Redescription of the pagurid hermit crab Catapaguroides fragilis (Melin, 1939) and descriptions of two new species from deep-sea off the Ryukyu Islands, Japan (Crustacea: Decapoda: Anomura).
Three species of the pagurid hermit crab genus Catapaguroides A. Milne-Edwards & Bouvier, 1892, all from Japanese waters, are reported. Catapaguroides fragilis (Melin, 1939) is redescribed on the basis of the holotype and additional material from southern Japan. Diagnostic characters of this poorly known species are fully assessed. Two new species, C. bythos and C. rubromaculatus, are described and illustrated on the basis of material from upper bathyal depths off the Ryukyu Islands. Catapaguroides rubromaculatus n. sp. resembles C. fragilis and C. hirsutus Komai & Rahayu, 2013, but the characteristic shape of the ocular peduncle and the elongate male right sexual tube with an anteriorly directed distal portion readily separate C. rubromaculatus n. sp. from the latter two congeners. Catapaguroides bythos n. sp. appears close to C. mortenseni de Saint Laurent, 1968 and C. pectinipes (Lewinsohn, 1969), but the different armature of the chelipeds distinguishes C. bythos n. sp. from the latter two allies. Catapaguroides is now represented by 30 species.


An effectiveness study comparing acupuncture, physiotherapy, and their combination in poststroke rehabilitation: a multicentered, randomized, controlled clinical trial.
Stroke is a leading cause of death and disability worldwide, being the third leading cause of death in the United States and the second and third most common causes of death in Chinese cities and rural areas, respectively. Evaluation of different rehabilitative modalities appears necessary to optimize treatment. To compare acupuncture and physiotherapy for effectiveness and reliability in treating hemiplegic patients after stroke. The research team designed a multicentered, three-arm, randomized controlled trial. Power calculations revealed a targeted sample size of 310 participants. The study took place at seven in-patient hospitals in China. The research team screened a total of 310 patients. Of that number, 274 completed the study, 15 did not meet the inclusion/exclusion criteria, and 21 dropped out. Adverse events were rare (less than 1%), mild, and temporary. The research team randomly divided participants into three groups that all received conventional care as needed-including psychological counseling, standard nursing care, and daily medical evaluation plus (1) acupuncture, (2) physiotherapy, or (3) acupuncture plus physiotherapy. The participants received treatments once a day, 6 days a week for 4 weeks. The research team evaluated all patients at baseline, after 2 weeks, and after 4 weeks using the Fugl-Meyer Assessment of Physical Performance (FMA), a modified Barthel Index (BI), and the Neurologic Defect Scale (NDS). No significant differences existed between the three groups at baseline. Compared to baseline, participants in all groups improved their FMA, BI, and NDS scores by the end of week 2 (P≤.05) and further improved by the end of week 4 (P≤.05) The study found no statistically significant differences in outcomes between the three groups after treatment (P>.05). Acupuncture plus conventional care was similar in effectiveness to physiotherapy treatment plus conventional care for poststroke rehabilitation. The study found no synergistic effects for the combination of acupuncture and physiotherapy in addition to conventional care; that combination of treatments was no more effective than either treatment by itself. The effectiveness and lack of adverse events associated with acupuncture in this study suggest that it may represent an additional treatment option for stroke patients.


Secular trends in some Russian populations.
Secular changes of body measurements in children have been the subject of studies in many different countries. In recent years, there has been an increase in BMI associated with a significant trend towards obesity in both Europe and the US. The aim of the present study was to analyze trends in body measurements and BMI in Russia from the 1960's to the beginning of the 21st century. This was done at three locations of the Russian Federation: the city of Moscow, the cities of Saratov and Naberezhnye Chelny in the Volga-river area. In addition, data on secular changes of Abkhazian children were analyzed. A large number of anthropometric measurements were taken on each individual including height, weight, arm, leg and trunk lengths (estimated), body diameters and circumferences, skinfold thickness, head and face dimensions. Stages of secondary sex characteristics also were evaluated; data on menarcheal age were collected by status-quo and retrospective methods. Changes in hand grip strength have been evaluated in some of the samples. While stature was increasing during these years, weight, chest circumference and BMI were characterized by negative changes, which became more obvious in elder girls. Changes in handgrip strength also showed negative trends. There were noticeable changes in head and face measurements, which were expressed in more elongated head and face forms, i.e. the head became longer and narrower with narrower and higher faces. Secular changes in head and facial morphology may be considered part of the general trend.


Woman-centred care in childbirth: A concept analysis (Part 1).
'Woman-centred care' in childbirth is a process in which a woman makes choices and is involved in and has control over her care and relationship with her midwife. The aim of this paper is to study the concept of woman-centred care through analysis in the context of childbirth. The attributes, antecedents and consequences of this concept are identified, and a model case, a borderline case and a contrary case constructed to achieve conceptual clarity. A concept analysis was undertaken as described by Walker and Avant (2011), with an extensive exploration of domain-specific literature and evidence from various disciplines. It was established from the concept analysis that 'woman-centred care' was complex and experienced individualistically. The analysis indicated that mothers' participation is supposed to be based on a more collaborative relationship and partnership. Participation is exhibited by open communication and the mother's involvement in decision-making, consultation and collaboration with the attending midwife, further characterised by mutual respect and the midwife listening to the mother's views. There is also an exchange of complete and unbiased information, recognition and honouring of cultural diversity and making of informed choices. Through an inductive discovery approach and drawing on inferences, attributes were clustered in an attempt to identify the apparent essence of the concept.From the results of the concept analysis described in this study, the researchers recommend the formulation of criteria that could facilitate implementation and evaluation of woman-centred care and its empirical referents in the context of the Batho Pele principles (Part 2).


Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration.
This programme of overviews of randomised trials was established to investigate the effects of angiotensin-converting-enzyme (ACE) inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients. We did separate overviews of trials comparing active treatment regimens with placebo, trials comparing more intensive and less intensive blood-pressure-lowering strategies, and trials comparing treatment regimens based on different drug classes. The hypotheses to be investigated, the trials to be included, and the outcomes to be studied were all selected before the results of any participating trial were known. Individual participant data or group tabular data were provided by each trial and combined by standard statistical techniques. The overview of placebo-controlled trials of ACE inhibitors (four trials, 12,124 patients mostly with coronary heart disease) revealed reductions in stroke (30% [95% CI 15-43]), coronary heart disease (20% [11-28]), and major cardiovascular events (21% [14-27]). The overview of placebo-controlled trials of calcium antagonists (two trials, 5520 patients mostly with hypertension) showed reductions in stroke (39% [15-56]) and major cardiovascular events (28% [13-41]). In the overview of trials comparing blood-pressure-lowering strategies of different intensity (three trials, 20,408 patients with hypertension), there were reduced risks of stroke (20% [2-35]), coronary heart disease (19% [2-33]), and major cardiovascular events (15% [4-24]) with more intensive therapy. In the overviews comparing different antihypertensive regimens (eight trials, 37,872 patients with hypertension), several differences in cause-specific effects were seen between calcium-antagonist-based therapy and other regimens, but each was of borderline significance. Strong evidence of benefits of ACE inhibitors and calcium antagonists is provided by the overviews of placebo-controlled trials. There is weaker evidence of differences between treatment regimens of differing intensities and of differences between treatment regimens based on different drug classes. Data from continuing trials of blood-pressure-lowering drugs will substantially increase the evidence available about any real differences that might exist between regimens.


High-resolution NMR structure of an RNA model system: the 14-mer cUUCGg tetraloop hairpin RNA.
We present a high-resolution nuclear magnetic resonance (NMR) solution structure of a 14-mer RNA hairpin capped by cUUCGg tetraloop. This short and very stable RNA presents an important model system for the study of RNA structure and dynamics using NMR spectroscopy, molecular dynamics (MD) simulations and RNA force-field development. The extraordinary high precision of the structure (root mean square deviation of 0.3 A) could be achieved by measuring and incorporating all currently accessible NMR parameters, including distances derived from nuclear Overhauser effect (NOE) intensities, torsion-angle dependent homonuclear and heteronuclear scalar coupling constants, projection-angle-dependent cross-correlated relaxation rates and residual dipolar couplings. The structure calculations were performed with the program CNS using the ARIA setup and protocols. The structure quality was further improved by a final refinement in explicit water using OPLS force field parameters for non-bonded interactions and charges. In addition, the 2'-hydroxyl groups have been assigned and their conformation has been analyzed based on NOE contacts. The structure currently defines a benchmark for the precision and accuracy amenable to RNA structure determination by NMR spectroscopy. Here, we discuss the impact of various NMR restraints on structure quality and discuss in detail the dynamics of this system as previously determined.


