Dysfunction of basal ganglia functional connectivity associated with subjective and cognitive fatigue in multiple sclerosis.

Objectives: Central fatigue is one of the most common symptoms in multiple sclerosis (MS). It has a profound impact on quality of life and a negative effect on cognition. Despite its widespread impact, fatigue is poorly understood and very difficult to measure. Whilst the basal ganglia has been implicated in fatigue the nature of its role and involvement with fatigue is still unclear. The aim of the present study was to establish the role of the basal ganglia in MS fatigue using functional connectivity measures. Methods: The present study examined the functional connectivity (FC) of the basal ganglia in a functional MRI study with 40 female participants with MS (mean age = 49.98 (SD = 9.65) years) and 40 female age-matched (mean age = 49.95 (SD = 9.59) years) healthy controls (HC). To measure fatigue the study employed the subjective self-report Fatigue Severity Scale and a performance measure of cognitive fatigue using an alertness-motor paradigm. To distinguish physical and central fatigue force measurements were also recorded. Results: The results suggest that decreased local FC within the basal ganglia plays a key role in cognitive fatigue in MS. Increased global FC between the basal ganglia and the cortex may sub serve a compensatory mechanism to reduce the impact of fatigue in MS. Conclusion: The current study is the first to show that basal ganglia functional connectivity is associated with both subjective and objective fatigue in MS. In addition, the local FC of the basal ganglia during fatigue inducing tasks could provide a neurophysiological biomarker of fatigue.

A pilot intervention to improve uptake and equality of childhood influenza vaccination in an area of Wales, through the introduction of a mixed delivery model including nursery school immunisation sessions.

The schools-based influenza vaccination programme has seen consistently high uptake in Wales, however coverage in pre-school two and three-year olds is lower. One health board area (Cwm Taf University Health Board (UHB)) developed an intervention to offer live attenuated influenza vaccine (LAIV) for three-year olds attending nursery schools alongside the existing general practice (GP) programme. During the pilot, sessions were delivered by health visitors, working with school nurses. The mixed delivery model led to vaccination data being recorded in two separate data systems. To evaluate the impact of the pilot on overall vaccine uptake, data linkage was carried out within the Secure Anonymised Information Linkage (SAIL) Databank. Overall influenza vaccine uptake was calculated for each health board in Wales for two and three-year olds for the 2015-16, 2016-17, and 2017-18 influenza programmes. Uptake in two-year olds in Cwm Taf UHB and also uptake in three-year olds in other health boards in Wales were the comparison groups. Uptake of influenza vaccine in the 2015-16 (pre-intervention) period was 41.0% for three-year olds in Cwm Taf UHB. Following the intervention, coverage increased to 70.7% and 71.5% for 2016-17 and 2017-18 respectively. The same increases in uptake were not seen in two-year olds in Cwm Taf UHB or in three-year olds in non-intervention health boards. In Cwm Taf UHB resident three-year olds in 2015-16 there was an inequality gap in the uptake of 17.4 percentage points between the most and least deprived areas. Uptake increased across all deprivation quintiles in 2016-17 and 2017-18; and the inequality gap decreased to 10.3 and 13.4 percentage points respectively. Influenza vaccination uptake and equality of uptake in three-year olds can be improved by adopting a mixed delivery model across nursery school based immunisation sessions with the additional option of influenza vaccination at GPs.

Photocatalytic setup for in situ and operando ambient-pressure X-ray photoelectron spectroscopy at MAX IV Laboratory.

The Ambient-Pressure X-ray Photoelectron Spectroscopy (APXPS) endstation at the SPECIES beamline at MAX IV Laboratory has been improved. The latest upgrades help in performing photo-assisted experiments under operando conditions in the mbar pressure range using gas and vapour mixtures whilst also reducing beam damage to the sample caused by X-ray irradiation. This article reports on endstation upgrades for APXPS and examples of scientific cases of in situ photocatalysis, photoreduction and photo-assisted atomic layer deposition (photo-ALD).

Dip-and-pull ambient pressure photoelectron spectroscopy as a spectroelectrochemistry tool for probing molecular redox processes.

Ambient pressure x-ray photoelectron spectroscopy (APXPS) can provide a compelling platform for studying an analyte's oxidation and reduction reactions in solutions. This paper presents proof-of-principle operando measurements of a model organometallic complex, iron hexacyanide, in an aqueous solution using the dip-and-pull technique. The data demonstrates that the electrochemically active liquid meniscuses on the working electrodes can undergo controlled redox reactions which were observed using APXPS. A detailed discussion of several critical experimental considerations is included as guidance for anyone undertaking comparable experiments.

