Large peridotite massifs are scattered along the 1500km length of the Yarlung-Zangbo Suture Zone (southern Tibet, China), the major suture between Asia and Greater India. Diamonds occur in the ...peridotites and chromitites of several massifs, together with an extensive suite of trace phases that indicate extremely low fO sub(2) (SiC, nitrides, carbides, native elements) and/or ultrahigh pressures (UHP) (diamond, TiO sub(2) II, coesite, possible stishovite). New physical and isotopic (C, N) studies of the diamonds indicate that they are natural, crystallized in a disequilibrium, high-T environment, and spent only a short time at mantle temperatures before exhumation and cooling. These constraints are difficult to reconcile with previous models for the history of the diamond-bearing rocks. Possible evidence for metamorphism in or near the upper part of the Transition Zone includes the following: (1) chromite (in disseminated, nodular and massive chromitites) containing exsolved pyroxenes and coesite, suggesting inversion from a high-P polymorph of chromite; (2) microstructural studies suggesting that the chromitites recrystallized from fine-grained, highly deformed mixtures of wadsleyite and an octahedral polymorph of chromite; (3) a new cubic Mg-silicate, with the space group of ringwoodite but an inverse-spinel structure (all Si in octahedral coordination); (4) harzburgites with coarsely vermicular symplectites of opx + Cr-Al spinel plus or minus cpx; reconstructions suggest that these are the breakdown products of majoritic garnets, with estimated minimum pressures to>13GPa. Evidence for a shallow pre-metamorphic origin for the chromitites and peridotites includes the following: (1) trace-element data showing that the chromitites are typical of suprasubduction-zone (SSZ) chromitites formed by magma mixing or mingling, consistent with Hf-isotope data from magmatic (375Ma) zircons in the chromitites; (2) the composition of the new cubic Mg-silicate, which suggests a low-P origin as antigorite, subsequently dehydrated; (3) the peridotites themselves, which carry the trace element signature of metasomatism in an SSZ environment, a signature that must have been imposed before the incorporation of the UHP and low-fO sub(2) phases. A proposed P-T-t path involves the original formation of chromitites in mantle-wedge harzburgites, subduction of these harzburgites at c. 375Ma, residence in the upper Transition Zone for >200 Myr, and rapid exhumation at c. 170-150Ma or 130-120Ma. Os-isotope data suggest that the subducted mantle consisted of previously depleted subcontinental lithosphere, dragged down by a subducting oceanic slab. Thermomechanical modeling shows that roll-back of a (much later) subducting slab would produce a high-velocity channelized upwelling that could exhume the buoyant harzburgites (and their chromitites) from the Transition Zone in<10 Myr. This rapid upwelling, which may explain some characteristics of the diamonds, appears to have brought some massifs to the surface in forearc or back-arc basins, where they provided a basement for oceanic crust. This model can reconcile many apparently contradictory petrological and geological datasets. It also defines an important, previously unrecognized geodynamic process that may have operated along other large suture zones such as the Urals.
The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet ...transplant program. Twenty islet recipients with C‐peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at median (interquartile range) 24 (13.5–36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7–50) episodes/patient‐year pretransplant to 0.3 (0–1.6) episodes/patient‐year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed pretransplant: Gold score 6 (5–7); 24 (13.5–36) months: 3 (1.5–4.5); p < 0.03. Target HbA1c of <7.0% was attained/maintained in 70% of recipients pretransplant: 8.0 (7.0–9.6)%; 24 (13.5–36) months: 6.2 (5.7–8.4)%; p < 0.001, with 60% reduction in insulin dose pretransplant: 0.51 (0.41–0.62) units/kg; 24 (13.5–36) months: 0.20 (0–0.37) units/kg; p < 0.001. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets 12 month stimulated C‐peptide: transported 788 (114–1764) pmol/L (n = 9); locally isolated 407 (126–830) pmol/L (n = 11); p = 0.32. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.
In this report on a cohort of recipients within the UK government–funded fully integrated islet transplant program, the authors demonstrate attainment of metabolic goals with both locally isolated and transported islets with comparable graft survival up to 36 months posttransplant.
Objectives
To differentiate the relation between the structure and timing of rest‐activity patterns and symptoms of impulsivity and mood instability in bipolar disorder (BD), borderline personality ...disorder (BPD) and healthy controls (HC).
