Relationship between childhood trauma and paranoia: a study of specificity and underlying theoretical mechanisms

Purpose: While biogenetic theories have traditionally dominated understandings of psychosis, there is now a large body of evidence suggesting a causal relationship between childhood trauma and psychosis. We sought to further study this relationship by adopting a psychotic experience specific approach and applying two of Bradford Hill’s causality criteria, namely specificity and underlying theoretical mechanisms, to the relationship between childhood trauma and paranoia. Method: Chapter 1 was a systematic review and meta-analysis that sought to examine the magnitude of the association between childhood sexual (CSA), physical (CPA) and emotional abuse (CEA) and physical (CPN) or emotional neglect (CEN) and paranoia across community and clinical samples. Chapter 2 is an empirical research study that sought to test whether negative core schema mediated the relationship between childhood trauma and paranoia. Study 1 sought to these relationships within the general population, whereas Study 2 aimed to test these in a clinical sample of people with persecutory delusions. We also sought to pilot a new measure of negative core schema, The Schema Rating Scale (SCIRATS). Correlation and mediation analysis were utilised to test our empirical study hypothesis. Results: Our meta-analysis found small associations between all forms of childhood trauma and paranoia examined, however the magnitude of the association may be somewhat greater for CEA and CPA than for the other forms of childhood we examined and paranoia . In Study 1, we found that negative-self, negative-other and both negative-self and negative-other core schema mediated the relationship between childhood trauma and paranoia. We found similar results when repeating these analyses with the SCIRATS. In Study 2, we found significant associations between childhood trauma and negative-self core schema that remained significant on the SCIRATS. Negative-self and negative-other core schema were also significantly associated with paranoia however, when we repeated this analysis with the SCIRATS, only negative-self core schema remained significant. We found no significant association between childhood trauma and paranoia. Positive initial feedback on the SCIRATS would suggest participants view this as an acceptable measure. Conclusions: Whilst acknowledging the limitations associated with our studies, our findings suggest that while there appears to be a general association between the forms of childhood trauma we examined and paranoia, this relationship may be somewhat greater for CEA and CPA and paranoia. They are consistent with cognitive models of psychosis and suggest that negative core schema may be important underlying mechanisms in the relationship between childhood trauma and paranoia. We make recommendations for future research to further examine the evidence for specificity and recommend that individuals with psychosis should be asked about childhood trauma and that future research should further examine the potential benefits of trauma-informed formulation and psychological therapies targeting negative core schema in reducing paranoia

Multi-scale modeling study of the source contributions to near-surface ozone and sulfur oxides levels over California during the ARCTAS-CARB period

Chronic high surface ozone (O3) levels and the increasing sulfur oxides (SOx = SO2+SO4) ambient concentrations over South Coast (SC) and other areas of California (CA) are affected by both local emissions and long-range transport. In this paper, multi-scale tracer, full-chemistry and adjoint simulations using the STEM atmospheric chemistry model are conducted to assess the contribution of local emission sourcesto SC O3 and to evaluate the impacts of transported sulfur and local emissions on the SC sulfur budgetduring the ARCTAS-CARB experiment period in 2008. Sensitivity simulations quantify contributions of biogenic and fire emissions to SC O3 levels. California biogenic and fire emissions contribute 3–4 ppb to near-surface O3 over SC, with larger contributions to other regions in CA. During a long-range transport event from Asia starting from 22 June, high SOx levels (up to ~0.7 ppb of SO2 and ~1.3 ppb of SO4) is observed above ~6 km, but they did not affect CA surface air quality. The elevated SOx observed at 1–4 km is estimated to enhance surface SOx over SC by ~0.25 ppb (upper limit) on ~24 June. The near-surface SOx levels over SC during the flight week are attributed mostly to local emissions. Two anthropogenic SOx emission inventories (EIs) from the California Air Resources Board (CARB) and the US Environmental Protection Agency (EPA) are compared and applied in 60 km and 12 km chemical transport simulations, and the results are compared withobservations. The CARB EI shows improvements over the National Emission Inventory (NEI) by EPA, but generally underestimates surface SC SOx by about a factor of two. Adjoint sensitivity analysis indicated that SO2 levels at 00:00 UTC (17:00 local time) at six SC surface sites were influenced by previous day maritime emissions over the ocean, the terrestrial emissions over nearby urban areas, and by transported SO2 from the north through both terrestrial and maritime areas. Overall maritime emissions contribute 10–70% of SO2 and 20–60% fine SO4 on-shore and over the most terrestrial areas, with contributions decreasing with in-land distance from the coast. Maritime emissions also modify the photochemical environment, shifting O3 production over coastal SC to more VOC-limited conditions. These suggest an important role for shipping emission controls in reducing fine particle and O3concentrations in SC

