords (and their synonyms). Two electronic databases were searched, namely Medline (biomedical literature) via Pubmed, and SPORTDiscus (sports and sports medicine literature) via EBSCOhost. The results showed that ankle, knee and shoulder injuries are the most common injuries sustained while playing volleyball. Results are presented separately for acute and overuse injuries, as well as for contact and non-contact injuries. Measures to prevent musculoskeletal injuries, anterior knee injuries and ankle injuries were identified in the scientific literature. These preventive measures were found to have a significant effect on decreasing the occurrence of volleyball injuries (for instance on ankle injuries with a reduction from 0.9 to 0.5 injuries per 1000 player hours). Our systematic review showed that musculoskeletal injuries are common among volleyball players, while effective preventive measures remain scarce. Further epidemiological studies should focus on other specific injuries besides knee and ankle injuries, and should also report their prevalence and not only the incidence. Additionally, high-quality studies on the aetiology and prevention of shoulder injuries are lacking and should be a focus of future studies.


High-efficient generation of induced pluripotent stem cells from human astrocytes.
The reprogramming of human somatic cells to induced pluripotent stem (hiPS) cells enables the possibility of generating patient-specific autologous cells for regenerative medicine. A number of human somatic cell types have been reported to generate hiPS cells, including fibroblasts, keratinocytes and peripheral blood cells, with variable reprogramming efficiencies and kinetics. Here, we show that human astrocytes can also be reprogrammed into hiPS (ASThiPS) cells, with similar efficiencies to keratinocytes, which are currently reported to have one of the highest somatic reprogramming efficiencies. ASThiPS lines were indistinguishable from human embryonic stem (ES) cells based on the expression of pluripotent markers and the ability to differentiate into the three embryonic germ layers in vitro by embryoid body generation and in vivo by teratoma formation after injection into immunodeficient mice. Our data demonstrates that a human differentiated neural cell type can be reprogrammed to pluripotency and is consistent with the universality of the somatic reprogramming procedure.


Optical parametric amplification pumped by a phase-aberrated beam.
In this paper we theoretically study the spatial characteristics of optical parametric amplification (OPA) or chirped pulse OPA (OPCPA) pumped with a phase-aberrated beam. Due to the fact that pump-to-signal phase transfer caused by walk-off effect is highly gain-dependent, in a high gain OPA system the signal beam-quality will be significantly degraded even for a weak walk-off, accompanied with beam tilting and converging or diverging. It is demonstrated that an OPA configuration with walkoff-compensated crystal pair is capable of reducing the phase transfer and hence ensuring signal beam-quality, which may be of importance for designing high-energy OPCPA systems.


The Effect in Topical Use of Lycogen(TM) via Sonophoresis for Anti-aging on Facial Skin.
Anti-aging skin care is a growing popular topic in cosmetic and aesthetic fields, and skin care rather then makeup tips draw more attention nowadays. The phenomenon of skin aging includes thinning of skin losses of elasticity and moisture, pigmented spot formation, and wrinkle development. Along with growth in age, the decreased rates of epithelium renewal and cellular recovery as well as the reduced contents of elastin, collagen, and glycosaminoglycans all contribute to creases or folds of skin. Available strategies for wrinkle treatments include topical use of skin care products with anti-aging contents, dermabrasion, laser, Botox injection, fillers injection, and facelift. Though all of these above options can provide different degrees of improvement in facial wrinkles, the cost-effect, pain of intervention therapy, and necessity of repetitive treatment may impact on choices made. Topical use of anti-aging skin products is the most convenient and cheap way to achieve skin anti-aging effect. Lycogen(TM) is an antioxidant, which can prevent the downregulation of pro-collagen I, intracellular accumulation of malondialdehyde (MDA) and achieve the aim of skin rejuvenation. Twenty-six female patients were included in our study with ages between 30 and 45. They were randomly assigned to two groups: the vehicle control group and the experimental group. Patients in the control group applied a skin care product without Lycogen(TM)to the face via sonophoresis after facial cleanser use in the morning and at night. The experimental group applied a Lycogen(TM) -containing skin care product via sonophoresis in the same time schedule. We evaluated results, including pigmented spots, wrinkles, texture, pores, and red area by VISIA on weeks 0, 1, 2, 4, 6, 8, and 10 respectively. In the aspect of pigmented spots, the experimental group showed significant difference in comparison with the vehicle control group on weeks 2, 6, 8, and 10. For wrinkles, the experimental group had better results on weeks 1, 2, 4, 8, and 10. Measured by texture, the experimental group had better results on weeks 1, 2, 4, 6, 8, and 10. Determined by pores, the experimental group had better results on weeks 2, 4, 6, 8, and 10. Concerning red areas, the experimental group had better results on weeks 6, 8, and 10. (p < 0.05). In our study, we applied a Lycogen(TM)- containing product by sonophoresis as the experimental group in comparison with a skin care product without LycogenTM. VISIA (Canfield Imaging Systems, Fairfield, NJ) was used to evaluate facial skin in aspects of pigmented spots, wrinkles, texture, pores, and red area. Overall, Lycogen(TM) had proven effectiveness on anti-oxidation as patients who used the Lycogen TM -containing product had better outcomes.