Functional electrical stimulation for foot drop in people with multiple sclerosis: The relevance and importance of addressing quality of movement.

Impaired mobility is common in people with multiple sclerosis (MS). Changes in gait have different causes and require individualised gait rehabilitation. A common and often early cause of mobility impairment is footdrop, inability to lift the foot during the swing phase of gait, with increased risk of falls, effortful walking and fatigue. Using literature review, we have characterised published data on footdrop treatment in MS, specifically functional electrical stimulation (FES) to better understand the reported outcomes relevant to the user. We discuss the strengths and weaknesses of FES and how far it meets the needs of people with footdrop. Physiotherapy combined with FES may further enhance the benefits of FES. MS studies emphasise the value of maintaining activity levels in early MS but discussion on how to achieve this is lacking. We emphasise the value of qualitative measures to broaden our understanding and improve treatment and adherence and identify areas for further research. Supplementary video material illustrates key features of MS gait and its correction using FES and physiotherapy.

An enormous sulfur isotope excursion indicates marine anoxia during the end-Triassic mass extinction.

The role of ocean anoxia as a cause of the end-Triassic marine mass extinction is widely debated. Here, we present carbonate-associated sulfate δ34S data from sections spanning the Late Triassic-Early Jurassic transition, which document synchronous large positive excursions on a global scale occurring in ~50 thousand years. Biogeochemical modeling demonstrates that this S isotope perturbation is best explained by a fivefold increase in global pyrite burial, consistent with large-scale development of marine anoxia on the Panthalassa margin and northwest European shelf. This pyrite burial event coincides with the loss of Triassic taxa seen in the studied sections. Modeling results also indicate that the pre-event ocean sulfate concentration was low (<1 millimolar), a common feature of many Phanerozoic deoxygenation events. We propose that sulfate scarcity preconditions oceans for the development of anoxia during rapid warming events by increasing the benthic methane flux and the resulting bottom-water oxygen demand.

Personalised profiling to identify clinically relevant changes in tremor due to multiple sclerosis.

BACKGROUND: There is growing interest in sensor-based assessment of upper limb tremor in multiple sclerosis and other movement disorders. However, previously such assessments have not been found to offer any improvement over conventional clinical observation in identifying clinically relevant changes in an individual's tremor symptoms, due to poor test-retest repeatability. METHOD: We hypothesised that this barrier could be overcome by constructing a tremor change metric that is customised to each individual's tremor characteristics, such that random variability can be distinguished from clinically relevant changes in symptoms. In a cohort of 24 people with tremor due to multiple sclerosis, the newly proposed metrics were compared against conventional clinical and sensor-based metrics. Each metric was evaluated based on Spearman rank correlation with two reference metrics extracted from the Fahn-Tolosa-Marin Tremor Rating Scale: a task-based measure of functional disability (FTMTRS B) and the subject's self-assessment of the impact of tremor on their activities of daily living (FTMTRS C). RESULTS: Unlike the conventional sensor-based and clinical metrics, the newly proposed 'change in scale' metrics presented statistically significant correlations with changes in self-assessed impact of tremor (max R2>0.5,p<0.05 after correction for false discovery rate control). They also outperformed all other metrics in terms of correlations with changes in task-based functional performance (R2=0.25 vs. R2=0.15 for conventional clinical observation, both p<0.05). CONCLUSIONS: The proposed metrics achieve an elusive goal of sensor-based tremor assessment: improving on conventional visual observation in terms of sensitivity to change. Further refinement and evaluation of the proposed techniques is required, but our core findings imply that the main barrier to translational impact for this application can be overcome. Sensor-based tremor assessments may improve personalised treatment selection and the efficiency of clinical trials for new treatments by enabling greater standardisation and sensitivity to clinically relevant changes in symptoms.

The medical care of the neovagina of transgender women: a review.

For transgender women, genital adjustment surgery involves removal of the natal reproductive organs and creation of a neovagina, vulva and clitoris. We conducted a review of the medical literature in order to summarise the issues that can affect the health of the neovagina in the long term, and to make recommendations on how to manage these issues.

Detection and removal of impurities in nitric oxide generated from air by pulsed electrical discharge.