Mapping preictal and ictal haemodynamic networks using video-electroencephalography and functional imaging

Ictal patterns on scalp-electroencephalography are often visible only after propagation, therefore rendering localization of the seizure onset zone challenging. We hypothesized that mapping haemodynamic changes before and during seizures using simultaneous video-electroencephalography and functional imaging will improve the localization of the seizure onset zone. Fifty-five patients with ≥2 refractory focal seizures/day, and who had undergone long-term video-electroencephalography monitoring were included in the study. ‘Preictal' (30 s immediately preceding the electrographic seizure onset) and ictal phases, ‘ictal-onset'; ‘ictalestablished' and ‘late ictal', were defined based on the evolution of the electrographic pattern and clinical semiology. The functional imaging data were analysed using statistical parametric mapping to map ictal phase-related haemodynamic changes consistent across seizures. The resulting haemodynamic maps were overlaid on co-registered anatomical scans, and the spatial concordance with the presumed and invasively defined seizure onset zone was determined. Twenty patients had typical seizures during functional imaging. Seizures were identified on video-electroencephalography in 15 of 20, on electroencephalography alone in two and on video alone in three patients. All patients showed significant ictal-related haemodynamic changes. In the six cases that underwent invasive evaluation, the ictal-onset phase-related maps had a degree of concordance with the presumed seizure onset zone for all patients. The most statistically significant haemodynamic cluster within the presumed seizure onset zone was between 1.1 and 3.5 cm from the invasively defined seizure onset zone, which was resected in two of three patients undergoing surgery (Class I post-surgical outcome) and was not resected in one patient (Class III post-surgical outcome). In the remaining 14 cases, the ictal-onset phase-related maps had a degree of concordance with the presumed seizure onset zone in six of eight patients with structural-lesions and five of six non-lesional patients. The most statistically significant haemodynamic cluster was localizable at sub-lobar level within the presumed seizure onset zone in six patients. The degree of concordance of haemodynamic maps was significantly better (P < 0.05) for the ictal-onset phase [entirely concordant/concordant plus (13/20; 65%) + some concordance (4/20; 20%) = 17/20; 85%] than ictal-established [entirely concordant/concordant plus (5/13; 38%) + some concordance (4/13; 31%) = 9/13; 69%] and late ictal [concordant plus (1/9; 11%) + some concordance (4/9; 44%) = 5/9; 55%] phases. Ictal propagation-related haemodynamic changes were also seen in symptomatogenic areas (9/20; 45%) and the default mode network (13/20; 65%). A common pattern of preictal changes was seen in 15 patients, starting between 98 and 14 s before electrographic seizure onset, and the maps had a degree of concordance with the presumed seizure onset zone in 10 patients. In conclusion, preictal and ictal haemodynamic changes in refractory focal seizures can non-invasively localize seizure onset at sub-lobar/gyral level when ictal scalp-electroencephalography is not helpfu

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs

In situ multi-frequency measurements of magnetic susceptibility as an indicator of planetary regolith maturity