Membrane microviscosity and plasma triacylglycerols in the rat.
1. Multiple cell membrane alterations have been described in humans and animals with various genetic forms of hypertension and/or dyslipidaemia. The aim of our study was to characterize membrane microviscosity, using two different fluorescent probes exploring either the outer membrane leaflet [trimethylamino-diphenylhexatriene (TMA-DPH)] or the lipid membrane core [diphenylhexatriene (DPH)], in platelets and erythrocytes of genetically hypertensive rats of the Prague hereditary hypertriglyceridaemic (HTG) strain. The relationships of membrane microviscosity to hypertension, hypertriglyceridaemia and cell calcium handling were also investigated. 2. Membrane microviscosity was similar in HTG and normotensive control Wistar rats when measured in platelets or erythrocyte ghosts incubated in Na(+)-containing medium. On the contrary, TMA-DPH fluorescence anisotropy was significantly reduced in HTG platelets incubated in Na(+)-free medium because external Na+ removal elicited a larger rise of TMA-DPH anisotropy in Wistar platelets. 3. Plasma triacylglycerols were associated positively with platelet TMA-DPH anisotropy and negatively with DPH anisotropy in both strains. The slopes of these relationships were reduced in HTG compared with Wistar rats. Platelet TMA-DPH anisotropy correlated positively and DPH anisotropy negatively with the cytosolic calcium concentration in unstimulated platelets, the slopes being almost identical in both strains. 4. Pulse pressure correlated negatively with TMA-DPH anisotropy and positively with DPH anisotropy found in erythrocyte ghosts. 5. The present results suggest that plasma triacylglycerols and cytosolic calcium are capable of modulating the membrane microviscosity in this new animal model of genetic hypertension associated with hypertriglyceridaemia.


Positive peritoneal cytology predicts unresectability of pancreatic adenocarcinoma.
Peritoneal cytology is clinically useful in gastric and gynecologic malignancies. Its role in pancreatic adenocarcinoma remains less well defined. Controversy exists as to the relationship between percutaneous fine needle aspiration (FNA) of the pancreas and shedding of malignant cells with the peritoneum. The aim of this study was to determine whether positive peritoneal cytology (PPC) predicts unresectability of pancreatic adenocarcinoma and impacts on overall survival. In addition, the study aimed to determine whether antecedent FNA increases the incidence of PPC. Between January 1993 and June 1996, 228 patients with radiographically resectable pancreatic adenocarcinoma underwent laparoscopic staging. Specimens were taken from right and left upper quadrants at the beginning of laparoscopy. Various prognostic factors were analyzed. PPC was identified in 34 patients (15%). Of patients that had an antecedent FNA, 20% had PPC, and 13% of those without an antecedent FNA had PPC (p = 0.22). The majority of patients with PPC had stage IV disease (26 of 34 [76%]) and only 8 (24%) had no evidence of metastases. Overall survival was significantly higher in patients with negative peritoneal cytology (NPC) compared with PPC (p<0.0006). PPC had a positive predictive value of 94.1%, specificity of 98.1%, and a sensitivity of 25.6% for determining unresectability of pancreatic adenocarcinoma. PPC was not an independent prognostic variable for survival on multivariate analysis. PPC is associated with advanced disease and is highly specific in predicting unresectability of pancreatic adenocarcinoma, resulting in decreased survival. Antecedent FNA is not associated with an increased the incidence of PPC, nor does it significantly impact on overall survival.


