Initial development and validation of a mitochondrial disease quality of life scale.

Mitochondrial diseases are a clinically diverse group of genetic disorders that often present to neurologists. Health related quality of life (HRQOL) is increasingly recognised as a fundamental patient based outcome measure in both clinical intervention and research. Generic outcome measures have been extensively validated to assess HRQOL across populations and different disease states. However, due to their inclusive construct, it is acknowledged that not all relevant aspects of a specific illness may be captured. Hence there is a need to develop disease specific HRQOL measures that centre on symptoms characteristic of a specific disease or condition and their impact. This study presents the initial conceptualisation, development and preliminary psychometric assessment (validity and reliability) of a mitochondrial disease specific HRQOL measure (Newcastle Mitochondrial Quality of life measure (NMQ)). NMQ is a valuable assessment tool and consists of 63 items within 16 unidimensional domains, each demonstrating good internal reliability (Cronbach's α≥0.83) and construct validity

Can the envisaged reductions of fossil fuel CO2 emissions be detected by atmospheric observations?

The lower troposphere is an excellent receptacle, which integrates anthropogenic greenhouse gases emissions over large areas. Therefore, atmospheric concentration observations over populated regions would provide the ultimate proof if sustained emissions changes have occurred. The most important anthropogenic greenhouse gas, carbon dioxide (CO2), also shows large natural concentration variations, which need to be disentangled from anthropogenic signals to assess changes in associated emissions. This is in principle possible for the fossil fuel CO2 component (FFCO2) by high-precision radiocarbon (14C) analyses because FFCO2 is free of radiocarbon. Long-term observations of 14CO2 conducted at two sites in south-western Germany do not yet reveal any significant trends in the regional fossil fuel CO2 component. We rather observe strong inter-annual variations, which are largely imprinted by changes of atmospheric transport as supported by dedicated transport model simulations of fossil fuel CO2. In this paper, we show that, depending on the remoteness of the site, changes of about 7–26% in fossil fuel emissions in respective catchment areas could be detected with confidence by high-precision atmospheric 14CO2 measurements when comparing 5-year averages if these inter-annual variations were taken into account. This perspective constitutes the urgently needed tool for validation of fossil fuel CO2 emissions changes in the framework of the Kyoto protocol and successive climate initiatives

The reliability of in-training assessment when performance improvement is taken into account

During in-training assessment students are frequently assessed over a longer period of time and therefore it can be expected that their performance will improve. We studied whether there really is a measurable performance improvement when students are assessed over an extended period of time and how this improvement affects the reliability of the overall judgement. In-training assessment results were obtained from 104 students on rotation at our university hospital or at one of the six affiliated hospitals. Generalisability theory was used in combination with multilevel analysis to obtain reliability coefficients and to estimate the number of assessments needed for reliable overall judgement, both including and excluding performance improvement. Students’ clinical performance ratings improved significantly from a mean of 7.6 at the start to a mean of 7.8 at the end of their clerkship. When taking performance improvement into account, reliability coefficients were higher. The number of assessments needed to achieve a reliability of 0.80 or higher decreased from 17 to 11. Therefore, when studying reliability of in-training assessment, performance improvement should be considered

Forecasting stroke-like episodes and outcomes in mitochondrial disease

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically-determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinic-radio-pathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA (mtDNA) variants (n = 23). The age of first stroke-like episode was available for 105 patients (mean [SD] age: 31.8 [16.1]); a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mtDNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82-0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration was more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% vs 44%, p G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice

Measurement of the branching fraction and CP content for the decay B(0) -> D(*+)D(*-)

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APS.We report a measurement of the branching fraction of the decay B0→D*+D*- and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4  fb-1 collected at the Υ(4S) resonance during 1999–2000, we have reconstructed 38 candidate signal events in the mode B0→D*+D*- with an estimated background of 6.2±0.5 events. From these events, we determine the branching fraction to be B(B0→D*+D*-)=[8.3±1.6(stat)±1.2(syst)]×10-4. The measured CP-odd fraction of the final state is 0.22±0.18(stat)±0.03(syst).This work is supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the A.P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Aberrant crossed corticospinal facilitation in muscles distant from a spinal cord injury.

Crossed facilitatory interactions in the corticospinal pathway are impaired in humans with chronic incomplete spinal cord injury (SCI). The extent to which crossed facilitation is affected in muscles above and below the injury remains unknown. To address this question we tested 51 patients with neurological injuries between C2-T12 and 17 age-matched healthy controls. Using transcranial magnetic stimulation we elicited motor evoked potentials (MEPs) in the resting first dorsal interosseous, biceps brachii, and tibialis anterior muscles when the contralateral side remained at rest or performed 70% of maximal voluntary contraction (MVC) into index finger abduction, elbow flexion, and ankle dorsiflexion, respectively. By testing MEPs in muscles with motoneurons located at different spinal cord segments we were able to relate the neurological level of injury to be above, at, or below the location of the motoneurons of the muscle tested. We demonstrate that in patients the size of MEPs was increased to a similar extent as in controls in muscles above the injury during 70% of MVC compared to rest. MEPs remained unchanged in muscles at and within 5 segments below the injury during 70% of MVC compared to rest. However, in muscles beyond 5 segments below the injury the size of MEPs increased similar to controls and was aberrantly high, 2-fold above controls, in muscles distant (>15 segments) from the injury. These aberrantly large MEPs were accompanied by larger F-wave amplitudes compared to controls. Thus, our findings support the view that corticospinal degeneration does not spread rostral to the lesion, and highlights the potential of caudal regions distant from an injury to facilitate residual corticospinal output after SCI

Does psychological status influence clinical outcomes in patients with inflammatory bowel disease (IBD) and other chronic gastroenterological diseases: An observational cohort prospective study

Background: Whether there is a temporal relationship between psychological problems and clinical outcomes in patients with diseases of the digestive tract has not been widely researched. Thus, our aims were 1) To observe and compare prospectively clinical outcomes in relation to psychological co-morbidity in patients with inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and chronic hepatitis C (HCV) and, 2) To test the hypothesis that patients with psychological co-morbidities are less likely to have a satisfactory response to standard treatment at 12 months. Methods: Overall, 139 patients were enrolled in this observational cohort prospective study. Over the ensuing year, physical and psychological measures were made at baseline and after 12 months (HADS, SCL90, SF-12 and disease activity measures). A logistic regression was conducted to observe any relationship between baseline characteristics and patients' clinical outcomes after 12 months. Results: Overall, there was no relationship between psychological status and quality of life at baseline and relapse at 12 months (p > 0.05). However, patients with inactive disease at baseline were at lower risk of relapse after 12 months (OR = 0.046, CI: 0.012–0.178). No significant relationship was found between psychological problems such as depression/anxiety and a total number of relapses in the IBD group. However, interestingly, patients with an active disease at baseline tended to have a greater number of relapses (OR = 3.07, CI: 1.650–5.738) and CD participants were found at lower risk of relapse than UC participants (OR = 0.382, CI: 0.198–0.736). Conclusion: In contrast to previous investigations, this study suggests that there is no temporal relationship between psychological problems at baseline and clinical outcomes over time. Longer and larger prospective studies are needed to better understand this result.Antonina A Mikocka-Walus, Deborah A Turnbull, Nicole T Moulding, Ian G Wilson, Gerald J Holtmann and Jane M Andrew