DSM-IV-TR suggests that clinicians should assess clinically relevant personality traits that do not necessarily constitute a formal personality disorder (PD), and should note these traits on Axis II, ...but DSM-IV-TR does not provide a trait model to guide the clinician. Our goal was to provide a provisional trait model and a preliminary corresponding assessment instrument, in our roles as members of the DSM-5 Personality and Personality Disorders Workgroup and workgroup advisors.
An initial list of specific traits and domains (broader groups of traits) was derived from DSM-5 literature reviews and workgroup deliberations, with a focus on capturing maladaptive personality characteristics deemed clinically salient, including those related to the criteria for DSM-IV-TR PDs. The model and instrument were then developed iteratively using data from community samples of treatment-seeking participants. The analytic approach relied on tools of modern psychometrics (e.g. item response theory models).
A total of 25 reliably measured core elements of personality description emerged that, together, delineate five broad domains of maladaptive personality variation: negative affect, detachment, antagonism, disinhibition, and psychoticism.
We developed a maladaptive personality trait model and corresponding instrument as a step on the path toward helping users of DSM-5 assess traits that may or may not constitute a formal PD. The inventory we developed is reprinted in its entirety in the Supplementary online material, with the goal of encouraging additional refinement and development by other investigators prior to the finalization of DSM-5. Continuing discussion should focus on various options for integrating personality traits into DSM-5.
Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical ...opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Riggs ER, Church DM, Hanson K, Horner VL, Kaminsky EB, Kuhn RM, Wain KE, Williams ES, Aradhya S, Kearney HM, Ledbetter DH, South ST, Thorland EC, Martin CL. Towards an evidence‐based process for the ...clinical interpretation of copy number variation.
The evidence‐based review (EBR) process has been widely used to develop standards for medical decision‐making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large‐scale case‐control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Water oxidation is the key kinetic bottleneck of photoelectrochemical devices for fuel synthesis. Despite advances in the identification of intermediates, elucidating the catalytic mechanism of this ...multi-redox reaction on metal-oxide photoanodes remains a significant experimental and theoretical challenge. Here, we report an experimental analysis of water oxidation kinetics on four widely studied metal oxides, focusing particularly on haematite. We observe that haematite is able to access a reaction mechanism that is third order in surface-hole density, which is assigned to equilibration between three surface holes and M(OH)-O-M(OH) sites. This reaction exhibits low activation energy (E
≈ 60 meV). Density functional theory is used to determine the energetics of charge accumulation and O-O bond formation on a model haematite (110) surface. The proposed mechanism shows parallels with the function of the oxygen evolving complex of photosystem II, and provides new insights into the mechanism of heterogeneous water oxidation on a metal oxide surface.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
There is a direct influence of global warming on precipitation. Increased heating leads to greater evaporation and thus surface drying, thereby increasing the intensity and duration of drought. ...However, the water holding capacity of air increases by about 7% per 1°C warming, which leads to increased water vapor in the atmosphere. Hence, storms, whether individual thunderstorms, extratropical rain or snow storms, or tropical cyclones, supplied with increased moisture, produce more intense precipitation events. Such events are observed to be widely occurring, even where total precipitation is decreasing:'it never rains but it pours!'This increases the risk of flooding. The atmospheric and surface energy budget plays a critical role in the hydrological cycle, and also in the slower rate of change that occurs in total precipitation than total column water vapor. With modest changes in winds, patterns of precipitation do not change much, but result in dry areas becoming drier (generally throughout the subtropics) and wet areas becoming wetter, especially in the mid- to high latitudes: the'rich get richer and the poor get poorer'. This pattern is simulated by climate models and is projected to continue into the future. Because, with warming, more precipitation occurs as rain instead of snow and snow melts earlier, there is increased runoff and risk of flooding in early spring, but increased risk of drought in summer, especially over continental areas. However, with more precipitation per unit of upward motion in the atmosphere, i.e.'more bang for the buck', atmospheric circulation weakens, causing monsoons to falter. In the tropics and subtropics, precipitation patterns are dominated by shifts as sea surface temperatures change, with El Niño a good example. The volcanic eruption of Mount Pinatubo in 1991 led to an unprecedented drop in land precipitation and runoff, and to widespread drought, as precipitation shifted from land to oceans and evaporation faltered, providing lessons for possible geoengineering. Most models simulate precipitation that occurs prematurely and too often, and with insufficient intensity, resulting in recycling that is too large and a lifetime of moisture in the atmosphere that is too short, which affects runoff and soil moisture.