Space weathering is now generally accepted to modify the optical and magnetic properties of airless planetary regoliths such as those on the Moon and Mercury. Under micrometeorite and ion bombardment, ferrous iron in such surfaces is reduced to metallic iron spheres, found in amorphous coatings on almost all exposed regolith grains. The size and number distribution of these particles and their location in the regolith all determine the nature and extent of the optical and magnetic changes. These parameters in turn reflect the formation mechanisms, temperatures, and durations involved in the evolution of the regolith. Studying them in situ is of intrinsic value to understanding the weathering process, and useful for determining the maturity of the regolith and providing supporting data for interpreting remotely sensed mineralogy. Fine-grained metallic iron has a number of properties that make it amenable to magnetic techniques, of which magnetic susceptibility is the simplest and most robust. The magnetic properties of the lunar regolith and laboratory regolith analogues are therefore reviewed and the theoretical basis for the frequency dependence of magnetic susceptibility presented. Proposed here is then an instrument concept using multi-frequency measurements of magnetic susceptibility to confirm the presence of fine grained magnetic material and attempt to infer its quantity and size distribution. Such an instrument would be invaluable on a future mission to an asteroid, the Moon, Mercury or other airless rocky Solar System body

TOI-2119: A transiting brown dwarf orbiting an active M-dwarf from NASA’s TESS mission

We report the discovery of TOI-2119b, a transiting brown dwarf (BD) that orbits and is completely eclipsed by an active M-dwarf star. Using light curve data from the Transiting Exoplanet Survey Satellite mission and follow-up high-resolution Doppler spectroscopic observations, we find the BD has a radius of $R_b = 1.08 \pm 0.03{\rm R_J}$, a mass of $M_b = 64.4 \pm 2.3{\rm M_J}$, an orbital period of $P = 7.200865 \pm 0.00002$ days, and an eccentricity of $e=0.337\pm 0.002$. The host star has a mass of $M_\star = 0.53 \pm 0.02{\rm M_\odot}$, a radius of $R_\star= 0.50 \pm 0.01{\rm R_\odot}$, an effective temperature of $T_{\rm eff} = 3621 \pm 48$K, and a metallicity of $\rm [Fe/H]=+0.06\pm 0.08$. TOI-2119b joins an emerging population of transiting BDs around M-dwarf host stars, with TOI-2119 being the ninth such system. These M-dwarf--brown dwarf systems typically occupy mass ratios near $q = M_b/M_\star \approx 0.1-0.2$, which separates them from the typical mass ratios for systems with transiting substellar objects and giant exoplanets that orbit more massive stars. The nature of the secondary eclipse of the BD by the star enables us to estimate the effective temperature of the substellar object to be $2030\pm 84$K, which is consistent with predictions by substellar evolutionary models.Comment: 14 pages, 13 figures, 4 tables, accepted in MNRA

The Type 2 Diabetes Knowledge Portal: an Open access Genetic Resource Dedicated to Type 2 Diabetes and Related Traits

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP\u27s comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic non-inferiority randomised controlled trial

Background: Bullous pemphigoid (BP) is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline conveys acceptable short-term blister control whilst conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods: Pragmatic multi-centre parallel-group randomised controlled trial of adults with BP (≥3 blisters ≥2 sites and linear basement membrane IgG/C3) plus economic evaluation. Participants were randomised to doxycycline (200 mg/day) or prednisolone (0·5 mg/kg/day). Localised adjuvant potent topical corticosteroids (<30 g/week) was permitted weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with ≤3 blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of noninferiority. The primary safety outcome was the proportion with severe, life-threatening or fatal treatment-related adverse events by 52 weeks. Analysis used a regression model adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Results: 132 patients were randomised to doxycycline and 121 to prednisolone from 54 UK and 7 German dermatology centres. Mean age was 77·7 years and 68.4% had moderate to severe baseline disease. For those starting doxycycline, 83/112 (74·1%) had ≤3 blisters at 6 weeks compared with 92/101 (91·1%) for prednisolone, a difference of 18·6% favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening and fatal events at 52 weeks were 18·5% for those starting doxycycline and 36·6% for prednisolone (mITT analysis), an adjusted difference of 19·0% (95% CI, 7·9%, 30·1%, p=0·001). Conclusions: A strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and significantly safer long-term