Measuring adherence to antiretroviral treatment in resource-poor settings: the feasibility of collecting routine data for key indicators.
An East African survey showed that among the few health facilities that measured adherence to antiretroviral therapy, practices and definitions varied widely. We evaluated the feasibility of collecting routine data to standardize adherence measurement using a draft set of indicators. Targeting 20 facilities each in Ethiopia, Kenya, Rwanda, and Uganda, in each facility we interviewed up to 30 patients, examined 100 patient records, and interviewed staff. In 78 facilities, we interviewed a total of 1,631 patients and reviewed 8,282 records. Difficulties in retrieving records prevented data collection in two facilities. Overall, 94.2% of patients reported perfect adherence; dispensed medicine covered 91.1% of days in a six month retrospective period; 13.7% of patients had a gap of more than 30 days in their dispensed medication; 75.8% of patients attended clinic on or before the date of their next appointment; and 87.1% of patients attended within 3 days.In each of the four countries, the facility-specific median indicators ranged from: 97%-100% for perfect self-reported adherence, 90%-95% of days covered by dispensed medicines, 2%-19% of patients with treatment gaps of 30 days or more, and 72%-91% of appointments attended on time. Individual facilities varied considerably.The percentages of days covered by dispensed medicine, patients with more than 95% of days covered, and patients with a gap of 30 days or more were all significantly correlated with the percentages of patients who attended their appointments on time, within 3 days, or within 30 days of their appointment. Self reported recent adherence in exit interviews was significantly correlated only with the percentage of patients who attended within 3 days of their appointment. Field tests showed that data to measure adherence can be collected systematically from health facilities in resource-poor settings. The clinical validity of these indicators is assessed in a companion article. Most patients and facilities showed high levels of adherence; however, poor levels of performance in some facilities provide a target for quality improvement efforts.


A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation.
Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.


Mapping research on health systems in Europe: a bibliometric assessment.
Europe's health care decision-makers are facing an increasingly complex and rapidly changing landscape. It is crucial that health care problems are addressed with evidence-informed policy and that evidence finding is aimed at those topics most urgent on policy agendas. Research on health systems addresses the macro-level of health care delivery and aims at generating evidence for policy-making. Our aim was to assess the field of health systems research in Europe, primarily based on an analysis of the published literature. Starting from current definitions of health systems, during 2004-09 we identified four thematic areas for research and defined keywords to construct a sensitive literature search limited to European research. The database search resulted in 26,945 hits between 2004-09. Until 2008, the annual number of publications on health systems research increased at an average rate of 5.2%. Most (88%) were in English. The largest producer of research on health systems has been the UK (nearly 10,000 in six years; 37% of the total for Europe), which is also the country most frequently the object of research. In contrast, seven countries had produced no publications. There were modest correlations between a country's research production and its gross domestic product (r = 0.62) but less so with its population size (0.33). The most frequent keywords were 'patients' (49% of all references), 'patient satisfaction' (27%), 'organization and administration' (23%), 'education' (19%) and 'attitude of health personnel' (13%). Closer inspection of a sub-sample of 1000 abstracts revealed that only 24% met our definition of 'health systems research' rather than other fields of health services research. There is a wide-spread need to develop health systems research capacity, in particular in eastern European countries, and to address the effects of health care reform, particularly the effects of privatization and commercialization of health services.


COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England.
Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic. We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs. Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37-43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13-20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38-46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12-29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29-45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2-9) in 2019 to 3 days (1-5) by the end of March, 2020. Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses. UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.


Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic β Cells.
Pancreatic β cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca(2+) action potentials due to the activation of voltage-dependent Ca(2+) channels (VDCCs), which leads to the exocytosis of insulin granules. We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca(2+) release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic β cells. NAADP-regulated Ca(2+) release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca(2+) from the endolysosomal system, resulting in localized Ca(2+) signals. We show here that NAADP-mediated Ca(2+) release from endolysosomal Ca(2+) stores activates inward membrane currents and depolarizes the β cell to the threshold for VDCC activation and thereby contributes to glucose-evoked depolarization of the membrane potential during stimulus-response coupling. Selective pharmacological inhibition of NAADP-evoked Ca(2+) release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulfonylurea-induced membrane currents, depolarization, cytoplasmic Ca(2+) signals, and insulin secretion. Our findings implicate NAADP-evoked Ca(2+) release from acidic Ca(2+) storage organelles in stimulus-secretion coupling in β cells.


The future of functionally-related structural change assessment.
The brain is continually changing its function and structure in response to changing environmental demands. Magnetic resonance imaging (MRI) methods can be used to repeatedly scan the same individuals over time and in this way have provided powerful tools for assessing such brain change. Functional MRI has provided important insights into changes that occur with learning or recovery but this review will focus on the complementary information that can be provided by structural MRI methods. Structural methods have been powerful in indicating when and where changes occur in both gray and white matter with learning and recovery. However, the measures that we derive from structural MRI are typically ambiguous in biological terms. An important future challenge is to develop methods that will allow us to determine precisely what has changed.


Behavioral genomics of honeybee foraging and nest defense.
The honeybee has been the most important insect species for study of social behavior. The recently released draft genomic sequence for the bee will accelerate honeybee behavioral genetics. Although we lack sufficient tools to manipulate this genome easily, quantitative trait loci (QTLs) that influence natural variation in behavior have been identified and tested for their effects on correlated behavioral traits. We review what is known about the genetics and physiology of two behavioral traits in honeybees, foraging specialization (pollen versus nectar), and defensive behavior, and present evidence that map-based cloning of genes is more feasible in the bee than in other metazoans. We also present bioinformatic analyses of candidate genes within QTL confidence intervals (CIs). The high recombination rate of the bee made it possible to narrow the search to regions containing only 17-61 predicted peptides for each QTL, although CIs covered large genetic distances. Knowledge of correlated behavioral traits, comparative bioinformatics, and expression assays facilitated evaluation of candidate genes. An overrepresentation of genes involved in ovarian development and insulin-like signaling components within pollen foraging QTL regions suggests that an ancestral reproductive gene network was co-opted during the evolution of foraging specialization. The major QTL influencing defensive/aggressive behavior contains orthologs of genes involved in central nervous system activity and neurogenesis. Candidates at the other two defensive-behavior QTLs include modulators of sensory signaling (Am5HT(7) serotonin receptor, AmArr4 arrestin, and GABA-B-R1 receptor). These studies are the first step in linking natural variation in honeybee social behavior to the identification of underlying genes.


Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis.
The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package ('Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes.


Young-onset amyotrophic lateral sclerosis: historical and other observations.
There is a wide range of age at initial symptom onset in amyotrophic lateral sclerosis despite a mean age of 65 years in population-based studies. 'Young-onset' amyotrophic lateral sclerosis typically refers to patients younger than ∼45 years and accounts for about 10% of cases in contemporary series. A review of published cases of amyotrophic lateral sclerosis from 1850 to 1950 revealed a far higher proportion of cases with young onset (>50%), with a steady decline to the contemporary figure. It is possible that this is not solely explained by increases in life expectancy. While there is still a rich variation in phenotypes among cases of young-onset amyotrophic lateral sclerosis, bulbar onset was found to be significantly under-represented in analysis of a large patient database, with implications for age-related vulnerabilities pertaining to focality of symptom onset. The timing of initiating pathological processes in relation to the emergence of symptoms is discussed, including the potential role of very early development and the interaction of epigenetic and environmental factors.


Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids.
We examined the in vivo behavior of liver natural killer T cells (NKT cells) by intravital fluorescence microscopic imaging of mice in which a green fluorescent protein cDNA was used to replace the gene encoding the chemokine receptor CXCR6. NKT cells, which account for most CXCR6(+) cells in liver, were found to crawl within hepatic sinusoids at 10-20 microm/min and to stop upon T cell antigen receptor activation. CXCR6-deficient mice exhibited a selective and severe reduction of CD1d-reactive NKT cells in the liver and decreased susceptibility to T-cell-dependent hepatitis. CXCL16, the cell surface ligand for CXCR6, is expressed on sinusoidal endothelial cells, and CXCR6 deficiency resulted in reduced survival, but not in altered speed or pattern of patrolling of NKT cells. Thus, NKT cells patrol liver sinusoids to provide intravascular immune surveillance, and CXCR6 contributes to liver-based immune responses by regulating their abundance.


