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Understanding what matters to people with Parkinson’s and their family is essential to derive relevant clinical outcome measures and guide clinical care. The purpose of this study was to explore what is important to people with Parkinson’s disease vs. family over time. A qualitative content-analysis of online survey data collected by Parkinson’s UK was conducted to identify types and frequencies of important symptoms and impacts of Parkinson’s for people with the disease vs. family of people with Parkinson’s. Independent T-tests were used to identify significance of between group differences for patients vs. family at < 2, 2–5, 6–10, 11–20, > 20-year durations. ANOVA was used to assess for within group differences by disease duration. We found that symptom priority changed significantly over time with longer disease duration. Tremor was reported less often later on, whereas mobility, dyskinesias, gait and speech/communication symptoms gained priority. In general, patients identified movement-related symptoms (e.g., walking, bradykinesia) as the most bothersome at all durations while family more strongly prioritized the physical and psychosocial impacts of disease (e.g., mobility, safety, interpersonal interactions, independence, and family impact). We conclude that important differences exist between family and patient perspectives of what matters and change over time with longer duration of disease.

Participants in clinical trials should be pro-actively offered the results of trials in which they have participated. This should be done in a way that is accessible and understandable for all participants. People who have taken part in research have a right to know the results of the studies in which they have taken part and should be given the option of receiving these results. Most trial participants want to receive the overall results. Key reasons for sharing results include respecting participants’ contributions, enhancing their understanding of research benefits, increasing transparency, and potentially improving recruitment and retention. We propose 8 principles to guide sharing of results with trial participants: 1. Trial teams should pro-actively offer overall study results to all clinical trial participants, irrespective of what the results show. 2. Participants should be given the choice of whether to receive research results. 3. Results should be offered to participants in a timely manner. 4. Trial teams should manage participants’ expectations around when the results will be available. 5. Results should be offered in a way that is accessible to participants, both in terms of the communication mechanism and the content. 6. Patient and public involvement is essential in sharing results with participants. 7. Sharing results with participants requires resources. 8. Consideration needs to be given to potential barriers/challenges to sharing results with participants from the planning stage of the study.

A comprehensive, patient-centered conceptual model of early Parkinson’s is lacking and is greatly needed. A systematic review and meta-synthesis of qualitative and quantitative research was conducted by a multi-stakeholder taskforce using JBI Mixed Methods Review criteria and GRADE-CERQual standards for assessment of evidence. Over 340 symptoms and impacts were identified across ten symptom domains (Movement, Cognitive, Psychiatric, Sleep, Sensory, Speech, Digestive, Urinary, Sexual, Autonomic) and two impact domains (Physical and Psychosocial functioning). A wide range of motor and non-motor symptoms were present in early disease, with strongest support for tremor, dexterity, gait, stiffness, slow movements, cognitive, mood, and sleep alterations, urinary dysfunction, constipation, pain, and fatigue. These affected mobility, self-concept, coping, effort of living, interactions and important activities, with evidence of many understudied concepts. This model offers the most comprehensive catalogue of symptoms and impacts in Parkinson’s to date and will support clinical practice and endpoint selection for therapeutic trials.

Objective In an era where digital devices become increasingly available, passive and active capturing of patient data during their everyday life becomes possible. However, it is still unclear to what extent people with chronic diseases are willing to use digital health technology (DHT) to assess study-relevant endpoints. The aim of the present study was therefore to determine such acceptance rates for clinical studies and which type of DHT patients prefer. Methods A survey with 492 people with Parkinson's disease (64 ± 11 years, 41% female) and 75 people with an immune-mediated inflammatory disease (58 ± 15 years, 99% female) was conducted. Results The vast majority of people (93%) were willing to use at least two devices simultaneously during a clinical study. Two-thirds indicated that they would use DHT for ≥6 days following a visit in the context of a study. The appearance of the device turned out to be important as the most popular devices were smartwatches, whereas more complex DHT, clearly recognisable as medical-grade were least popular. The effects of gender, age and disease could be detected, such as, for example, a tendency for men to be willing to use more devices simultaneously than women. Conclusion Overall, our findings suggest a willingness among individuals with Parkinson's disease and immune-mediated inflammatory disease to engage in clinical studies involving DHT. It is also evident that elderly patients can be integrated into these studies provided that the participation demands are aligned with clinical imperatives and the devices are user friendly.

