Some solutions to the multivariate Behrens-Fisher problem for dissimilarity-based analyses

The essence of the generalised multivariate Behrens–Fisher problem (BFP) is how to test the null hypothesis of equality of mean vectors for two or more populations when their dispersion matrices differ. Solutions to the BFP usually assume variables are multivariate normal and do not handle high‐dimensional data. In ecology, species' count data are often high‐dimensional, non‐normal and heterogeneous. Also, interest lies in analysing compositional dissimilarities among whole communities in non‐Euclidean (semi‐metric or non‐metric) multivariate space. Hence, dissimilarity‐based tests by permutation (e.g., PERMANOVA, ANOSIM) are used to detect differences among groups of multivariate samples. Such tests are not robust, however, to heterogeneity of dispersions in the space of the chosen dissimilarity measure, most conspicuously for unbalanced designs. Here, we propose a modification to the PERMANOVA test statistic, coupled with either permutation or bootstrap resampling methods, as a solution to the BFP for dissimilarity‐based tests. Empirical simulations demonstrate that the type I error remains close to nominal significance levels under classical scenarios known to cause problems for the un‐modified test. Furthermore, the permutation approach is found to be more powerful than the (more conservative) bootstrap for detecting changes in community structure for real ecological datasets. The utility of the approach is shown through analysis of 809 species of benthic soft‐sediment invertebrates from 101 sites in five areas spanning 1960 km along the Norwegian continental shelf, based on the Jaccard dissimilarity measure

Cost of care for cancer patients in England: evidence from population-based patient-level data

background: Health systems are facing the challenge of providing care to an increasing population of patients with cancer. However, evidence on costs is limited due to the lack of large longitudinal databases. methods: We matched cost of care data to population-based, patient-level data on cancer patients in England. We conducted a retrospective cohort study including all patients age 18 and over with a diagnosis of colorectal (275 985 patients), breast (359 771), prostate (286 426) and lung cancer (283 940) in England between 2001 and 2010. Incidence costs, prevalence costs, and phase of care costs were estimated separately for patients age 18–64 and greater than or equal to65. Costs of care were compared by patients staging, before and after diagnosis, and with a comparison population without cancer. results: Incidence costs in the first year of diagnosis are noticeably higher in patients age 18–64 than age greater than or equal to65 across all examined cancers. A lower stage diagnosis is associated with larger cost savings for colorectal and breast cancer in both age groups. The additional costs of care because of the main four cancers amounts to £1.5 billion in 2010, namely 3.0% of the total cost of hospital care. conclusions: Population-based, patient-level data can be used to provide new evidence on the cost of cancer in England. Early diagnosis and cancer prevention have scope for achieving large cost savings for the health system

Using ultra-low frequency waves and their characteristics to diagnose key physics of substorm onset

Substorm onset is marked in the ionosphere by the sudden brightening of an existing auroral arc or the creation of a new auroral arc. Also present is the formation of auroral beads, proposed to play a key role in the detonation of the substorm, as well as the development of the large-scale substorm current wedge (SCW ), invoked to carry the current diversion. Both these phenomena, auroral beads and the SCW, have been intimately related to ultra-low frequency (ULF) waves of specific frequencies as observed by ground-based magnetometers. We present a case study of the absolute and relative timing of Pi1 and Pi2 ULF wave bands with regard to a small substorm expansion phase onset. We find that there is both a location and frequency dependence for the onset of ULF waves. A clear epicentre is observed in specific wave frequencies concurrent with the brightening of the substorm onset arc and the presence of “auroral beads”. At higher and lower wave frequencies, different epicentre patterns are revealed, which we conclude demonstrate different characteristics of the onset process; at higher frequencies, this epicentre may demonstrate phase mixing, and at intermediate and lower frequencies these epicentres are characteristic of auroral beads and cold plasma approximation of the “Tamao travel time” from near-earth neutral line reconnection and formation of the SCW

Phytoplankton dynamics in relation to seasonal variability and upwelling and relaxation patterns at the mouth of Ria de Aveiro (West Iberian Margin) over a four-year period