Sustained reduction of hypertension by deep brain stimulation.
Deep brain stimulators were implanted in the left periaqueductal gray matter (PAG) and sensory thalamus for right sided neuropathic facial pain refractory to other treatments in a man aged 58 years. PAG stimulation 8 months later acutely reduced systolic blood pressure by 25 mm Hg during revision surgery. One year post procedure, ambulatory blood pressure monitoring demonstrated significant and sustained reduction in blood pressure with PAG stimulation. Mean systolic blood pressure decreased by 12.6mm Hg and diastolic by 11.0mm Hg, alongside reductions in variability of heart rate and pulse pressure. This neurosurgical treatment may prove beneficial for medically refractory hypertension.


Vaginal birth after cesarean: new insights.
To synthesize the published literature on vaginal birth after cesarean (VBAC). Specifically, to review the trends and incidence of VBAC, maternal benefits and harms, infant benefits and harms, relevant factors influencing each, and the directions for future research. Relevant studies were identified from multiple searches of MEDLINE; DARE; the Cochrane databases (1966 to September 2009); and from recent systematic reviews, reference lists, reviews, editorials, Web sites, and experts. Specific inclusion and exclusion criteria were developed to determine study eligibility. The target population includes healthy women of reproductive age, with a singleton gestation, in the U.S. with a prior cesarean who are eligible for a trial of labor (TOL) or elective repeat cesarean delivery (ERCD). All eligible studies were quality rated and data were extracted from good or fair quality studies, entered into tables, summarized descriptively and, when appropriate, pooled for analysis. The primary focus of the report was term pregnancies. However, due to a small number of studies on term pregnancies, general population studies including all gestational ages (GA) were included in appropriate areas. We identified 3,134 citations and reviewed 963 papers for inclusion, of which 203 papers met inclusion and were quality rated. Studies of maternal and infant outcomes reported data based upon actual rather than intended router of delivery. The range for TOL and VBAC rates was large (28-82 percent and 49-87 percent, respectively) with the highest rates being reported in studies outside of the U.S. Predictors of women having a TOL were having a prior vaginal delivery and settings of higher-level care (e.g., tertiary care centers). TOL rates in U.S. studies declined in studies initiated after 1996 from 63 to 47 percent, but the VBAC rate remained unimproved. Hispanic and African American women were less likely than their white counterparts to have a vaginal delivery. Overall rates of maternal harms were low for both TOL and ERCD. While rare for both TOL and ERCD, maternal mortality was significantly increased for ERCD at 13.4 per 100,000 versus 3.8 per 100,000 for TOL. The rates of maternal hysterectomy, hemorrhage, and transfusions did not differ significantly between TOL and ERCD. The rate of uterine rupture for all women with prior cesarean is 3 per 1,000 and the risk was significantly increased with TOL (4.7/1,000 versus 0.3/1,000 ERCD). Six percent of uterine ruptures were associated with perinatal death. No models have been able to accurately predict women who are more likely to deliver by VBAC or to rupture. Women with one prior cesarean delivery and previa had a statistically significant increased risk of adverse events compared with previa patients without a prior cesarean delivery; blood transfusion (15 versus 32.2 percent), hysterectomy (0.7 to 4 percent versus 10 percent), and composite maternal morbidity (15 versus 23-30 percent). Perinatal mortality was significantly increased for TOL at 1.3 per 1,000 versus 0.5 per 1,000 for ERCD. Insufficient data were found on nonmedical factors such as medical liability, economics, hospital staffing, structure and setting, which all appear to be important drivers for VBAC. Each year 1.5 million childbearing women have cesarean deliveries, and this population continues to increase. This report adds stronger evidence that VBAC is a reasonable and safe choice for the majority of women with prior cesarean. Moreover, there is emerging evidence of serious harms relating to multiple cesareans. Relatively unexamined contextual factors such as medical liability, economics, hospital structure, and staffing may need to be addressed to prioritize VBAC services. There is still no evidence to inform patients, clinicians, or policymakers about the outcomes of intended route of delivery because the evidence is based largely on the actual route of delivery. This inception cohort is the equivalent of intention to treat for randomized controlled trials and this gap in information is critical. A list of future research considerations as prioritized by national experts is also highlighted in this report.


Child consent in South African law: implications for researchers, service providers and policy-makers.
Children under 18 are legal minors who, in South African law, are not fully capable of acting independently without assistance from parents/legal guardians. However, in recognition of the evolving capacity of children, there are exceptional circumstances where the law has granted minors the capacity to act independently. We describe legal norms for child consent to health-related interventions in South Africa, and argue that the South African parliament has taken an inconsistent approach to: the capacity of children to consent; the persons able to consent when children do not have capacity; and restrictions on the autonomy of children or their proxies to consent. In addition, the rationale for the differing age limitations, capacity requirements and public policy restrictions has not been specified. These inconsistencies make it difficult for stakeholders interacting with children to ensure that they act lawfully.


Minimally invasive endoscopic resection of intraparenchymal brain tumors.
To report a minimally invasive, nontubular endoscopic technique to resect intraparenchymal brain tumors and assess the feasibility, safety, and surgical resection margins achievable by this novel technique. Over a 21-month period, 48 patients underwent 50 consecutive endoscopic intraparenchymal tumor resections. Data on surgical morbidity and mortality and length of stay were collected prospectively. The percentage of surgical resection and residual tumor volumes were calculated using preoperative and postoperative volume computed tomography or magnetic resonance imaging. All tumors were resected through a 2-cm minicraniotomy using a high-definition rigid endoscope with a 30-degree viewing angle. Bimanual resection was performed using standard microsurgical technique. Mean patient age was 53 years. There were 42 supratentorial (19 frontal, 17 temporal, 3 occipital, 1 parietal, and 2 parafalcine) tumors and 8 infratentorial tumors. Mean tumor volume was 41 cm(3). There were 12 metastases, 24 glioblastomas, 4 World Health Organization grade III gliomas, 5 World Health Organization grade I-II gliomas, 3 meningiomas, and 2 hemangioblastomas. On volumetric analysis, the overall mean percent resection was 96%. In 70% of cases, >95% resection was achieved; total resection was achieved in 48% of cases. At 30 days postoperatively, there was 1 new postoperative neurologic deficit; there were no deaths during this period. Our experience demonstrates that resection of intraparenchymal tumors using a minimally invasive endoscopic technique is technically feasible and safe, achieves good tumor resection margins, and has some potential advantages over a traditional microscopic technique.


Genomic Response to Vitamin D Supplementation in the Setting of a Randomized, Placebo-Controlled Trial.
Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomized trials may afford an opportunity to systematically assess molecular responses. In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), a double-blind, placebo-controlled, dose-finding, randomized clinical trial, 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D3 4000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline, and transcriptome and plasma levels of cytokines (IFN-γ, IL-10, IL-8, IL-6 and TNF-α) at baseline and after 12 months, were measured. The trial had >90% power to detect 1.2-fold changes in gene expression. Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D, 4000 IU regimen), but had no significant effect on whole-blood gene expression (FDR < 5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose, but not in the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose). No significant associations involving vitamin D supplementation response eQTLs were found. We performed a comprehensive functional genomics and molecular analysis of vitamin D supplementation in a randomized, placebo-controlled trial. Although this study was limited to mostly Caucasian individuals aged over 65 years, the results differ from many previous studies and do not support a strong effect of vitamin D on long-term transcriptomic changes in blood or on plasma cytokine levels. The trial demonstrates the feasibility of applying functional genomic and genetic approaches in randomized trials to assess molecular and individual level responses. Supplementation with high-dose vitamin D in older people for 12 months in a randomized, placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of selected cytokines. SRCTN registry (Number 07034656) and the European Clinical Trials Database (EudraCT Number 2011-005763-24).


Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults.
Oxycodone is a strong opioid agonist used to treat severe pain. It is commonly combined with milder analgesics such as paracetamol. This review updates a previous review that concluded, based on limited data, that all doses of oxycodone exceeding 5 mg, with or without paracetamol, provided analgesia in postoperative pain, but with increased incidence of adverse events compared with placebo. Additional new studies provide more reliable estimates of efficacy and harm. To assess efficacy, duration of action, and associated adverse events of single dose oral oxycodone, with or without paracetamol, in acute postoperative pain in adults. Cochrane CENTRAL, MEDLINE, EMBASE and Oxford Pain Relief Database, searched in May 2009. Randomised, double blind, placebo-controlled trials of single dose orally administered oxycodone, with or without paracetamol, in adults with moderate to severe acute postoperative pain. Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants remedicating over specified time periods, and time-to-use of rescue medication, were sought as additional measures of efficacy. Adverse events and withdrawals information was collected. This updated review includes 20 studies, with 2641 participants. For oxycodone 15 mg alone compared with placebo, the NNT for at least 50% pain relief was 4.6 (95% Confidence Interval 2.9 to 11). For oxycodone 10 mg plus paracetamol 650 mg, the NNT was 2.7 (2.4 to 3.1). A dose response was demonstrated for this outcome with combination therapy. Duration of effect was 10 hours with oxycodone 10 mg plus paracetamol 650 mg, and 4 hours with half that dose. Fewer participants needed rescue medication over 6 hours at the higher dose. Adverse events occurred more frequently with combination therapy than placebo, but were generally described as mild to moderate in severity and rarely led to withdrawal. Single dose oxycodone is an effective analgesic in acute postoperative pain at doses over 5 mg; oxycodone is two to three times stronger than codeine. Efficacy increases when combined with paracetamol. Oxycodone 10 mg plus paracetamol 650 mg provides good analgesia to half of those treated, comparable to commonly used non-steroidal anti-inflammatory drugs, with the benefit of longer duration of action.


The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated.
Both the recognition of HIV-infected cells and the immunogenicity of candidate CTL vaccines depend on the presentation of a peptide epitope at the cell surface, which in turn depends on intracellular antigen processing. Differential antigen processing maybe responsible for the differences in both the quality and the quantity of epitopes produced, influencing the immunodominance hierarchy of viral epitopes. Previously, we showed that the magnitude of the HIV-2 gag-specific T-cell response is inversely correlated with plasma viral load, particularly when responses are directed against an epitope, 165 DRFYKSLRA173 , within the highly conserved Major Homology Region of gag-p26. We also showed that the presence of three proline residues, at positions 119, 159 and 178 of gag-p26, was significantly correlated with low viral load. Since this proline motif was also associated with stronger gag-specific CTL responses, we investigated the impact of these prolines on proteasomal processing of the protective 165 DRFYKSLRA173 epitope. Our data demonstrate that the 165 DRFYKSLRA173 epitope is most efficiently processed from precursors that contain two flanking proline residues, found naturally in low viral-load patients. Superior antigen processing and enhanced presentation may account for the link between infection with HIV-2 encoding the "PPP-gag" sequence and both strong gag-specific CTL responses as well as lower viral load.


High levels of genetic recombination among cotransfected plasmid DNAs in poxvirus-infected mammalian cells.
The frequency of recombination between transfected plasmid DNAs was measured by using cultured cells infected with a variety of poxviruses. Plasmid derivatives of pBR322 containing XhoI linker insertion mutations in the tetracycline gene were used to assess recombination frequencies in rabbit cells infected with the leporipoxviruses Shope fibroma virus and myxoma virus and the orthopoxvirus vaccinia virus. Recombination frequencies were calculated by Southern blotting, which detects novel plasmid restriction fragments generated by genetic recombination, and by a plasmid rescue procedure in which the reconstruction of an intact tetracycline gene in the transfected rabbit cell was monitored by transformation back into Escherichia coli. The highest recombination frequencies were measured in cells infected with Shope fibroma virus and myxoma virus, and a minimum recombination frequency of at least one recombination event per 7 kilobases was calculated within 24 h posttransfection under these conditions. The deduced recombination frequency in vaccinia virus-infected cells was at least fivefold lower and was not detectable in mock-infected cells, suggesting that the induced recombination activity detected by these methods was under viral control. The results of kinetic studies, analysis with methylation-sensitive restriction enzymes, and the use of phosphonoacetic acid, a specific inhibitor of poxvirus DNA polymerase, indicated that recombination between transfecting DNAs occurred concomitantly with DNA replication but that the two processes could be partially uncoupled. We conclude that the dramatic expansion of recombination activities in the cytoplasm of poxvirus-infected cells is virus specific and offers a good model system with which to analyze the mechanism of recombination in a eucaryotic environment.


Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A.
The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.


Protocol for prospective collaborative overviews of major randomized trials of blood-pressure-lowering treatments. World Health Organization-International Society of Hypertension Blood Pressure Lowering Treatment Trialists' Collaboration.
To conduct prospectively planned overviews (meta-analyses) of the ongoing randomized trials of blood-pressure-lowering drugs. These overviews should provide reliable data about the effects of newer classes of blood-pressure-lowering drugs (such as angiotensin converting enzyme inhibitors and calcium antagonists) on major causes of cardiovascular mortality and morbidity for a variety of patient groups. A registry of major ongoing or planned randomized trials (with more than 1000 patient-years of follow-up for each randomized group) of blood-pressure-lowering agents has been established. The principal investigators of each of these studies have been invited to collaborate in the project and to provide, upon completion of the study, a limited data set for inclusion in the overview analyses. The principal comparisons will be of newer versus older classes of blood-pressure-lowering drugs in treating patients with hypertension and of newer blood-pressure-lowering treatments versus untreated or less treated control conditions for a variety of other groups of patients with a high risk of cardiovascular events. Separate analyses will be conducted for the main drug classes and for major subgroups of patients defined by characteristics such as age, gender, blood pressure, diabetes, and history of renal disease, coronary heart disease or cerebrovascular disease. The principal study outcomes are stroke, major coronary heart disease events, heart failure, total cardiovascular deaths, total cardiovascular events and total mortality. In total 36 trials of blood-pressure-lowering treatments potentially eligible for inclusion in this project have been identified and agreement to collaborate has been confirmed by the investigators in 30 trials, with collaboration pending for six recently identified studies. The first round of analyses will be conducted in 1999 and will be based on total cardiovascular events observed among a total of about 64,000 patients, involving about 240,000 patient-years of follow-up. The second round of analyses will be conducted in 2003 on data from at least 195,000 patients and 899,000 patient-years of follow-up. By that time it is estimated that a total of about 8000 strokes, 12,000 coronary heart disease events and 23,000 cardiovascular events in total will have occurred. This should provide good statistical power to detect even modest cause-specific differences in the incidence of the main study outcomes. The combination of trial results in prospectively planned, systematic overviews both reduces random errors and avoids biases. As a consequence, this project should provide more reliable information about the effects of newer blood-pressure-lowering drugs than would any one study alone. The use of data from individual patients in these overviews will facilitate investigation of the separate effects of various drug regimens in treating members of major patient subgroups.


Significance of elevated MB isoenzyme with normal creatine kinase in acute myocardial infarction.
The significance of elevated levels of the MB isomer of creatine kinase (CK-MB) when creatine kinase (CK) level is normal was studied in 400 patients with suspected acute myocardial infarction (AMI). In 350 patients both CK and CK-MB were elevated (group 1), in 21 only CK-MB was elevated (group 2), in 24 neither enzyme was elevated (group 3) and in 5 only CK was elevated (group 4). In 57% of patients in group 2 the CK level was doubled, with a characteristic enzyme curve, within the normal range, suggesting that an increase in CK had been missed because arbitrary definitions of "normal" were used. The median CK increase (60 IU/liter) in group 2 was greater than that in group 3 (23 IU/liter) (p less than 0.001). Patients in group 1 with small AMIs had a relative increase in CK similar to that in group 2. However, patients in group 2 had a lower baseline CK level so that peak CK did not become abnormally high despite a 5-fold increase in some patients. In patients in group 1 with small AMIs, CK was elevated in fewer samples than CK-MB. If only 2 samples were obtained in all patients, elevation of CK levels would have been missed in 63 group 1 patients, erroneously increasing the number of patients in group 2 fourfold (to 84 of 400, or 21%, instead of 21 of 400, or only 5%). Conversely, if patients in group 2 with a doubling of CK are excluded, the prevalence of elevated CK-MB with normal CK would be only 9 of 400 (2%).(ABSTRACT TRUNCATED AT 250 WORDS)


In vivo measurement of total knee replacement wear.
Polyethylene wear is one of the most important causes of failure of total knee replacements (TKRs). Currently, wear can only be accurately measured by retrieval studies. There is a need for a method to measure wear accurately in vivo. We have developed a Roentgen stereophotogrammetric analysis (RSA) system that can measure penetration of the metallic femoral component into the polyethylene of the tibia. We have used this system to study six AGC TKRs at 6 years postoperatively and six control AGC TKRs at 2 weeks postoperatively. The mean difference between the RSA measured bearing thickness and the manufacturer's quoted values for the control group was -0.03 mm (S.D. 0.17). The average linear penetration in the study group was 0.8 mm (S.D. 0.46). This was significantly (P<0.0001) different from the control group. The average linear penetration rate was 0.13 mm per year (S.D. 0.08). We would expect the penetration to deepen with time. In young active patients, this could be a cause for concern, particularly with a thin bearing. The current system is accurate enough to measure wear at 5 years post TKR. It has the potential for predicting long-term wear problems with new designs of TKR and new materials within 2 years.