Developmental exposure to oxytocin facilitates partner preferences in male prairie voles (Microtus ochrogaster).
The authors investigated the effects of postnatal manipulations of oxytocin (OT) on the subsequent tendency to form a partner preference in male prairie voles (Microtus ochrogaster). Neonatally, males received either an injection of OT, an oxytocin antagonist (OTA), 0.9% saline vehicle, or handling without injection. As adults, males were tested for partner preference following 1 hr of cohabitation with a nonestrous female. In a 3-hr preference test, males neonatally exposed to exogenous OT exhibited a significant partner preference, not seen in males receiving OTA or saline. Both OT and OTA voles had significantly higher levels of social contact than saline controls. A single neonatal injection of OT increased both total and selective social behaviors in male prairie voles.


Tissue and hepatic subcellular distribution of liposomes containing bleomycin after intravenous administration to patients with neoplasms.
1. Liposomes containing 111In-labelled bleomycin were injected intravenously into two patients. One patient had a hepatoma and the other had secondary adenocarcinomatous deposits in the liver. 2. The tissue distribution of 111In was determined by whole-body scanning and by measurement of the radioactivity in organs at autopsy. 3. Scans in vivo and post-mortem measurement of radioactivity indicated that liposomes accumulate predominantly in the liver, but that there is no selective uptake of liposomes by the malignant tissue. 4. The subcellular distribution of radioactivity in the liver was measured 90 min after injection by fractionation of percutaneous liver biopsies on sucrose density gradients. 5. Radioactivity within the liver was concentrated in lysosomes. 6. Electron microscopy of tissue obtained before the administration of liposomes revealed particles morphologically indistinguishable from liposomes in hepatoma cells and hepatocytes.


Ethmoidal encephalocoele associated with seizures in a puppy.
A six-month-old puppy was presented for investigation of a seizure disorder. Neurological examination indicated persistent cerebral dysfunction in the absence of any identifiable metabolic disorder and magnetic resonance imaging revealed extension of the rostral lobes of the cerebrum into the nasal cavity. Despite symptomatic treatment, the puppy continued to exhibit seizures and appeared distressed and so was euthanased. Postmortem examination confirmed the abnormal anatomy of the rostral part of the brain and absence of a cribriform plate. There was extensive grey and white matter degeneration plus intraparenchymal haemorrhage in the abnormal brain tissue. The findings are consistent with a diagnosis of ethmoldal encephalocoele--a condition that has not previously been reported in the dog.


The morphological and behavioral analysis of geographically separated Rammeihippus turcicus (Orthoptera: Acrididae: Gomphocerinae) populations: data result in taxonomical conflict.
Rammeihippus Woznessenskij, 1996 (Orthoptera: Acrididae: Gomphocerinae) is a genus represented by two species. Rammeihippus turcicus (Ramme, 1939) is the only known species of the genus from Anatolia. As for most of the Gomphocerinae species in Anatolia, all populations of the species are intermittently distributed at high altitudes. In this study, three populations of R. turcicus were studied for the first time to determine the song and mating behavior. Males of the species produce typical calling song for Gomphocerinae and complex courtship songs and mating behavior. Thus, an accurate taxonomy requires extensive material and different character sources. In this study, the Anatolian Rammeihippus was re-examined on the basis of qualitative and morphometric morphology, male songs, and behavioral characteristics. There was no agreement between the results of the song and morphology. Acoustic analysis suggested one species and patchy distribution in the area, whereas morphology pointed out that each population was a different taxonomical unit. The results of the study show that the aberrant morphology does not necessarily indicate a new species in the Gomphocerinae genus.