From June 2004 to December 2007, samples were weekly collected at a fixed station located at the mouth of Ria de Aveiro (West Iberian Margin). We examined the seasonal and inter-annual fluctuations in composition and community structure of the phytoplankton in relation to the main environmental drivers and assessed the influence of the oceano-graphic regime, namely changes in frequency and intensity of upwelling events, over the dynamics of the phytoplankton assemblage. The samples were consistently handled and a final subset of 136 OTUs (taxa with relative abundance > 0.01%) was subsequently submitted to various multivariate analyses. The phytoplankton assemblage showed significant changes at all temporal scales but with an overriding importance of seasonality over longer-(inter-annual) or shorter-term fluctuations (upwelling-related). Sea-surface temperature, salinity and maximum upwelling index were retrieved as the main driver of seasonal change. Seasonal signal was most evident in the fluctuations of chlorophyll a concentration and in the high turnover from the winter to spring phytoplankton assemblage. The seasonal cycle of production and succession was disturbed by upwelling events known to disrupt thermal stratification and induce changes in the phytoplankton assemblage. Our results indicate that both the frequency and intensity of physical forcing were important drivers of such variability, but the outcome in terms of species composition was highly dependent on the available local pool of species and the timing of those events in relation to the seasonal cycle. We conclude that duration, frequency and intensity of upwelling events, which vary seasonally and inter-annually, are paramount for maintaining long-term phytoplankton diversity likely by allowing unstable coexistence and incorporating species turnover at different scales. Our results contribute to the understanding of the complex mechanisms of coastal phytoplankton dynamics in relation to changing physical forcing which is fundamental to improve predictability of future prospects under climate change.Portuguese Foundation for Science and Technology (FCT, Portugal) [SFRH/BPD/ 94562/2013]; FEDER funds; national funds; CESAM [UID/AMB/50017]; FCT/MEC through national funds; FEDERinfo:eu-repo/semantics/publishedVersio

Testing the cognitive-behavioural maintenance models across DSM-5 bulimic-type eating disorder diagnostic groups: A multi-centre study

The original cognitive-behavioural (CB) model of bulimia nervosa, which provided the basis for the widely used CB therapy, proposed that specific dysfunctional cognitions and behaviours maintain the disorder. However, amongst treatment completers, only 40–50 % have a full and lasting response. The enhanced CB model (CB-E), upon which the enhanced version of the CB treatment was based, extended the original approach by including four additional maintenance factors. This study evaluated and compared both CB models in a large clinical treatment seeking sample (N = 679), applying both DSM-IV and DSM-5 criteria for bulimic-type eating disorders. Application of the DSM-5 criteria reduced the number of cases of DSM-IV bulimic-type eating disorders not otherwise specified to 29.6 %. Structural equation modelling analysis indicated that (a) although both models provided a good fit to the data, the CB-E model accounted for a greater proportion of variance in eating-disordered behaviours than the original one, (b) interpersonal problems, clinical perfectionism and low self-esteem were indirectly associated with dietary restraint through over-evaluation of shape and weight, (c) interpersonal problems and mood intolerance were directly linked to binge eating, whereas restraint only indirectly affected binge eating through mood intolerance, suggesting that factors other than restraint may play a more critical role in the maintenance of binge eating. In terms of strength of the associations, differences across DSM-5 bulimic-type eating disorder diagnostic groups were not observed. The results are discussed with reference to theory and research, including neurobiological findings and recent hypotheses

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.

Risk assessment and decision making about in-labour transfer from rural maternity care: a social judgment and signal detection analysis