Acupuncture to point Baihui prevents ischemia-induced functional impairment of cortical GABAergic neurons.
Ischemia impairs brain function and networks, in which the vulnerability of GABAergic neurons causes neural excitotoxicity and nerve cell death. Acupuncture presumably improves the outcome of stroke patients; however, cellular mechanisms underlying this improvement remain to be elusive. We have investigated whether electrical stimuli to acupoint Baihui prevent ischemia- induced impairment of cortical GABAergic neurons. After acupuncture to a Baihui-point of mice for a week, we examined the responses of cortical GABAergic neurons to ischemia by whole-cell recording. Compared with the data from a group of ischemia only, the acupuncture prevents the impairments of spike encoding and synaptic transmission at GABAergic neurons from ischemia. This prevention is associated with the resistance of these cells to ischemia-induced changes in spike threshold potentials and refractory periods Therefore, acupuncture to Baihui-point improves ischemic stroke via preventing the impairment of cortical GABAergic neurons.


Automated classification of synaptic vesicles in electron tomograms of C. elegans using machine learning.
Synaptic vesicles (SVs) are a key component of neuronal signaling and fulfil different roles depending on their composition. In electron micrograms of neurites, two types of vesicles can be distinguished by morphological criteria, the classical "clear core" vesicles (CCV) and the typically larger "dense core" vesicles (DCV), with differences in electron density due to their diverse cargos. Compared to CCVs, the precise function of DCVs is less defined. DCVs are known to store neuropeptides, which function as neuronal messengers and modulators [1]. In C. elegans, they play a role in locomotion, dauer formation, egg-laying, and mechano- and chemosensation [2]. Another type of DCVs, also referred to as granulated vesicles, are known to transport Bassoon, Piccolo and further constituents of the presynaptic density in the center of the active zone (AZ), and therefore are important for synaptogenesis [3]. To better understand the role of different types of SVs, we present here a new automated approach to classify vesicles. We combine machine learning with an extension of our previously developed vesicle segmentation workflow, the ImageJ macro 3D ART VeSElecT. With that we reliably distinguish CCVs and DCVs in electron tomograms of C. elegans NMJs using image-based features. Analysis of the underlying ground truth data shows an increased fraction of DCVs as well as a higher mean distance between DCVs and AZs in dauer larvae compared to young adult hermaphrodites. Our machine learning based tools are adaptable and can be applied to study properties of different synaptic vesicle pools in electron tomograms of diverse model organisms.


Tree nut phytochemicals: composition, antioxidant capacity, bioactivity, impact factors. A systematic review of almonds, Brazils, cashews, hazelnuts, macadamias, pecans, pine nuts, pistachios and walnuts.
Tree nuts contain an array of phytochemicals including carotenoids, phenolic acids, phytosterols and polyphenolic compounds such as flavonoids, proanthocyanidins (PAC) and stilbenes, all of which are included in nutrient databases, as well as phytates, sphingolipids, alkylphenols and lignans, which are not. The phytochemical content of tree nuts can vary considerably by nut type, genotype, pre- and post-harvest conditions, as well as storage conditions. Genotype affects phenolic acids, flavonoids, stilbenes and phytosterols, but data are lacking for many other phytochemical classes. During the roasting process, tree nut isoflavones, flavanols and flavonols were found to be more resistant to heat than the anthocyanins, PAC and trans-resveratrol. The choice of solvents used for extracting polyphenols and phytosterols significantly affects their quantification, and studies validating these methods for tree nut phytochemicals are lacking. The phytochemicals found in tree nuts have been associated with antioxidant, anti-inflammatory, anti-proliferative, antiviral, chemopreventive and hypocholesterolaemic actions, all of which are known to affect the initiation and progression of several pathogenic processes. While tree nut phytochemicals are bioaccessible and bioavailable in humans, the number of intervention trials conducted to date is limited. The objectives of the present review are to summarise tree nut: (1) phytochemicals; (2) phytochemical content included in nutrient databases and current publications; (3) phytochemicals affected by pre- and post-harvest conditions and analytical methodology; and (4) bioactivity and health benefits in humans.


Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial.
Metformin reduces cardiovascular risk in patients with type 2 diabetes seemingly independent of lowering blood glucose concentration. We assessed the cardiovascular effects of metformin in individuals without type 2 diabetes. We did a single-centre, double-blind, placebo-controlled trial at the Glasgow Clinical Research Facility (Glasgow, UK). We enrolled patients taking statins who did not have type 2 diabetes but who did have coronary heart disease and large waist circumferences. Participants were randomly assigned (1:1) by computer to either metformin (850 mg twice daily) or matching placebo in block sizes of four. Patients, investigators, trial staff, and statisticians were masked to treatment allocation. The primary endpoint was progression of mean distal carotid intima-media thickness (cIMT) over 18 months in the modified intention-to-treat population. Secondary endpoints were changes in carotid plaque score (in six regions), measures of glycaemia (HbA1c, fasting glucose, and insulin concentrations, and Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]), and concentrations of lipids, high sensitivity C-reactive protein, and tissue plasminogen activator. The trial was registered at ClinicalTrials.gov, number NCT00723307. We screened 356 patients, of whom we enrolled 173 (86 in the metformin group, 87 in the placebo group). Average age was 63 years. At baseline, mean cIMT was 0·717 mm (SD 0·129) and mean carotid plaque score was 2·43 (SD 1·55). cIMT progression did not differ significantly between groups (slope difference 0·007 mm per year, 95% CI -0·006 to 0·020; p=0·29). Change of carotid plaque score did not differ significantly between groups (0·01 per year, 95% CI -0·23 to 0·26; p=0·92). Patients taking metformin had lower HbA1c, insulin, HOMA-IR, and tissue plasminogen activator compared with those taking placebo, but there were no significant differences for total cholesterol, HDL-cholesterol, non-HDL-cholesterol, triglycerides, high sensitivity C-reactive protein, or fasting glucose. 138 adverse events occurred in 64 patients in the metformin group versus 120 in 60 patients in the placebo group. Diarrhoea and nausea or vomiting were more common in the metformin group than in the placebo group (28 vs 5). Metformin had no effect on cIMT and little or no effect on several surrogate markers of cardiovascular disease in non-diabetic patients with high cardiovascular risk, taking statins. Further evidence is needed before metformin can be recommended for cardiovascular benefit in this population. Chief Scientist Office (Scotland).


Neural plasticity in human brain connectivity: the effects of long term deep brain stimulation of the subthalamic nucleus in Parkinson's disease.
Positive clinical outcomes are now well established for deep brain stimulation, but little is known about the effects of long-term deep brain stimulation on brain structural and functional connectivity. Here, we used the rare opportunity to acquire pre- and postoperative diffusion tensor imaging in a patient undergoing deep brain stimulation in bilateral subthalamic nuclei for Parkinson's Disease. This allowed us to analyse the differences in structural connectivity before and after deep brain stimulation. Further, a computational model of spontaneous brain activity was used to estimate the changes in functional connectivity arising from the specific changes in structural connectivity. We found significant localised structural changes as a result of long-term deep brain stimulation. These changes were found in sensory-motor, prefrontal/limbic, and olfactory brain regions which are known to be affected in Parkinson's Disease. The nature of these changes was an increase of nodal efficiency in most areas and a decrease of nodal efficiency in the precentral sensory-motor area. Importantly, the computational model clearly shows the impact of deep brain stimulation-induced structural alterations on functional brain changes, which is to shift the neural dynamics back towards a healthy regime. The results demonstrate that deep brain stimulation in Parkinson's Disease leads to a topological reorganisation towards healthy bifurcation of the functional networks measured in controls, which suggests a potential neural mechanism for the alleviation of symptoms. The findings suggest that long-term deep brain stimulation has not only restorative effects on the structural connectivity, but also affects the functional connectivity at a global level. Overall, our results support causal changes in human neural plasticity after long-term deep brain stimulation and may help to identify the underlying mechanisms of deep brain stimulation.