Inhalation of nitric oxide (NO) produces selective pulmonary vasodilation without dilating the systemic circulation. However, the current NO/N2 cylinder delivery system is cumbersome and expensive. We developed a lightweight, portable, and economical device to generate NO from air by pulsed electrical discharge. The objective of this study was to investigate and optimize the purity and safety of NO generated by this device. By using low temperature streamer discharges in the plasma generator, we produced therapeutic levels of NO with very low levels of nitrogen dioxide (NO2) and ozone. Despite the low temperature, spark generation eroded the surface of the electrodes, contaminating the gas stream with metal particles. During prolonged NO generation there was gradual loss of the iridium high-voltage tip (-90 µg/day) and the platinum-nickel ground electrode (-55 µg/day). Metal particles released from the electrodes were trapped by a high-efficiency particulate air (HEPA) filter. Quadrupole mass spectroscopy measurements of effluent gas during plasma NO generation showed that a single HEPA filter removed all of the metal particles. Mice were exposed to breathing 50 parts per million of electrically generated NO in air for 28 days with only a scavenger and no HEPA filter; the mice did not develop pulmonary inflammation or structural changes and iridium and platinum particles were not detected in the lungs of these mice. In conclusion, an electric plasma generator produced therapeutic levels of NO from air; scavenging and filtration effectively eliminated metallic impurities from the effluent gas.

Pulmonary hypertension after prolonged hypoxic exposure in mice with a congenital deficiency of Cyp2j.

Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pulmonary vascular tone and hypoxic pulmonary vasoconstriction. We investigated whether the attenuated acute vasoconstrictor response to hypoxic exposure of Cyp2j(-/-) mice would protect these mice against the pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia. Cyp2j(-/-) and Cyp2j(+/+) male and female mice continuously breathed an inspired oxygen fraction of 0.21 (normoxia) or 0.10 (hypoxia) in a normobaric chamber for 6 weeks. We assessed hemoglobin (Hb) concentrations, right ventricular (RV) systolic pressure (RVSP), and transthoracic echocardiographic parameters (pulmonary acceleration time [PAT] and RV wall thickness). Pulmonary Cyp2c29, Cyp2c38, and sEH mRNA levels were measured in Cyp2j(-/-) and Cyp2j(+/+) male mice. At baseline, Cyp2j(-/-) and Cyp2j(+/+) mice had similar Hb levels and RVSP while breathing air. After 6 weeks of hypoxia, circulating Hb concentrations increased but did not differ between Cyp2j(-/-) and Cyp2j(+/+) mice. Chronic hypoxia increased RVSP in Cyp2j(-/-) and Cyp2j(+/+) mice of either gender. Exposure to chronic hypoxia decreased PAT and increased RV wall thickness in both genotypes and genders to a similar extent. Prolonged exposure to hypoxia produced similar levels of RV hypertrophy in both genotypes of either gender. Pulmonary Cyp2c29, Cyp2c38, and sEH mRNA levels did not differ between Cyp2j(-/-) and Cyp2j(+/+) male mice after breathing at normoxia or hypoxia for 6 weeks. These results suggest that murine Cyp2j deficiency does not attenuate the development of murine pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia in mice of both genders.

One year follow-up of a pragmatic multi-centre randomised controlled trial of a group-based fatigue management programme (FACETS) for people with multiple sclerosis.

BACKGROUND: Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS). The aim was to evaluate the effectiveness at 1-year follow-up of a manualised group-based programme ('FACETS') for managing MS-fatigue. METHODS: One-year follow-up of a pragmatic multi-centre randomised controlled trial. People with MS and significant fatigue were randomised to FACETS plus current local practice (FACETS) or current local practice alone (CLP), using concealed computer-generated randomisation. Participant blinding was not possible. Primary outcome measures were fatigue severity (Global Fatigue Severity subscale of the Fatigue Assessment Instrument), self-efficacy (MS-Fatigue Self-Efficacy) and disease-specific quality of life (MS Impact Scale). RESULTS: Between May 2008 and November 2009, 164 participants were randomised. Primary outcome data were available at 1 year for 131 (80%). The benefits demonstrated at 4-months in the FACETS arm for fatigue severity and self-efficacy largely persisted, with a slight reduction in standardised effect sizes (SES) (-0.29, p = 0.06 and 0.34, p = 0.09, respectively). There was a significant difference on the MS Impact Scale favouring FACETS that had not been present at 4-months (SES -0.24, p = 0.046). No adverse events were reported. CONCLUSIONS: Improvements in fatigue severity and self-efficacy at 4-months follow-up following attendance of FACETS were mostly sustained at 1 year with additional improvements in MS impact. The FACETS programme provides modest long-term benefits to people with MS-fatigue. TRIAL REGISTRATION: ISRCTN76517470.