Although the impacts of surface water acidification on Atlantic salmon (Salmo salar L.) and brown trout (Salmo trutta L.) are well described, factors affecting recovery following pollution abatement are poorly understood. Paradoxically, despite increasing average pH over the last two decades, stocking efforts to rehabilitate damaged populations have not been successful. One possible explanation is that average pH measurements mask the effects of episodic fluctuations during high flow when pH is transiently reduced, metal concentrations are elevated and some organisms are affected adversely. However, because salmonid fish (i) avoid acid water and (ii) shelter within stream bed interstices, assessing the effects of acid episodes on their populations requires some understanding of how refuge use, refuge availability and refuge conditions affect recolonisation opportunities. This project therefore examined the effects of acid episodes on the behaviour of Atlantic salmon at different life stages as a possible explanation for the limited recovery of re-stocked populations. Sampling in acid sensitive-streams at low and high (episodic) flow revealed that the stream hyporheos was less acid than surface water in the same streams, with temperature and conductivity also more favourable in interstices. Laboratory experiments were then used to examine (i) the behaviour of Atlantic salmon alevins during a simulated episode in a vertical substrate-filled tank (Chapter 3) (ii) the behaviour of Atlantic salmon parr during a simulated episode in a shelter choice tank (Chapter 4) and (iii) if differences resulting from rearing environment affected the behaviour of Atlantic salmon parr during a simulated acid episode (Chapter 5). Hatchery-reared alevins avoided episodically acid conditions by moving into an area of more neutral pH opercular rate and mortality were both greater in acid water. Hatchery-reared pan- preferentially used a neutral shelter acid exposure also resulted in increased activity and opercular rate. Fish reared in a simulated wild environment were better able to avoid acid pulses (i.e. they showed greater use of neutral refuges) than hatchery-reared fish, but other behavioural responses (activity and opercular rate) were similar. These results illustrate the potential importance of the streambed during acid episodes as chemical refuges to salmonids, which both alevins and parr are able to exploit. However, at least for hatchery-reared fish, the success of re-stocking programmes could be improved by subjecting fish to acid stress- conditioning regimes prior to release.

In April 2015, Public Health England implemented whole genome sequencing (WGS) as a routine typing tool for public health surveillance of Salmonella , adopting a multilocus sequence typing (MLST) approach as a replacement for traditional serotyping. The WGS derived sequence type (ST) was compared to the phenotypic serotype for 6,887 isolates of S. enterica subspecies I, and of these, 6,616 (96%) were concordant. Of the 4% ( n = 271) of isolates of subspecies I exhibiting a mismatch, 119 were due to a process error in the laboratory, 26 were likely caused by the serotype designation in the MLST database being incorrect and 126 occurred when two different serovars belonged to the same ST. The population structure of S. enterica subspecies II–IV differs markedly from that of subspecies I and, based on current data, defining the serovar from the clonal complex may be less appropriate for the classification of this group. Novel sequence types that were not present in the MLST database were identified in 8.6% of the total number of samples tested (including S. enterica subspecies I–IV and S. bongori ) and these 654 isolates belonged to 326 novel STs. For S. enterica subspecies I, WGS MLST derived serotyping is a high throughput, accurate, robust, reliable typing method, well suited to routine public health surveillance. The combined output of ST and serovar supports the maintenance of traditional serovar nomenclature while providing additional insight on the true phylogenetic relationship between isolates.

Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. Here, we find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causing degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Thus, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.