Refractory epilepsy and deep brain stimulation.
Up to one-third of all patients with epilepsy have epilepsy refractory to medical therapy. Surgical options include temporal lobectomy, focal neocortical resection, stereotactic lesioning and neurostimulation. Neurostimulatory options comprise vagal nerve stimulation, trigeminal nerve stimulation and deep brain stimulation (DBS). DBS enables structures in the brain to be stimulated electrically by an implanted pacemaker after a minimally invasive neurosurgical procedure and has become the therapy of choice for Parkinson's disease refractory to or complicated by drug therapy. Here we review DBS for epilepsy, a powerful emerging treatment in the surgical armamentarium for drug refractory epilepsy, with a focus on extratemporal epilepsy.


Multiple functions of Cerberus cooperate to induce heart downstream of Nodal.
The TGFbeta family member Nodal has been implicated in heart induction through misexpression of a dominant negative version of the type I Nodal receptor (Alk4) and targeted deletion of the co-receptor Cripto in murine ESCs and mouse embryos; however, whether Nodal acts directly or indirectly to induce heart tissue or interacts with other signaling molecules or pathways remained unclear. Here we present Xenopus embryological studies demonstrating an unforeseen role for the DAN family protein Cerberus within presumptive foregut endoderm as essential for differentiation of cardiac mesoderm in response to Nodal. Ectopic activation of Nodal signaling in non-cardiogenic ventroposterior mesendoderm, either by misexpression of the Nodal homologue XNr1 together with Cripto or by a constitutively active Alk4 (caAlk4), induced both cardiac markers and Cerberus. Mosaic lineage tracing studies revealed that Nodal/Cripto and caAlk4 induced cardiac markers cell non-autonomously, thus supporting the idea that Cerberus or another diffusible factor is an essential mediator of Nodal-induced cardiogenesis. Cerberus alone was found sufficient to initiate cardiogenesis at a distance from its site of synthesis. Conversely, morpholino-mediated specific knockdown of Cerberus reduced both endogenous cardiomyogenesis and ectopic heart induction resulting from misactivation of Nodal/Cripto signaling. Since the specific knockdown of Cerberus did not abrogate heart induction by the Wnt antagonist Dkk1, Nodal/Cripto and Wnt antagonists appear to initiate cardiogenesis through distinct pathways. This idea was further supported by the combinatorial effect of morpholino-medicated knockdown of Cerberus and Hex, which is required for Dkk1-induced cardiogenesis, and the differential roles of essential downstream effectors: Nodal pathway activation did not induce the transcriptional repressor Hex while Dkk-1 did not induce Cerberus. These studies demonstrated that cardiogenesis in mesoderm depends on Nodal-mediated induction of Cerberus in underlying endoderm, and that this pathway functions in a pathway parallel to cardiogenesis initiated through the induction of Hex by Wnt antagonists. Both pathways operate in endoderm to initiate cardiogenesis in overlying mesoderm.


Phylogeographic analyses point to long-term survival on the spot in micro-endemic Lycian salamanders.
Lycian salamanders (genus Lyciasalamandra) constitute an exceptional case of micro-endemism of an amphibian species on the Asian Minor mainland. These viviparous salamanders are confined to karstic limestone formations along the southern Anatolian coast and some islands. We here study the genetic differentiation within and among 118 populations of all seven Lyciasalamandra species across the entire genus' distribution. Based on circa 900 base pairs of fragments of the mitochondrial 16SrDNA and ATPase genes, we analysed the spatial haplotype distribution as well as the genetic structure and demographic history of populations. We used 253 geo-referenced populations and CHELSA climate data to infer species distribution models which we projected on climatic conditions of the Last Glacial Maximum (LGM). Within all but one species, distinct phyloclades were identified, which only in parts matched current taxonomy. Most haplotypes (78%) were private to single populations. Sometimes population genetic parameters showed contradicting results, although in several cases they indicated recent population expansion of phyloclades. Climatic suitability of localities currently inhabited by salamanders was significantly lower during the LGM compared to recent climate. All data indicated a strong degree of isolation among Lyciasalamandra populations, even within phyloclades. Given the sometimes high degree of haplotype differentiation between adjacent populations, they must have survived periods of deteriorated climates during the Quaternary on the spot. However, the alternative explanation of male biased dispersal combined with a pronounced female philopatry can only be excluded if independent nuclear data confirm this result.


Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87-1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98-1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87-1·03; p=0·24). In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. UK Research and Innovation (Medical Research Council) and National Institute of Health Research.


The evaluation of a mind/body intervention to reduce psychological distress and perceived stress in college students.
The authors examined the effect of a 6-week mind/body intervention on college students' psychological distress, anxiety, and perception of stress. One hundred twenty-eight students were randomly assigned to an experimental group (n = 63) or a waitlist control group (n = 65). The experimental group received 6 90-minute group-training sessions in the relaxation response and cognitive behavioral skills. The Symptom Checklist-90-Revised, Spielberger State-Trait Anxiety Inventory, and the Perceived Stress Scale were used to assess the students' psychological state before and after the intervention. Ninety students (70% of the initial sample) completed the postassessment measure. Significantly greater reductions in psychological distress, state anxiety, and perceived stress were found in the experimental group. This brief mind/body training may be useful as a preventive intervention for college students, according to the authors, who called for further research to determine whether the observed treatment effect can be sustained over a longer period of time.


GAT: a simulation framework for testing the association of genomic intervals.
A common question in genomic analysis is whether two sets of genomic intervals overlap significantly. This question arises, for example, when interpreting ChIP-Seq or RNA-Seq data in functional terms. Because genome organization is complex, answering this question is non-trivial. We present Genomic Association Test (GAT), a tool for estimating the significance of overlap between multiple sets of genomic intervals. GAT implements a null model that the two sets of intervals are placed independently of one another, but allows each set's density to depend on external variables, for example, isochore structure or chromosome identity. GAT estimates statistical significance based on simulation and controls for multiple tests using the false discovery rate. GAT's source code, documentation and tutorials are available at http://code.google.com/p/genomic-association-tester.


Low-protein diets for hepatic encephalopathy debunked: let them eat steak.
Hepatic encephalopathy (HE) is an incompletely understood phenomenon and serves as a poor prognosis in patients with cirrhosis. Confusion from HE can affect the ability to eat adequately. Despite the prevalence of malnutrition in cirrhotic patients in the 1950s, it was reported that bouts of overt HE were controlled with low protein intake. This largely uncontrolled observation led to restriction of protein intake in cirrhotic patients with or without HE and was an accepted standard of care for many decades to follow. Published in 2004, the pivotal article "Normal Protein Diet for Episodic Hepatic Encephalopathy: Results of a Randomized Study" by Cordoba and colleagues was the first controlled study randomizing cirrhotic patients with HE to receive different amounts of dietary protein. At the completion of the study, the authors concluded that a normal-protein diet was safe and did not exacerbate HE. The Cordoba study suggests that low-protein diets should be abandoned. In light of this evidence, nutrition guidelines have proposed that protein restriction should be avoided in patients with HE as protein requirements are increased in cirrhosis. Despite the advice of experts in the field, it has been shown in recent years that some physicians still believe that protein restriction is needed in patients with HE. This belief has not been substantiated in controlled studies, and societal recommendations have changed. There is no real evidence documenting the advantages of protein restriction in HE. On the contrary, Cordoba and colleagues' article has shown that there are disadvantages to restricting protein in HE.