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According to the literature and our experience, the most common sites of non-small cell lung cancer (NSCLC) metastases include the brain, bone, liver, adrenal glands, contralateral lung and distant ...lymph nodes. Metastases to other organs are relatively rare. There have been numerous case reports and a few small case series of uncommon metastases derived from NSCLC.
We defined all organs except the common metastatic sites mentioned above as uncommon sites of metastasis. Patients with uncommon metastases among 2,872 consecutive NSCLC patients with stage IV disease at the Guangdong Lung Cancer Institute (GLCI) from 2006 to 2012 were included in this study. The diagnosis of uncommon metastases was based on pathology or imaging studies.
Uncommon metastases were diagnosed in 193 cases at anatomical sites such as the soft tissue, kidney, pancreas, spleen, peritoneum, intestine, bone marrow, eye, ovary, thyroid, heart, breast, tonsil and nasal cavity. Uncommon metastases were identified as independent poor prognostic factors through a multivariate analysis with a HR (hazard ratio) of 1.29 95% confidence interval (CI) 1.09-1.52, P < 0.01. Those patients who received systemic therapy plus local treatment had a better survival rate than did those who received systemic therapy only (P < 0.01); all patients received best supportive care.
Metastases to the above mentioned sites are infrequent. The presentation of uncommon metastases tends to indicate a poor outcome, and selected patients may benefit from local treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This article summarizes recent progress and regulatory guidance on design of trials to assess the efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, ...placebo-controlled, parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively, a sham procedure and control intervention with similar expectation of benefit, but lacking the treatment principle, are recommended. Investigators should be aware of, and attempt to minimize, expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location before initiation and results should be published regardless of outcome.
Understanding quantum tunnelling of the magnetisation (QTM) in single-molecule magnets (SMMs) is crucial for improving performance and achieving molecule-based information storage above liquid ...nitrogen temperatures. Here, through a field- and temperature-dependent study of the magnetisation dynamics of Dy(
BuO)Cl(THF)
BPh
·2THF, we elucidate the different relaxation processes: field-independent Orbach and Raman mechanisms dominate at high temperatures, a single-phonon direct process dominates at low temperatures and fields >1 kOe, and a field- and temperature-dependent QTM process operates near zero field. Accounting for the exponential temperature dependence of the phonon collision rate in the QTM process, we model the magnetisation dynamics over 11 orders of magnitude and find a QTM tunnelling gap on the order of 10
to 10
cm
. We show that removal of Dy nuclear spins does not suppress QTM, and argue that while internal dipolar fields and hyperfine coupling support QTM, it is the dynamic crystal field that drives efficient QTM.
5-hydroxytryptamine type 3 (5-HT
3
) receptor antagonists are used in the prevention of chemotherapy- induced, radiation-induced and postoperative nausea and vomiting.
CYP2D6
polymorphisms can ...influence the metabolism of some of these drugs (i.e. ondansetron and tropisetron) thereby affecting drug efficacy. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for ondansetron and tropisetron based on
CYP2D6
genotype (updates at
www.pharmgkb.org
).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Intrinsic apoptosis, reliant on BAX and BAK, has been postulated to be fundamental for morphogenesis, but its precise contribution to this process has not been fully explored in mammals. Our ...structural analysis of BOK suggests close resemblance to BAX and BAK structures. Notably, Bok−/−Bax−/−Bak−/− animals exhibited more severe defects and died earlier than Bax−/−Bak−/− mice, implying that BOK has overlapping roles with BAX and BAK during developmental cell death. By analyzing Bok−/−Bax−/−Bak−/− triple-knockout mice whose cells are incapable of undergoing intrinsic apoptosis, we identified tissues that formed well without this process. We provide evidence that necroptosis, pyroptosis, or autophagy does not substantially substitute for the loss of apoptosis. Albeit very rare, unexpected attainment of adult Bok−/−Bax−/−Bak−/− mice suggests that morphogenesis can proceed entirely without apoptosis mediated by these proteins and possibly without cell death in general.
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•BOK, BAX, and BAK have similar structures and overlapping roles during development•BOK/BAX/BAK triple-null mice have more severe defects than BAX/BAK double knockouts•Intrinsic apoptosis is critical for midline fusion and aortic arch formation•A small number of BOK/BAX/BAK triple-null mice develop entirely without apoptosis
Although apoptosis has been observed in many organs and tissues during embryonic development, it is not strictly required for the development of most organs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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