Background: The importance of respecting women's wishes to give birth close to their local community is supported by policy in many developed countries. However, persistent concerns about the quality and safety of maternity care in rural communities have been expressed. Safe childbirth in rural communities depends on good risk assessment and decision making as to whether and when the transfer of a woman in labour to an obstetric led unit is required. This is a difficult decision. Wide variation in transfer rates between rural maternity units have been reported suggesting different decision making criteria may be involved; furthermore, rural midwives and family doctors report feeling isolated in making these decisions and that staff in urban centres do not understand the difficulties they face. In order to develop more evidence based decision making strategies greater understanding of the way in which maternity care providers currently make decisions is required. This study aimed to examine how midwives working in urban and rural settings and obstetricians make intrapartum transfer decisions, and describe sources of variation in decision making. Methods: The study was conducted in three stages. 1. 20 midwives and four obstetricians described factors influencing transfer decisions. 2. Vignettes depicting an intrapartum scenario were developed based on stage one data. 3. Vignettes were presented to 122 midwives and 12 obstetricians who were asked to assess the level of risk in each case and decide whether to transfer or not. Social judgment analysis was used to identify the factors and factor weights used in assessment. Signal detection analysis was used to identify participants' ability to distinguish high and low risk cases and personal decision thresholds. Results: When reviewing the same case information in vignettes midwives in different settings and obstetricians made very similar risk assessments. Despite this, a wide range of transfer decisions were still made, suggesting that the main source of variation in decision making and transfer rates is not in the assessment but the personal decision thresholds of clinicians. Conclusions: Currently health care practice focuses on supporting or improving decision making through skills training and clinical guidelines. However, these methods alone are unlikely to be effective in improving consistency of decision making

Antibacterial activity of some selected medicinal plants of Pakistan

<p>Abstract</p> <p>Background</p> <p>Screening of the ethnobotenical plants is a pre-requisite to evaluate their therapeutic potential and it can lead to the isolation of new bioactive compounds.</p> <p>Methods</p> <p>The crude extracts and fractions of six medicinal important plants (<it>Arisaema flavum</it>, <it>Debregeasia salicifolia</it>, <it>Carissa opaca</it>, <it>Pistacia integerrima</it>, <it>Aesculus indica</it>, and <it>Toona ciliata</it>) were tested against three Gram positive and two Gram negative ATCC bacterial species using the agar well diffusion method.</p> <p>Results</p> <p>The crude extract of <it>P. integerrima </it>and <it>A. indica </it>were active against all tested bacterial strains (12-23 mm zone of inhibition). Other four plant's crude extracts (<it>Arisaema flavum</it>, <it>Debregeasia salicifolia</it>, <it>Carissa opaca</it>, and <it>Toona ciliata</it>) were active against different bacterial strains. The crude extracts showed varying level of bactericidal activity. The aqueous fractions of <it>A. indica </it>and <it>P. integerrima </it>crude extract showed maximum activity (19.66 and 16 mm, respectively) against <it>B. subtilis</it>, while the chloroform fractions of <it>T. ciliata </it>and <it>D. salicifolia </it>presented good antibacterial activities (13-17 mm zone of inhibition) against all the bacterial cultures tested.</p> <p>Conclusion</p> <p>The methanol fraction of <it>Pistacia integerrima</it>, chloroform fractions of <it>Debregeasia salicifolia </it>&<it>Toona ciliata </it>and aqueous fraction of <it>Aesculus indica </it>are suitable candidates for the development of novel antibacterial compounds.</p

Nanoscale structure of amyloid-β plaques in Alzheimer’s disease

Abstract Soluble amyloid-β (Aβ) is considered to be a critical component in the pathogenesis of Alzheimer’s disease (AD). Evidence suggests that these non-fibrillar Aβ assemblies are implicated in synaptic dysfunction, neurodegeneration and cell death. However, characterization of these species comes mainly from studies in cellular or animal models, and there is little data in intact human samples due to the lack of adequate optical microscopic resolution to study these small structures. Here, to achieve super-resolution in all three dimensions, we applied Array Tomography (AT) and Stimulated Emission Depletion microscopy (STED), to characterize in postmortem human brain tissue non-fibrillar Aβ structures in amyloid plaques of cases with autosomal dominant and sporadic AD. Ultrathin sections scanned with super-resolution STED microscopy allowed the detection of small Aβ structures of the order of 100 nm. We reconstructed a whole human amyloid plaque and established that plaques are formed by a dense core of higher order Aβ species (~0.022 µm3) and a peripheral halo of smaller Aβ structures (~0.003 µm3). This work highlights the potential of AT-STED for human neuropathological studies