Methods
Eighty‐seven participants (31 BD, 21 BPD and 35 HC) underwent actigraph monitoring for 28 days as part of the Automated Monitoring of Symptom Severity (AMoSS) study. Impulsivity was assessed at study entry using the BIS‐11. Mood instability was subsequently longitudinally monitored using the digital Mood Zoom questionnaire.
Results
BPD participants show several robust and significant correlations between non‐parametric circadian rest‐activity variables and worsened symptoms. Impulsivity was associated with low interdaily stability (r = −0.663) and weak amplitude (r = −0.616). Mood instability was associated with low interdaily stability (r = −0.773), greater rhythm fragmentation (r = 0.662), weak amplitude (r = −0.694) and later onset of daily activity (r = 0.553). These associations were not present for BD or HCs. Classification analysis using actigraphic measures determined that later L5 onset reliably distinguished BPD from BD and HC but did not sufficiently discriminate between BD and HC.
Conclusions
Rest‐activity pattern disturbance indicative of perturbed sleep and circadian function is an important predictor of symptom severity in BPD. This appears to validate the greater subjective complaints of BPD individuals that are sometimes regarded as exaggerated by clinicians. We suggest that treatment strategies directed towards improving sleep and circadian entrainment may in the future be investigated in BPD.
Introduction
Differences in the relationship between mood and digital communication metrics have been shown to act as a diagnostic marker in Bipolar Disorder (BD) and Borderline Personality Disorder ...(BPD). Anxiety has been associated with mobile-phone use in non-clinical populations, although a potential association between anxiety and digital communications in BD or BPD populations hasn’t been studied.
Objectives
To explore the association between self-reported anxiety symptoms and objective, naturalistic digital communications metrics in BD and BPD participants.
Methods
BD (n= 17) and BPD (n=17) cohorts were provided with a smartphone application which monitored phone call and SMS frequency and duration, alongside weekly self-reported anxiety (Generalised Anxiety Disorder 7-item scale). Linear mixed-effects regression models assessed the association between digital communications, anxiety state and interaction effects between anxiety and diagnosis.
Results
Self-reported anxiety state was negatively associated with decreased total call frequency (B=-5.150, p=0.002), cumulative total call duration (seconds; B=-1456.779, p<0.001), cumulative outgoing call duration (seconds; B=-1108.23, p<0.001), total SMS frequency (B=-31.412, p<0.001), outgoing SMS frequency (B=-16.443, p<0.001), cumulative total SMS length (characters; B=-1664.78, p=0.001) and cumulative outgoing SMS length (characters; B=-857.770, p=0.005) for BD, but not BPD, participants. Associations remained significant after adjusting for mood.
Conclusions
These results further suggest that BPD individuals, compared to BD individuals, exhibit persistent social interaction during mental distress. Together with previous findings, this effect appears to be common, but independent, for both self-reported anxiety and depression. These findings inform our understanding of the psychopathology of the two conditions, and may contribute to the development of tools to aid their diagnostic differentiation.
Conflict of interest
Prof Goodwin is a NIHR Emeritus Senior Investigator, holds shares in P1vital and P1Vital products and has served as consultant, advisor or CME speaker in the last 3 years for Compass pathways, Evapharm, Janssen, Lundbeck, Medscape, P1Vital, Sage, Servier.
Introduction
Disturbances to sleep-wake patterns are associated with bipolar disorder (BD) and borderline personality disorder (BPD). Objective assessment typically involves actigraphy monitoring, ...although it may be possible to derive sleep-wake metrics from other digital data, such as smartphone battery degradation.
Objectives
To assess whether common actigraphy-derived phase markers of the sleep-wake pattern (L5 and M10 onset) are in agreement with measures derived from smartphone battery data and explore if battery metrics differ between people with BD, BPD , and a healthy control group (HC).
Methods
High frequency smartphone battery data was collected from 30 BD, 19 BPD and 33 HC participants enrolled in the Automated Monitoring of Symptom Severity (AMoSS) study, over 28 days. Participants also wore an actigraph during this period. L5 and M10 values were calculated separately based on the rate of smartphone battery degradation and conventional actigraphy methods. Bland-Altman analyses were performed to assess agreement between battery-derived and actigraphy-derived values, and Kruskal-Wallis tests used to compare diagnostic groups.