Similarities and differences between potassium and ammonium ions in liquid water: a first-principles study.
Understanding ion solvation in liquid water is critical in optimizing materials for a wide variety of emerging technologies, including water desalination and purification. In this work, we report a systematic investigation and comparison of solvated K+ and NH4+ using first-principles molecular dynamics simulations. Our simulations reveal a strong analogy in the solvation properties of the two ions, including the size of the solvation shell as well as the solvation strength. On the other hand, we find that the local water structure in the ion solvation is significantly different; specifically, NH4+ yields a smaller number of water molecules and a more ordered water structure in the first solvation shell due to the formation of hydrogen bonds between the ion and water molecules. Finally, our simulations indicate that a comparable solvation strength of the two ions is a result of an interplay between the nature of ion-water interaction and number of water molecules that can be accommodated in the ion solvation shell.


Coercive forms of sexual risk and associated violence perpetrated by male partners of female adolescents.
Partner violence is associated with STDs among female adolescents, but the mechanisms underlying this association remain unclear. Sexually coercive and deceptive behaviors of male partners that increase female STD risk may be factors in this relationship. A sample of 356 females aged 14-20 who attended adolescent health clinics in Greater Boston between April and December 2006 were assessed for physical and sexual violence perpetrated by male partners and for exposure to sexual risk factors. Adjusted logistic regression models were used to examine the associations between intimate partner violence and standard sexual risk behaviors (e.g., multiple partnerships) and coercive or deceptive sexual risk factors (e.g., coerced condom nonuse). More than two-fifths of the sample had experienced intimate partner violence. In adjusted analyses, adolescents reporting intimate partner violence were more likely than others to report standard sexual risk behaviors--multiple partners, anal sex and unprotected anal sex (odds ratios, 1.7-2.2). They also were more likely to report coercive or deceptive sexual risk factors--partner sexual infidelity, fear of requesting condom use, negative consequences of condom request, and coerced condom nonuse (2.9-5.3). The high prevalence of intimate partner violence against young women attending adolescent clinics strongly indicates the need to target this population for abuse-related interventions. This need is underlined by the observed association between partner violence and sexual risk involving coercion or deception by male partners. Clinic-based STD and pregnancy prevention efforts should include assessment of sexual risk factors that are beyond the control of young women, particularly for those experiencing abuse.


Identification and sequence analysis of Potato yellow vein virus capsid protein minor gene.
Potato yellow vein virus (PYVV) is a whitefly-transmitted (Trialeurodes vaporariorum) closterovirus (WTC) with an as yet unidentified genome composition. PYVV dsRNA preparations consist of three high molecular weight dsRNA species (dsRNAs 1, 2 and 3) 8.0, 5.5 and 4.0 kbp in size respectively, as well as two low molecular weight dsRNA species of 2.0 and 1.8 kbp (denoted x and y). The PYVV capsid protein minor (CPm) gene was identified on the dsRNA 3 species, and was subsequently cloned and sequenced. The PYVV CPm gene is 2022 nucleotides long and putatively encodes a protein with estimated size 77.5 kDa. The PYVV CPm gene product is considerably larger than the equivalent proteins encoded by the bipartite criniviruses, Lettuce infectious yellows virus (LIYV) and Cucurbit yellow stunting disorder virus (CYSDV) (52 and 53 kDa, respectively). The PYVV CPm possesses a centralized domain which is absent from both the LIYV and CYSDV CPm counterparts. Pairwise comparisons as well as phylogenetic analysis based on the available amino acid sequences of the CPm of various WTCs, showed that PYVV is closely related to LIYV, CYSDV and also Beet pseudo-yellows virus.