Tools for Assessing the Protective Efficacy of TB Vaccines in Humans: in vitro Mycobacterial Growth Inhibition Predicts Outcome of in vivo Mycobacterial Infection.
Tuberculosis (TB) remains a leading global cause of morbidity and mortality and an effective new vaccine is urgently needed. A major barrier to the rational development of novel TB vaccines is the lack of a validated immune correlate or biomarker of protection. Mycobacterial Growth Inhibition Assays (MGIAs) provide an unbiased measure of ability to control mycobacterial growth in vitro, and may represent a functional correlate of protection. However, the biological relevance of any potential correlate can only be assessed by determining the association with in vivo protection from either a controlled mycobacterial infection or natural development of TB disease. Our data demonstrate that the direct MGIA using peripheral blood mononuclear cells (PBMC) is measuring a biologically relevant response that correlates with protection from in vivo human BCG infection across two independent cohorts. This is the first report of an MGIA correlating with in vivo protection in the species-of-interest, humans, and furthermore on a per-individual as well as per-group basis. Control of mycobacterial growth in the MGIA is associated with a range of immune parameters measured post-BCG infection in vivo including the IFN-γ ELISpot response, frequency of PPD-specific IFN-γ or TNF-α producing CD4+ T cells and frequency of specific sub-populations of polyfunctional CD4+ T cells. Distinct transcriptomic profiles are associated with good vs. poor mycobacterial control in the MGIA, with good controllers showing enrichment for gene sets associated with antigen processing/presentation and the IL-23 pathway, and poor controllers showing enrichment for hypoxia-related pathways. This study represents an important step toward biologically validating the direct PBMC MGIA for use in TB vaccine development and furthermore demonstrates the utility of this assay in determining relevant immune mechanisms and pathways of protection.


Asymmetrical brain electrical activity discriminates between psychometrically-matched verbal and spatial cognitive tasks.
This study compared the asymmetry of different features of brain electrical activity during the performance of a verbal task (word finding) and a spatial task (dot localization) that had been carefully matched on psychometric properties and accompanying motor activity. Nineteen right-handed subjects were tested. EEG was recorded from F3, F4, C3, C4, P3, and P4, referred to both CZ and computer-derived averaged-ears references, and Fourier transformed. Power in the delta, theta, alpha, and beta bands was computed. There were significant Task X Hemisphere effects in all bands for CZ-referenced data and for the alpha and beta bands for ears-referenced data. The effects were always either greater power suppression in the hemisphere putatively most engaged in task processing or greater power in the opposite hemisphere. Correlations between EEG and task performance indicated that CZ-referenced parietal alpha asymmetry accounted for the most variance in verbal task performance. Power within individual hemispheres or across hemispheres was unrelated to task performance. The findings indicate robust differences in asymmetrical brain physiology that are produced by well-matched verbal and spatial cognitive tasks.


A response to issues raised in a recent paper concerning the Oxford knee score.
In a recently published paper, authors were critical of the Oxford Knee Score (OKS) patient based measure. We discuss a number of the interesting issues that this paper raised and point out some obvious misunderstandings. The OKS, whilst not perfect, has been shown in independent comparative studies to perform more satisfactorily than other measures. It remains one of a small number of measures with satisfactory measurement properties. It would be a great pity if clinicians were deterred from using the OKS on the basis of comments made in the recent publication.


Bacterial porin disrupts mitochondrial membrane potential and sensitizes host cells to apoptosis.
The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (DeltaPsi(m)). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of DeltaPsi(m). The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce DeltaPsi(m) loss and apoptosis, demonstrating that dissipation of DeltaPsi(m) is a requirement for cell death caused by neisserial infection.


Gene expression profiles of human dendritic cells interacting with Aspergillus fumigatus in a bilayer model of the alveolar epithelium/endothelium interface.
The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.


Automatically augmenting lifelog events using pervasively generated content from millions of people.
In sensor research we take advantage of additional contextual sensor information to disambiguate potentially erroneous sensor readings or to make better informed decisions on a single sensor's output. This use of additional information reinforces, validates, semantically enriches, and augments sensed data. Lifelog data is challenging to augment, as it tracks one's life with many images including the places they go, making it non-trivial to find associated sources of information. We investigate realising the goal of pervasive user-generated content based on sensors, by augmenting passive visual lifelogs with "Web 2.0" content collected by millions of other individuals.


A comparison of American and English hospital discharge rates for pediatric bipolar disorder, 2000 to 2010.
Controversy exists over the diagnosis and prevalence of pediatric bipolar disorder (PBD). Although several small surveys suggest that the rate of the PBD diagnosis in clinical settings is higher in the United States than in other countries, no comprehensive cross-national comparisons of clinical practice have been performed. Here, we used longitudinal national datasets from 2000 to 2010 to compare US and English hospital discharge rates for PBD in patients aged 1 to 19 years. We used the English National Health Service (NHS) Hospital Episode Statistics (HES) dataset and the United States National Hospital Discharge Survey (NHDS) to compare US and English discharge rates for PBD (bipolar I disorder [BP-I], bipolar II disorder [BP-II], bipolar disorder not otherwise specified [BP-NOS], and cyclothymia). We also conducted cross-national comparisons for all other psychiatric diagnoses in youth and for adults with bipolar disorder (BD). There was a 72.1-fold difference in discharge rates for PBD in youth between the United States and England (United States, 100.9 per 100,000 population, 95% confidence interval = 98.1-103.8, versus England, 1.4 per 100,000 population, 95% CI = 1.4-1.5). After controlling for cross-national differences in length of stay, discharge rates for PBD remained 12.5 times higher in the United States than in England. For all other child psychiatric diagnoses, the discharge rate was 3.9-fold higher, and for adults with BD 7.2-fold higher, in the United States than in England. The disparity between US and English discharge rates for PBD is markedly greater than the disparity for child psychiatric discharge rates overall and for adult rates of BD. This suggests that the difference in discharge rates for PBD may be due to differing diagnostic practices for PBD in the United States versus in England.


Response of Gait Output and Handgrip Strength to Changes in Body Fat Mass in Pre- and Postmenopausal Women.
Available preliminary data on menopause does not relate changes in body fat mass (BFM) and handgrip strength (HGS) (an indicator of body/muscle strength) to gait parameters. To determine the relationship between BFM, HGS and gait parameters, namely, stride length (SL) (an indicator of walking balance/postural stability), stride frequency (SF), and velocity (V) (gait output), to guide gait training. Ninety consenting (45 postmenopausal and 45 premenopausal) female staff of the University of Nigeria Teaching Hospital, Enugu, were randomly selected and assessed for BFM and HGS with a hydration monitor and dynamometer, respectively, in an observational study. The mean of 2 trials of the number of steps and time taken to cover a 10-m distance at normal speed was used to calculate SF, SL, and V. Data were analyzed using an independent t test and a Pearson correlation coefficient at P < 0.05. Premenopausal (BFM = 42.93% [12.61%], HGS = 27.89 [7.52] kg, stride ratio = 1.43, and velocity = 1.04 [0.01] m/sec) and postmenopausal (BFM = 41.55% [12.71%], HGS = 30.91 [7.07] kg, stride ratio = 1.44, and velocity = 1.06 [0.01] m/sec) women showed no significant differences in gait output/velocity (t = 0.138; P = 0.89; d = 0.029). At postmenopause, BFM was significantly and negatively (r = -0.369; r 2 = 0.1362; P = 0.013) correlated with SL, whereas HGS was positively and significantly (r = 0.323; r 2 = 0.104; P = 0.030) correlated with gait output at premenopause. BFM may adversely influence walking balance at postmenopause, whereas HGS may enhance gait output at premenopause but not postmenopause. Therefore, muscle strengthening alone may not enhance gait output in postmenopausal women without balance training.


Hyperplasia of pulmonary neuroepithelial bodies (NEB) in lungs of prolyl hydroxylase -1(PHD-1) deficient mice.
Pulmonary NEB, widely distributed within the airway mucosa of mammalian lungs, are presumed hypoxia sensitive airway O(2) sensors responding to changes in airway gas concentration. NEB cell hyperplasia has been reported after exposure to chronic hypoxia and in a variety of paediatric and adult lung disorders. Prolyl hydroxylases (PHD 1-3) regulate the stability of hypoxia-inducible factors (HIF's) in an O(2)-dependent manner and function as intrinsic oxygen sensors. To determine a possible role of PHD-1in NEB cells we have quantitated NEB's in lungs of neonatal (P2) and adult (2 months) PHD-1-deficient mice and compared them to wild type (WT) control mice. Lung tissues fixed in formalin and embedded in paraffin were processed for immunoperoxidase method and frozen sections for multilabel immunoflourescence using antibodies for NEB markers synaptophysin, synaptic vesicle protein 2 and the peptide CGRP. The frequency and size of NEB in lungs of PHD-1 deficient neonatal mice (P2) and at 2 months was increased significantly compared to WT controls (p < 0.01). The present data suggests an important role for PHD enzymes in NEB cell biology deserving further studies. Since the PHD-1 deficient mouse appears to be the first animal model showing NEB cell hyperplasia it may be useful for studies of NEB physiology and pathobiology.