Results
For L5, battery-derived and actigraphy-derived values had a bias of 0.46 -0.10, 1.02, upper limit of agreement (LOA): 5.45 4.49, 6.41, and lower LOA: -4.53 -3.56, -5.49. For M10, the bias was 0 -0.92, 0.92, upper LOA: 8.19 6.61, 9.76, and lower LOA: -8.19 -6.61, -9.76. Between diagnostic groups, there was no difference for battery-derived M10 (p=0.652), or L5 (p=0.122).
Conclusions
Our results suggest battery-derived and actigraphy-derived M10 and L5 show good overall equivalence. However, battery-derived methods exhibit large variability, which limits the clinical utility of smartphone battery data to infer sleep-wake metrics.
Disclosure
No significant relationships.
Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition that has been strongly associated with changes in sleep and circadian rhythms. Circadian rhythms are near 24-h ...cycles that are primarily generated by an endogenous circadian timekeeping system, encoded at the molecular level by a panel of clock genes. Stimulant and non-stimulant medication used in the management of ADHD has been shown to potentially impact on circadian processes and their behavioral outputs. In the current study, we have analyzed circadian rhythms in daily activity and sleep, and the circadian gene expression in a cohort of healthy controls (N = 22), ADHD participants not using ADHD-medication (N = 17), and participants with ADHD and current use of ADHD medication (N = 17). Rhythms of sleep/wake behavior were assessed via wrist-worn actigraphy, whilst rhythms of circadian gene expression were assessed ex-vivo in primary human-derived dermal fibroblast cultures. Behavioral data indicate that patients with ADHD using ADHD-medication have lower relative amplitudes of diurnal activity rhythms, lower sleep efficiency, more nocturnal activity but not more nocturnal wakenings than both controls and ADHD participants without medication. At the molecular level, there were alterations in the expression of PER2 and CRY1 between ADHD individuals with no medication compared to medicated ADHD patients or controls, whilst CLOCK expression was altered in patients with ADHD and current medication. Analysis of fibroblasts transfected with a BMAL1:luc reporter showed changes in the timing of the peak expression across the three groups. Taken together, these data support the contention that both ADHD and medication status impact on circadian processes.
Background & AimAdoptive immunotherapy with Epstein-Barr virus (EBV)-specific T cells has proven efficacious for patients with EBV-related malignancies. Clinical manufacture of T cells for therapy ...requires a fast, scalable, cost-effective generation protocol that conforms to GMP regulations. We report the development and implementation of an allogeneic EBV-specific T cell bank generated by expansion of interferon-gamma selected virus-specific T cells (VST). The establishment of an closed-process system for VST culture, and validation of flow-based assays for initial product screening, in-process controls and final product release are described.Methods, Results & ConclusionPre-screening of prospective donors was made by seropositivity and EBV peptide-induced cytokine expression analysis, confirming that EBV seropositivity alone was insufficient to ensure virus-specific T cell response in vitro. Virus-specific T cells were isolated from leukapheresis using an IFN-gamma based cytokine capture system (Miltenyi) using a CliniMACS Prodigy, followed by co-culture with irradiated autologous leukocytes in GMP-compliant medium supplemented with IL-2. Cells were cultured in closed process culture flasks (G-Rex M100CS, Wilson Wolf) over 19-21 days then harvested and cryopreserved at therapeutic dose (1.5 × 10 8 T cells per dose, 4 doses per treatment). Flow cytometric analysis for surface phenotype and intracellular functional markers was used as an in-process control to assess VST content, expansion and differentiation throughout culture. A release criteria flow cytometry panel was validated for final product quality. We generated 8 VST products in pre-production and a further 5 products after Process Validation. The pre-production process generated a mean of 1.27 × 10 10 VST (range 0.3–2.54 × 10 10) from a starting isolate of 5.6 × 10 7 IFN-gamma positive cells (0.1–1.8 × 10 7), a mean expansion of 3000 fold. The protocol also reduced processing time from 3 months (in our previous EBV-VST bank) to 20 days, generating an average of 96.8 ± 16.8 adult doses per single production run, offering a very significant improvement over lymphoblastic cell line-based VST culture in both quantity and cost of generating therapeutic T cell products. The use of fully GMP-compliant reagents, closed process manufacturing and suitable quality management has offered an effective approach to our clinical manufacture of EBV-specific T cells in terms of speed, cost and complexity, and determination of functional quality through flow cytometry.