Response Selection Contributes to the Preparation Cost for Bimanual Asymmetric Movements.
Movement preparation of bimanual asymmetric movements takes more time than bimanual symmetric movements in choice reaction-time conditions. This bimanual asymmetric cost may be caused by increased processing demands on any stage of movement preparation. The authors tested the contributions of each stage of movement preparation to the asymmetric cost by using the additive factors method. This involved altering the stimulus contrast, response compatibility, and response complexity. These manipulations changed the processing demands on stimulus identification, response selection, and response programming, respectively. Any manipulation with a larger reaction time cost than control suggests that stage contributes to the bimanual asymmetric cost. The bimanual asymmetric cost was larger for incompatible stimuli, which supports that response selection contributes to the bimanual asymmetric cost.


Genome sequence of the palaeopolyploid soybean.
Soybean (Glycine max) is one of the most important crop plants for seed protein and oil content, and for its capacity to fix atmospheric nitrogen through symbioses with soil-borne microorganisms. We sequenced the 1.1-gigabase genome by a whole-genome shotgun approach and integrated it with physical and high-density genetic maps to create a chromosome-scale draft sequence assembly. We predict 46,430 protein-coding genes, 70% more than Arabidopsis and similar to the poplar genome which, like soybean, is an ancient polyploid (palaeopolyploid). About 78% of the predicted genes occur in chromosome ends, which comprise less than one-half of the genome but account for nearly all of the genetic recombination. Genome duplications occurred at approximately 59 and 13 million years ago, resulting in a highly duplicated genome with nearly 75% of the genes present in multiple copies. The two duplication events were followed by gene diversification and loss, and numerous chromosome rearrangements. An accurate soybean genome sequence will facilitate the identification of the genetic basis of many soybean traits, and accelerate the creation of improved soybean varieties.


Reconstructing complex regions of genomes using long-read sequencing technology.
Obtaining high-quality sequence continuity of complex regions of recent segmental duplication remains one of the major challenges of finishing genome assemblies. In the human and mouse genomes, this was achieved by targeting large-insert clones using costly and laborious capillary-based sequencing approaches. Sanger shotgun sequencing of clone inserts, however, has now been largely abandoned, leaving most of these regions unresolved in newer genome assemblies generated primarily by next-generation sequencing hybrid approaches. Here we show that it is possible to resolve regions that are complex in a genome-wide context but simple in isolation for a fraction of the time and cost of traditional methods using long-read single molecule, real-time (SMRT) sequencing and assembly technology from Pacific Biosciences (PacBio). We sequenced and assembled BAC clones corresponding to a 1.3-Mbp complex region of chromosome 17q21.31, demonstrating 99.994% identity to Sanger assemblies of the same clones. We targeted 44 differences using Illumina sequencing and find that PacBio and Sanger assemblies share a comparable number of validated variants, albeit with different sequence context biases. Finally, we targeted a poorly assembled 766-kbp duplicated region of the chimpanzee genome and resolved the structure and organization for a fraction of the cost and time of traditional finishing approaches. Our data suggest a straightforward path for upgrading genomes to a higher quality finished state.


Micro-fragmented adipose tissue injection associated with arthroscopic procedures in patients with symptomatic knee osteoarthritis.
The social impact of degenerative diseases is steadily increasing, because of the continued rise in the mean age of the active population. Articular cartilage lesions are generally associated with disability and symptoms such as joint pain and reduced function, and remain a challenge for the orthopaedic surgeon. Several non-invasive solution have been proposed, but the results achieved to date are far from being completely satisfactory. Recently, new therapeutic approaches, such as the use of mesenchymal stem cells, have been developed. Among the many sources, the adipose tissue is nowadays considered one of the smartest, due to its abundance and easy access. The aim of this retrospective study is to explore whether patients affected by symptomatic knee osteoarthritis treated with micro-fragmented adipose tissue associated with a chondral shaving procedure experience an improvement in symptoms and function. Thirty-eight patients affected by symptomatic knee osteoarthritis were treated in 2015 with an arthroscopic procedure associated with an injection of autologous and micro-fragmented adipose tissue. Micro-fragmented adipose tissue was obtained using a minimal manipulation technique in a closed system. Clinical outcomes were determined at 1, 3, 6, and 12 months follow-up using Knee Injury and Osteoarthritis Outcome Score questionnaire and direct physical examination. Safety of the procedure, recording type and incidence of any adverse event, was also assessed. A steady and statistically significant improvement of all the clinical scores from pre-operative evaluation to 1, 3, 6, and 12 months follow-up was observed, with KOOS sport and quality of life being the most improved scores. On average, 92% of the patients clinically improved and 100% of them were satisfied with the treatment. No adverse events nor relevant complications were recorded. The result of the study pointed to micro-fragmented adipose tissue as a safe and beneficial adjuvant in the surgical treatment of degenerative knee chondropathy. The procedure is simple, sustainable, quick, minimally invasive, one-step, and safe. After one year, the results are very satisfactory and promising. A longer follow-up is needed to draw definitive conclusions and enlarge the indications. Registered at clinicaltrials.gov as NCT03527693 on 27 April 2018 (retrospectively registered).