Two-photon-induced fluorescence of isomorphic nucleobase analogs.

Five isomorphic fluorescent uridine mimics have been subjected to two-photon (2P) excitation analysis to investigate their potential applicability as non-perturbing probes for the single-molecule detection of nucleic acids. We find that small structural differences can cause major changes in the 2P excitation probability, with the 2P cross sections varying by over one order of magnitude. Two of the probes, both thiophene-modified uridine analogs, have the highest 2P cross sections (3.8 GM and 7.6 GM) reported for nucleobase analogs, using a conventional Ti:sapphire laser for excitation at 690 nm; they also have the lowest emission quantum yields. In contrast, the analogs with the highest reported quantum yields have the lowest 2P cross sections. The structure-photophysical property relationship presented here is a first step towards the rational design of emissive nucleobase analogs with controlled 2P characteristics. The results demonstrate the potential for major improvements through judicious structural modifications.

Imaging circulating monocytic cells fusing to endothelial cells in acutely injured and regenerating capillaries.

The present studies focus on monocytic circulating cells (CCs) interacting with the endothelial cells of pulmonary capillaries in acute lung injury. The CCs are further defined into sub-sets based on their structural profiles, i.e. CC(1-3). They are shown to move into close apposition to adjacent capillary endothelium and to fuse to endothelial plasmalemmal membranes. Similarly, CCs are seen to fuse to the endothelial cells of regenerating capillaries after injury. Immunogold labeling studies demonstrate that CCs express a mediator promoting endothelial cell migration, proliferation and stability, i.e. VEGF, further supporting the potential of a paracrine interaction between the fusing cells, while the expression of CXCR4 by CCs, and of SDF-1α by adjacent endothelial cells, demonstrates a mechanism for retention of these cells at the capillary surface. Myeloid VEGF-R2(+)CD11b(+) precursors and PDGF-Rß(+) expressing cells are identified within the CC population. The findings establish that, by fusing to endothelial cells, the monocytic CC population studied has the potential to promote capillary surface stability/integrity through a paracrine mechanism.

Multiple wall in-folds sub-divide single segments during capillary regression in hyperoxic acute lung injury.

The present study provides further insight into the structural processes that remodel pulmonary capillaries in the injured adult lung. Early in hyperoxia acute lung injury (HALI), many sub-dividing segments are present throughout the capillary network before segment occlusion and loss predominate and capillary density decreases later in the period. A second segment sub-division triggered in regenerating capillaries after air breathing (post-HALI) demonstrates a similar mechanism of organization at a time of contrasting change in the capillary density. As we have previously reported, the process of segment sub-division includes in-folding of the endothelial-epithelial surface (alveolar-capillary membrane) to form inter-luminal structures (ILSs) and loops, with loop separation increasing segment number. Unexpectedly, the findings support remodeling of the capillary density by wall in-folding in acute lung injury, demonstrating a similar mechanism in capillary regression as well as in regeneration in the adult lung.

Mechanisms of growth of a pulmonary capillary network in adult lung.

The present study provides new insight into structural processes remodeling pulmonary capillaries in adult lung. The data highlight mechanisms underlying the expansion and increased density of capillary segments on return to air breathing (FiO2 0.21) after injury in high oxygen (FiO2 0.75). As segments expand and increase in number, endothelial cells extend their processes to bridge the lumen and support the walls of developing interluminal structures (ILSs); endothelial-epithelial surfaces infold as a single unit (sheet) into the lumen, increasing the length of each surface and subdividing segments by loop formation and by the formation of ILSs; segments further increase in number as lumen subdivision proceeds by intussusceptive microvascular growth (IMG).

Alveolar oxygen tension and angio-architecture of the distal adult lung.

The present study demonstrates the fine structure of pulmonary capillaries first injured and then undergoing growth in response to a change in the ambient alveolar oxygen tension. Breathing a high fraction of inspired oxygen (FiO2 0.75) triggers restriction by endothelial cell injury and effacement leading to segment narrowing and shortening and segment loss as demonstrated by a fall in density. Subsequently, breathing a relatively low fraction (FiO2 0.21) triggers capillary assembly (angiogenesis), which reverses the changes. The data underscore the structural reprogramming (reduction and restoration) of pulmonary capillaries in response to significant shifts in oxygen tension.