The prevalence and diversity of plant parasitic nematodes in Northern Ireland cereal and grassland was determined from 191 agricultural fields. A total of 18 nematode genera were detected, including ...economically important pests, Meloidogyne spp., Heterodera spp. and Pratylenchus spp., each of which were above economic damage thresholds in a significant proportion of the sites (92.4%, 70% and 28.6%, respectively). The detection of the root knot nematode, Meloidogyne minor (6% prevalence), was significant given its recent emergence across the turf grass sector and the prospect of M. minor becoming a common agricultural pest. Analyses of nematode prevalence and abundance highlighted significant associations with grass and cereals, soil types, soil grade (proxy for soil quality) and rainfall levels. Specifically, nematode populations varied between the two major soils (brown earths and gleys), while significant trends for increased nematode diversity and greater prevalence of both Meloidogyne and Pratylenchus with increasing rainfall were also observed. Multivariate analyses were performed to determine interactive effects and the relative importance of the factors affecting nematode populations. Notably, rainfall, in combination with either crop type or soil grade, had a significant effect on nematode abundance and diversity. The findings suggest significant changes in nematode populations have occurred over the last several decades and the possibility that these are linked to changing climate and cropping practices are discussed, as well as future concerns for plant parasitic nematode management.
The European Society of Hypertension (ESH), the American Heart Association (AHA) and the American Society of Hypertension (ASH) have published guidelines for self-monitoring of blood pressure (SBPM). ...We aimed to demonstrate the equivalence of SBPM with ambulatory blood pressure monitoring (ABPM) in the assessment of hypertension. A total of 87 consecutive subjects referred from primary care for standard ABPM underwent a 1-week period of SBPM, as defined by the ESH guidelines, either before or after ABPM. There was no difference in mean blood pressure (BP): SBPM 142/87 mm Hg, daytime average ABPM 141/86 mm Hg. The intra-class correlation coefficient was 0.72 and 0.89 for systolic and diastolic pressure, respectively. SBPM is concordant with ABPM in classifying subjects as hypertensive or normotensive in 87% of cases (κ=0.56). The coefficient of variation of SBPM compared with ABPM was 5%. In answer to a direct question 81% of subjects preferred SBPM to ABPM. The current self-monitoring schedule recommended by the ESH, AHA and ASH is valid. The mean BP obtained from SBPM is equivalent to awake-time BP on ABPM, the accepted reference standard for 'out of office' BP measurement. SBPM is simpler to carry out, preferred by patients and should be considered on a par with ABPM.
Bisphosphonates inhibit osteoclast-mediated bone resorption by mechanisms that have only recently become clear. Whereas nitrogen-containing bisphosphonates affect osteoclast function by preventing ...protein prenylation (especially geranylgeranylation), non-nitrogen-containing bisphosphonates have a different molecular mechanism of action. In this study, we demonstrate that nitrogen-containing bisphosphonates (risedronate, alendronate, pamidronate, and zoledronic acid) and non-nitrogen-containing bisphosphonates (clodronate and etidronate) cause apoptosis of rabbit osteoclasts, human osteoclastoma-derived osteoclasts, and human osteoclast-like cells generated in cultures of bone marrow in vitro. Osteoclast apoptosis was shown to involve characteristic morphological changes, loss of mitochondrial membrane potential, and the activation of caspase-3-like proteases capable of cleaving peptide substrates with the sequence DEVD. Caspase-3-like activity could be visualized in unfixed, dying osteoclasts and osteoclast-like cells using a cell-permeable, fluorogenic substrate. Bisphosphonate-induced osteoclast apoptosis was dependent on caspase activation, because apoptosis resulting from alendronate, clodronate, or zoledronic acid treatment was suppressed by zVAD-fmk, a broad-range caspase inhibitor, or by SB-281277, a specific isatin sulfonamide inhibitor of caspase-3/-7. Furthermore, caspase-3 (but not caspase-6 or caspase-7) activity could be detected and quantitated in lysates from purified rabbit osteoclasts, whereas the p17 fragment of active caspase-3 could be detected in human osteoclast-like cells by immunofluorescence staining. Caspase-3, therefore, appears to be the major effector caspase activated in osteoclasts by bisphosphonate treatment. Caspase activation and apoptosis induced by nitrogen-containing bisphosphonates are likely to be the consequence of the loss of geranylgeranylated rather than farnesylated proteins, because the ability to cause apoptosis and caspase activation was mimicked by GGTI-298, a specific inhibitor of protein geranylgeranylation, whereas FTI-277, a specific inhibitor of protein farnesylation, had no effect on apoptosis or caspase activity.
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