The treatment of achalasia patients with esophageal varices: an international study

Background: Treatment options for achalasia include endoscopic and surgical techniques that carry the risk of esophageal bleeding and perforation. The rare coexistence of esophageal varices has only been anecdotally described and treatment is presumed to carry additional risk. Methods: Experience from physicians/surgeons treating this rare combination of disorders was sought through the International Manometry Working Group. Results: Fourteen patients with achalasia and varices from seven international centers were collected (mean age 61 9 years). Five patients were treated with botulinum toxin injections (BTI), four had dilation, three received peroral endoscopic myotomy (POEM), one had POEM then dilation, and one patient underwent BTI followed by Heller’s myotomy. Variceal eradication preceded achalasia treatment in three patients. All patients experienced a significant symptomatic improvement (median Eckardt score 7 vs 1; p < 0.0001) at 6 months follow-up, with treatment outcomes resembling those of 20 non- cirrhotic achalasia patients who underwent similar therapy. No patients had recorded complications of bleeding or perforation. Conclusion: This study shows an excellent short-term symptomatic response in patients with esophageal achalasia and varices and demonstrates that the therapeutic outcomes and complications, other than transient encephalopathy in both patients who had a portosystemic shunt, did not differ to disease-matched patients without varices

James Hutton’s geological tours of Scotland : romanticism, literary strategies, and the scientific quest

This article explores a somewhat neglected part of the story of the emergence of geology as a science and discourse in the late eighteenth century – James Hutton’s posthumously published accounts of the geological tours of Scotland that he undertook in the years 1785 to 1788 in search of empirical evidence in support of his theory of the Earth and that he intended to include in the projected third volume of his Theory of the Earth of 1795. The article brings some of the assumptions and techniques of literary criticism to bear on Hutton’s scientific travel writing in order to open up new connections between geology, Romantic aesthetics and eighteenth-century travel writing about Scotland. Close analysis of Hutton’s accounts of his field trips to Glen Tilt, Galloway and Arran, supplemented by later accounts of the discoveries at Jedburgh and Siccar Point, reveals the interplay between desire, travel and the scientific quest and foregrounds the textual strategies that Hutton uses to persuade his readers that they share in the experience of geological discovery and interpretation as ‘virtual witnesses’. As well as allowing us to revisit the interrelation between scientific theory and discovery, this article concludes that Hutton was a much better writer than he has been given credit for and suggests that if these geological tours had been published in 1795 they would have made it impossible for critics to dismiss him as an armchair geologist

Dopamine Augmented Rehabilitation in Stroke (DARS): a multicentre double-blind, randomised controlled trial of co-careldopa compared with placebo, in addition to routine NHS occupational and physical therapy, delivered early after stroke on functional recovery

BACKGROUND: Dopamine is a key modulator of striatal function and learning, and may improve motor recovery after stroke. Seven small trials of dopamine agonists after stroke have provided equivocal evidence of the clinical effectiveness of dopamine agonists in improving motor recovery. DESIGN: Dopamine Augmented Rehabilitation in Stroke was a multicentre, randomised, double-blind, placebo-controlled trial with stroke patients randomised to receive 6 weeks of co-careldopa (Sinemet®, Merck Sharp & Dohme Ltd) or placebo in combination with occupational and physical rehabilitation. METHODS: The primary outcome measure was the proportion of patients walking independently at 8 weeks [Rivermead Mobility Index (RMI) score of ≥ 7 points and ‘yes’ to item 7 on the RMI]. Secondary outcome measures assessed physical functioning, pain, cognition, mood, fatigue and carer burden at 8 weeks, 6 months and 12 months. RESULTS: Between May 2011 and March 2014, 593 patients (mean age 68.5 years) and 165 carers (mean age 59.7 years) were recruited from stroke rehabilitation units; 308 patients were randomised to co-careldopa and 285 to placebo at a median of 15 days following stroke onset. The study drug was to be taken 45–60 minutes before therapy, which included motor activities (mean 23.2 and 24.8 sessions in the co-careldopa and placebo groups, respectively). The mean number of investigational medicinal product doses taken was 20.6 in the co-careldopa group and 22.4 in the placebo group. Ability to walk independently was not improved at 8 weeks [40.6% (co-careldopa) vs. 44.6% (placebo); odds ratio 0.78, 95% confidence interval (CI) 0.53 to 1.15], 6 months [51.6% (co-careldopa) vs. 53.3% (placebo)] or 12 months [51.6% (co-careldopa) vs. 56.8% (placebo)]. There were no significant differences for Barthel Index, Nottingham Extended Activities of Daily Living, ABILHAND Manual Ability Measure or Modified Rankin Scale, pain or fatigue at any time point. Montreal Cognitive Assessment scores did not significantly differ; the majority of participants had cognitive impairment at baseline, which improved during 12 months’ follow-up. No difference was observed in General Health Questionnaire 12-item version scores between groups at 8 weeks and 12 months but, at 6 months, those in the co-careldopa group reported significantly better general health [mean difference (MD) –1.33, 95% CI –2.57 to –0.10]. Mortality at 12 months was not significantly different. Carers in the placebo group reported significantly greater burden at 6 months (MD 5.05, 95% CI 0.10 to 10.01) and 12 months (MD 7.52, 95% CI 1.87 to 13.18). CONCLUSION: Co-careldopa in addition to routine NHS occupational and physical therapy is not clinically effective or cost-effective in improving walking, physical functioning, mood or cognition following stroke. We recommend further research to develop imaging and clinical markers that would allow identification of promising drug therapies that would enhance motor therapy in improving walking ability and arm function. Further research is needed to compare strategies of giving drug therapy intermittently immediately prior to therapy sessions or as continuous background daily administration. LIMITATIONS: In total, 10.3% of patients were lost to follow-up at 8 weeks and < 10% of patients met the strict per-protocol definition. Despite this, the findings are robust and generalisable to patients with limited mobility in the first few weeks after stroke. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99643613. FUNDING: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership

Recombination dynamics of a human Y-chromosomal palindrome:rapid GC-biased gene conversion, multi-kilobase conversion tracts, and rare inversions

The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten paralogous sequence variants (PSVs) within the arms of P6 in 378 Y chromosomes whose evolutionary relationships within the SNP-defined Y phylogeny are known. This allowed the identification of 146 historical gene conversion events involving individual PSVs, occurring at a rate of 2.9-8.4×10(-4) events per generation. A consideration of the nature of nucleotide change and the ancestral state of each PSV showed that the conversion process was significantly biased towards the fixation of G or C nucleotides (GC-biased), and also towards the ancestral state. Determination of haplotypes by long-PCR allowed likely co-conversion of PSVs to be identified, and suggested that conversion tract lengths are large, with a mean of 2068 bp, and a maximum in excess of 9 kb. Despite the frequent formation of recombination intermediates implied by the rapid observed gene conversion activity, resolution via crossover is rare: only three inversions within P6 were detected in the sample. An analysis of chimpanzee and gorilla P6 orthologs showed that the ancestral state bias has existed in all three species, and comparison of human and chimpanzee sequences with the gorilla outgroup confirmed that GC bias of the conversion process has apparently been active in both the human and chimpanzee lineages

By hook or by crook? Morphometry, competition and cooperation in rodent sperm

Background Sperm design varies enormously across species and sperm competition is thought to be a major factor influencing this variation. However, the functional significance of many sperm traits is still poorly understood. The sperm of most murid rodents are characterised by an apical hook of the sperm head that varies markedly in extent across species. In the European woodmouse Apodemus sylvaticus (Muridae), the highly reflected apical hook of sperm is used to form sperm groups, or “trains,” which exhibited increased swimming velocity and thrusting force compared to individual sperm. Methodology/Principal Findings Here we use a comparative study of murine rodent sperm and demonstrate that the apical hook and sperm cooperation are likely to be general adaptations to sperm competition in rodents. We found that species with relatively larger testes, and therefore more intense sperm competition, have a longer, more reflected apical sperm hook. In addition, we show that sperm groups also occur in rodents other than the European woodmouse. Conclusions Our results suggest that in rodents sperm cooperation is more widespread than assumed so far and highlight the importance of diploid versus haploid selection in the evolution of sperm design and function

Measurement of the decay of laser-driven linear plasma wakefields.

We present measurements of the temporal decay rate of one-dimensional (1D), linear Langmuir waves excited by an ultrashort laser pulse. Langmuir waves with relative amplitudes of approximately 6% were driven by 1.7J, 50fs laser pulses in hydrogen and deuterium plasmas of density n_{e0}=8.4×10^{17}cm^{-3}. The wakefield lifetimes were measured to be τ_{wf}^{H_{2}}=(9±2) ps and τ_{wf}^{D_{2}}=(16±8) ps, respectively, for hydrogen and deuterium. The experimental results were found to be in good agreement with 2D particle-in-cell simulations. In addition to being of fundamental interest, these results are particularly relevant to the development of laser wakefield accelerators and wakefield acceleration schemes using multiple pulses, such as multipulse laser wakefield accelerators