Transformation of nonfunctional spinal circuits into functional states after the loss of brain input.
After complete spinal cord transections that removed all supraspinal inputs in adult rats, combinations of serotonergic agonists and epidural electrical stimulation were able to acutely transform spinal networks from nonfunctional to highly functional and adaptive states as early as 1 week after injury. Using kinematics, physiological and anatomical analyses, we found that these interventions could recruit specific populations of spinal circuits, refine their control via sensory input and functionally remodel these locomotor pathways when combined with training. The emergence of these new functional states enabled full weight-bearing treadmill locomotion in paralyzed rats that was almost indistinguishable from voluntary stepping. We propose that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping. These findings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control.


Modular soft robotic microdevices for dexterous biomanipulation.
We present a methodology for building biologically inspired, soft microelectromechanical systems (MEMS) devices. Our strategy combines several advanced techniques including programmable colloidal self-assembly, light-harvesting with plasmonic nanotransducers, and in situ polymerization of compliant hydrogel mechanisms. We synthesize optomechanical microactuators using a template-assisted microfluidic approach in which gold nanorods coated with thermoresponsive poly(N-isopropylmethacrylamide) (pNIPMAM) polymer function as nanoscale building blocks. The resulting microactuators exhibit mechanical properties (4.8 ± 2.1 kPa stiffness) and performance metrics (relative stroke up to 0.3 and stress up to 10 kPa) that are comparable to that of bioengineered muscular constructs. Near-infrared (NIR) laser illumination provides effective spatiotemporal control over actuation (sub-micron spatial resolution at millisecond temporal resolution). Spatially modulated hydrogel photolithography guided by an experimentally validated finite element-based design methodology allows construction of compliant poly(ethylene glycol) diacrylate (PEGDA) mechanisms around the microactuators. We demonstrate the versatility of our approach by manufacturing a diverse array of microdevices including lever arms, continuum microrobots, and dexterous microgrippers. We present a microscale compression device that is developed for mechanical testing of three-dimensional biological samples such as spheroids under physiological conditions.


The effects of Project ALERT one year past curriculum completion.
School-based drug prevention curricula constitute the nation's most prevalent strategy to prevent adolescent drug use. We evaluated the effects of one such curriculum, Project ALERT, on adolescent substance use. In particular, we sought to determine if a single effect on 30-day alcohol use, noted shortly following the completion of the 2-year program, could be detected 1 year later. We also looked for delayed effects on other outcomes of interest, namely lifetime alcohol use, and 30-day and lifetime use of cigarettes, marijuana, and inhalants. We employed a randomized controlled trial that used school as the unit of assignment. Thirty-four schools with grades 6-8 from 11 states completed the study. Seventy-one Project ALERT instructors taught 11 core lessons to sixth graders and 3 booster lessons to seventh graders. Students were assessed prior to the onset of the intervention, as sixth graders, after the completion of the 2-year curriculum, as seventh graders, and again 1 year later as eighth graders. This paper examines data from the pretest and final posttest. Using hierarchical nonlinear modeling, we found that our earlier effect on 30-day alcohol use did not persist. Further, we continued to find no effects for lifetime alcohol use and both the lifetime and 30-day use of cigarettes, marijuana, and inhalants. Our findings do not support the long-term effectiveness of Project ALERT, when delivered to sixth graders.