A pragmatic parallel arm multi-centre randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based fatigue management programme (FACETS) for people with multiple sclerosis.

BACKGROUND: Fatigue is a common and troubling symptom for people with multiple sclerosis (MS). AIM: To evaluate the effectiveness and cost-effectiveness of a six-session group-based programme for managing MS-fatigue (Fatigue: Applying Cognitive behavioural and Energy effectiveness Techniques to lifeStyle (FACETS)). METHODS: Three-centre parallel arm randomised controlled trial with economic evaluation. Patients with MS and significant fatigue were randomised to FACETS plus current local practice (FACETS) or current local practice alone (CLP), using concealed computer-generated randomisation. Participant blinding was not possible. Primary outcomes were fatigue severity (Fatigue Assessment Instrument), self-efficacy (Multiple Sclerosis-Fatigue Self-Efficacy) and disease-specific quality of life (Multiple Sclerosis Impact Scale (MSIS-29)) at 1 and 4 months postintervention (follow-up 1 and 2). Quality adjusted life years (QALYs) were calculated (EuroQoL 5-Dimensions questionnaire and the Short-form 6-Dimensions questionnaire). RESULTS: Between May 2008 and November 2009, 164 patients were randomised; primary outcome data were available for 146 (89%). Statistically significant differences favour the intervention group on fatigue self-efficacy at follow-up 1 (mean difference (MD) 9, 95% CI (4 to 14), standardised effect size (SES) 0.54, p=0.001) and follow-up 2 (MD 6, 95% CI (0 to 12), SES 0.36, p=0.05) and fatigue severity at follow-up 2 (MD -0.36, 95% CI (-0.63 to -0.08), SES -0.35, p=0.01) but no differences for MSIS-29 or QALYs. No adverse events reported. Estimated cost per person for FACETS is £453; findings suggest an incremental cost-effectiveness ratio of £2157 per additional person with a clinically significant improvement in fatigue. CONCLUSIONS: FACETS is effective in reducing fatigue severity and increasing fatigue self-efficacy. However, it is difficult to assess the additional cost in terms of cost-effectiveness (ie, cost per QALY) as improvements in fatigue are not reflected in the QALY outcomes, with no significant differences between FACETS and CLP. The strengths of this trial are its pragmatic nature and high external validity. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76517470.

A quantitative ultrastructural study of circulating (monocytic) cells interacting with endothelial cells in high oxygen-injured and spontaneously re-forming (FVB) mouse lung capillaries.

The present study demonstrates the fine structure of blood-borne (monocytic) circulating cells (CCs), and their interaction with endothelial cells, in a mouse model of lung capillary injury and repair. Quantitative analysis highlights the diversity of CC profiles entering the lung, where they form contact and adhesion/fusion sites to endothelial plasmalemmal membranes, and to complexes of endothelial/basement membrane remnants, as capillary networks reorganize over time. Temporal patterns of CC influx and efflux in the lung, changing CC phenotypes, and the range of CC interactions with endothelium, underscore the potential for a complex angiogenic/immunogenic response, as capillary networks stabilize and undergo expansion and growth.

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis.

BACKGROUND: Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. METHODS/DESIGN: This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. DISCUSSION: This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76517470.

VEGFR2+PDGFRbeta+ circulating precursor cells participate in capillary restoration after hyperoxia acute lung injury (HALI).

The in vivo morphology and phenotype of circulating cells that spontaneously contribute to new vessel formation in adults remain unclear. Here, we use high-resolution imaging and flow cytometry to characterize the morphology and phenotype of a distinct population of circulating mononuclear cells contributing to spontaneous new vessel formation after hyperoxia acute lung injury (HALI). We identify a subpopulation of myeloid (CD11b/Mac1(+)) haematopoietic cells co-expressing vascular endothelial growth factor receptor 2 (VEGFR2) and platelet derived growth factor receptor beta (PDGFRbeta). Moreover, we show that these CD11b(+)VEGFR2(+)PDGFRbeta(+) circulating precursor cells (CPCs) contribute structurally to the luminal surface of capillaries re-forming 2 weeks post-HALI. This indicates that these myeloid CPCs may function, at least transiently, as putative vascular precursors, and has important implications for capillary growth and repair in injury and in pathologies of the lung and other organs.