Relationships between functional and structural corticospinal tract integrity and walking post stroke.
Studies on upper limb recovery following stroke have highlighted the importance of the structural and functional integrity of the corticospinal tract (CST) in determining clinical outcomes. However, such relationships have not been fully explored for the lower limb. We aimed to test whether variation in walking impairment was associated with variation in the structural or functional integrity of the CST. Transcranial magnetic stimulation was used to stimulate each motor cortex while EMG recordings were taken from the vastus lateralis (VL) bilaterally; these EMG measures were used to calculate both ipsilateral and contralateral recruitment curves for each lower limb. The slope of these recruitment curves was used to examine the strength of functional connectivity from the motor cortex in each hemisphere to the lower limbs in chronic stroke patients and to calculate a ratio between ipsilateral and contralateral outputs referred to as the functional connectivity ratio (FCR). The structural integrity of the CST was assessed using diffusion tensor MRI to measure the asymmetry in fractional anisotropy (FA) of the internal capsule. Lower limb impairment and walking speed were also measured. The FCR for the paretic leg correlated with walking impairment, such that greater relative ipsilateral connectivity was associated with slower walking speeds. Asymmetrical FA values, reflecting reduced structural integrity of the lesioned CST, were associated with greater walking impairment. FCR and FA asymmetry were strongly positively correlated with each other. Patients with relatively greater ipsilateral connectivity between the contralesional motor cortex and the paretic lower limb were more behaviorally impaired and had more structural damage to their ipsilesional hemisphere CST. Measures of structural and functional damage may be useful in the selection of therapeutic strategies, allowing for more tailored and potentially more beneficial treatments.


The Ribosome Cooperates with the Assembly Chaperone pICln to Initiate Formation of snRNPs.
The formation of macromolecular complexes within the crowded environment of cells often requires aid from assembly chaperones. PRMT5 and SMN complexes mediate this task for the assembly of the common core of pre-mRNA processing small nuclear ribonucleoprotein particles (snRNPs). Core formation is initiated by the PRMT5-complex subunit pICln, which pre-arranges the core proteins into spatial positions occupied in the assembled snRNP. The SMN complex then accepts these pICln-bound proteins and unites them with small nuclear RNA (snRNA). Here, we have analyzed how newly synthesized snRNP proteins are channeled into the assembly pathway to evade mis-assembly. We show that they initially remain bound to the ribosome near the polypeptide exit tunnel and dissociate upon association with pICln. Coincident with its release activity, pICln ensures the formation of cognate heterooligomers and their chaperoned guidance into the assembly pathway. Our study identifies the ribosomal quality control hub as a site where chaperone-mediated assembly of macromolecular complexes can be initiated.


Use of modified ciclosporin in the management of feline pemphigus foliaceus: a retrospective analysis.
Glucocorticoids as sole therapy for pemphigus foliaceus (PF) in cats are not always successful, and it is common to need additional immunomodulating agents to manage the disease. This retrospective study evaluated the use of modified ciclosporin as an adjuvant or sole immunomodulating drug in cats with PF and compared their response to PF cats managed with chlorambucil. Fifteen client-owned cats diagnosed with PF that received ciclosporin and/or chlorambucil as part of their treatment and had adequate follow-up to assess treatment response were evaluated. Records were reviewed from feline PF patients presented between the years of 1999 and 2009. Cats were divided into two treatment groups: those treated with ciclosporin and those treated with chlorambucil. Most cats in both groups also received concurrent systemic glucocorticoids. Each group contained six patients. Three cats were treated with both medications and are discussed separately. Time to disease remission, remission-inducing glucocorticoid dose, maintenance or final glucocorticoid dose, disease response and adverse effects were assessed. There was no significant difference in remission times or disease response between groups. All six patients maintained with ciclosporin for PF management were weaned off systemic glucocorticoids, while glucocorticoid therapy was stopped in only one of the six cats receiving chlorambucil. Modified ciclosporin is effective in the management of feline pemphigus foliaceus and is glucocorticoid sparing.


Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling.
We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Na(v)1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject.


Directing spatial attention in mental representations: Interactions between attentional orienting and working-memory load.
Orienting spatial attention to locations in the extrapersonal world has been intensively investigated during the past decades. Recently, it was demonstrated that it is also possible to shift attention to locations within mental representations held in working memory. This is an important issue, since the allocation of our attention is not only guided by external stimuli, but also by their internal representations and the expectations we build upon them. The present experiment used behavioural measures and event-related functional magnetic resonance imaging to investigate whether spatial orienting to mental representations can modulate the search and retrieval of information from working memory, and to identify the neural systems involved, respectively. Participants viewed an array of coloured crosses. Seconds after its disappearance, they were cued to locations in the array with valid or neutral cues. Subsequently, they decided whether a probe stimulus was presented in the array. The behavioural results indicated that orienting of spatial attention within working memory attenuates the well-known effect of decreasing performance when memory load is increased. So "internal" spatial orienting seems to highlight information or facilitate search within working memory, which leads to advantages in retrieval. Imaging enabled the separation of brain areas supporting spatial orienting functions from those sensitive to working-memory load. Orienting of spatial attention to the contents of working memory activated posterior parietal cortex bilaterally, the insula, and lateral and medial frontal cortices.


Feasibility of Obtaining Measures of Lifestyle From a Smartphone App: The MyHeart Counts Cardiovascular Health Study.
Studies have established the importance of physical activity and fitness, yet limited data exist on the associations between objective, real-world physical activity patterns, fitness, sleep, and cardiovascular health. To assess the feasibility of obtaining measures of physical activity, fitness, and sleep from smartphones and to gain insights into activity patterns associated with life satisfaction and self-reported disease. The MyHeart Counts smartphone app was made available in March 2015, and prospective participants downloaded the free app between March and October 2015. In this smartphone-based study of cardiovascular health, participants recorded physical activity, filled out health questionnaires, and completed a 6-minute walk test. The app was available to download within the United States. The feasibility of consent and data collection entirely on a smartphone, the use of machine learning to cluster participants, and the associations between activity patterns, life satisfaction, and self-reported disease. From the launch to the time of the data freeze for this study (March to October 2015), the number of individuals (self-selected) who consented to participate was 48 968, representing all 50 states and the District of Columbia. Their median age was 36 years (interquartile range, 27-50 years), and 82.2% (30 338 male, 6556 female, 10 other, and 3115 unknown) were male. In total, 40 017 (81.7% of those who consented) uploaded data. Among those who consented, 20 345 individuals (41.5%) completed 4 of the 7 days of motion data collection, and 4552 individuals (9.3%) completed all 7 days. Among those who consented, 40 017 (81.7%) filled out some portion of the questionnaires, and 4990 (10.2%) completed the 6-minute walk test, made available only at the end of 7 days. The Heart Age Questionnaire, also available after 7 days, required entering lipid values and age 40 to 79 years (among 17 245 individuals, 43.1% of participants). Consequently, 1334 (2.7%) of those who consented completed all fields needed to compute heart age and a 10-year risk score. Physical activity was detected for a mean (SD) of 14.5% (8.0%) of individuals' total recorded time. Physical activity patterns were identified by cluster analysis. A pattern of lower overall activity but more frequent transitions between active and inactive states was associated with equivalent self-reported cardiovascular disease as a pattern of higher overall activity with fewer transitions. Individuals' perception of their activity and risk bore little relation to sensor-estimated activity or calculated cardiovascular risk. A smartphone-based study of cardiovascular health is feasible, and improvements in participant diversity and engagement will maximize yield from consented participants. Large-scale, real-world assessment of physical activity, fitness, and sleep using mobile devices may be a useful addition to future population health studies.