The West Antarctic Ice Sheet (WAIS) is one of the largest potential sources of future sea-level rise, with glaciers draining the WAIS thinning at an accelerating rate over the past 40 years. Due to complexities in calibrating palaeoceanographic proxies for the Southern Ocean, it remains difficult to assess whether similar changes have occurred earlier during the Holocene or whether there is underlying centennial- to millennial-scale forcing in oceanic variability. Archaeal lipid-based proxies, specifically glycerol dialkyl glycerol tetraether (GDGT; e.g. TEX86 and TEX86L), are powerful tools for reconstructing ocean temperature, but these proxies have been shown previously to be difficult to apply to the Southern Ocean. A greater understanding of the parameters that control Southern Ocean GDGT distributions would improve the application of these biomarker proxies and thus help provide a longer-term perspective on ocean forcing of Antarctic ice sheet changes. In this study, we characterised intact polar lipid (IPL)-GDGTs, representing (recently) living archaeal populations in suspended particulate matter (SPM) from the Amundsen Sea and the Scotia Sea. SPM samples from the Amundsen Sea were collected from up to four water column depths representing the surface waters through to Circumpolar Deep Water (CDW), whereas the Scotia Sea samples were collected along a transect encompassing the sub-Antarctic front through to the southern boundary of the Antarctic Circumpolar Current. IPL-GDGTs with low cyclic diversity were detected throughout the water column with high relative abundances of hydroxylated IPL-GDGTs identified in both the Amundsen and Scotia seas. Results from the Scotia Sea show shifts in IPL-GDGT signatures across well-defined fronts of the Southern Ocean. Indicating that the physicochemical parameters of these water masses determine changes in IPL-GDGT distributions. The Amundsen Sea results identified GDGTs with hexose-phosphohexose head groups in the CDW, suggesting active GDGT synthesis at these depths. These results suggest that GDGTs synthesised at CDW depths may be a significant source of GDGTs exported to the sedimentary record and that temperature reconstructions based on TEX86 or TEX86L proxies may be significantly influenced by the warmer waters of the CDW.

ObjectiveTo investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness.DesignPhase 3b multicentre, double-blind, randomised placebo-controlled trial.SettingTwenty-one hospitals in the UK.ParticipantsChildren aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308.InterventionTwo doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment.Main outcome measureThe primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended.Secondary outcome measuresThe secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data.Results18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG.ConclusionsThe IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis.Trial registration numberClinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

Healthy lifestyle interventions have a positive impact on multiple disease trajectories, including cancer-related outcomes. Specifically, appropriate habitual physical activity, adequate sleep, and a regular wholesome diet are of paramount importance for the wellness and supportive care of survivors of cancer. Mobile health (mHealth) apps have the potential to support novel tailored lifestyle interventions. This observational pilot study aims to assess the feasibility of mHealth multidimensional longitudinal monitoring in survivors of cancer. The primary objective is to test the compliance (user engagement) with the monitoring solution. Secondary objectives include recording clinically relevant subjective and objective measures collected through the digital solution. This is a monocentric pilot study taking place in Bangor, Wales, United Kingdom. We plan to enroll up to 100 adult survivors of cancer not receiving toxic anticancer treatment, who will provide self-reported behavioral data recorded via a dedicated app and validated questionnaires and objective data automatically collected by a paired smartwatch over 16 weeks. The participants will continue with their normal routine surveillance care for their cancer. The primary end point is feasibility (eg, mHealth monitoring acceptability). Composite secondary end points include clinically relevant patient-reported outcome measures (eg, the Edmonton Symptom Assessment System score) and objective physiological measures (eg, step counts). This trial received a favorable ethical review in May 2023 (Integrated Research Application System 301068). This study is part of an array of pilots within a European Union funded project, entitled \"GATEKEEPER,\" conducted at different sites across Europe and covering various chronic diseases. Study accrual is anticipated to commence in January 2024 and continue until June 2024. It is hypothesized that mHealth monitoring will be feasible in survivors of cancer; specifically, at least 50% (50/100) of the participants will engage with the app at least once a week in 8 of the 16 study weeks. In a population with potentially complex clinical needs, this pilot study will test the feasibility of multidimensional remote monitoring of patient-reported outcomes and physiological parameters. Satisfactory compliance with the use of the app and smartwatch, whether confirmed or infirmed through this study, will be propaedeutic to the development of innovative mHealth interventions in survivors of cancer. PRR1-10.2196/52957.