Past Achievements and Future Challenges in 3D Photonic Metamaterials

Photonic metamaterials are man-made structures composed of tailored micro- or nanostructured metallo-dielectric sub-wavelength building blocks that are densely packed into an effective material. This deceptively simple, yet powerful, truly revolutionary concept allows for achieving novel, unusual, and sometimes even unheard-of optical properties, such as magnetism at optical frequencies, negative refractive indices, large positive refractive indices, zero reflection via impedance matching, perfect absorption, giant circular dichroism, or enhanced nonlinear optical properties. Possible applications of metamaterials comprise ultrahigh-resolution imaging systems, compact polarization optics, and cloaking devices. This review describes the experimental progress recently made fabricating three-dimensional metamaterial structures and discusses some remaining future challenges

Dementia Care Mapping™ to reduce agitation in care home residents with dementia: the EPIC cluster RCT

Background The quality of care for people with dementia in care homes is of concern. Interventions that can improve care outcomes are required. Objective To investigate the clinical effectiveness and cost-effectiveness of Dementia Care Mapping™ (DCM) for reducing agitation and improving care outcomes for people living with dementia in care homes, versus usual care. Design A pragmatic, cluster randomised controlled trial with an open-cohort design, follow-up at 6 and 16 months, integrated cost-effectiveness analysis and process evaluation. Clusters were not blinded to allocation. The primary end point was completed by staff proxy and independent assessors. Setting Stratified randomisation of 50 care homes to the intervention and control groups on a 3 : 2 ratio by type, size, staff exposure to dementia training and recruiting hub. Participants Fifty care homes were randomised (intervention, n = 31; control, n = 19), with 726 residents recruited at baseline and a further 261 recruited after 16 months. Care homes were eligible if they recruited a minimum of 10 residents, were not subject to improvement notices, had not used DCM in the previous 18 months and were not participating in conflicting research. Residents were eligible if they lived there permanently, had a formal diagnosis of dementia or a score of 4+ on the Functional Assessment Staging Test of Alzheimer’s Disease, were proficient in English and were not terminally ill or permanently cared for in bed. All homes were audited on the delivery of dementia and person-centred care awareness training. Those not reaching a minimum standard were provided training ahead of randomisation. Eighteen homes took part in the process evaluation. Intervention Two staff members from each intervention home were trained to use DCM and were asked to carry out three DCM cycles; the first was supported by an external expert. Main outcome measures The primary outcome was agitation (Cohen-Mansfield Agitation Inventory), measured at 16 months. Secondary outcomes included resident behaviours and quality of life. Results There were 675 residents in the final analysis (intervention, n = 388; control, n = 287). There was no evidence of a difference in agitation levels between the treatment arms. The adjusted mean difference in Cohen-Mansfield Agitation Inventory score was –2.11 points, being lower in the intervention group than in the control (95% confidence interval –4.66 to 0.44; p = 0.104; adjusted intracluster correlation coefficient: control = 0, intervention = 0.001). The sensitivity analyses results supported the primary analysis. No differences were detected in any of the secondary outcomes. The health economic analyses indicated that DCM was not cost-effective. Intervention adherence was problematic; only 26% of homes completed more than their first DCM cycle. Impacts, barriers to and facilitators of DCM implementation were identified. Limitations The primary completion of resident outcomes was by staff proxy, owing to self-report difficulties for residents with advanced dementia. Clusters were not blinded to allocation, although supportive analyses suggested that any reporting bias was not clinically important. Conclusions There was no benefit of DCM over control for any outcomes. The implementation of DCM by care home staff was suboptimal compared with the protocol in the majority of homes. Future work Alternative models of DCM implementation should be considered that do not rely solely on leadership by care home staff. Trial registration Current Controlled Trials ISRCTN82288852. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 16. See the NIHR Journals Library website for further project information

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

On the Chemical Origin of the Gap Bowing in (GaAs)1−xGe2x Alloys: A Combined DFT–QSGW Study

Motivated by the research and analysis of new materials for photovoltaics and by the possibility of tailoring their optical properties for improved solar energy conversion, we have focused our attention on the (GaAs)1−xGe2x series of alloys. We have investigated the structural properties of some (GaAs)1−xGe2x compounds within the local-density approximation to density-functional theory, and their optical properties within the Quasiparticle Self-consistent GW approximation. The QSGW results confirm the experimental evidence of asymmetric bandgap bowing. It is explained in terms of violations of the octet rule, as well as in terms of the order–disorder phase transition