The usability of daytime and night-time heart rate dynamics as digital biomarkers of depression severity.

BACKGROUND: Alterations in heart rate (HR) may provide new information about physiological signatures of depression severity. This 2-year study in individuals with a history of recurrent major depressive disorder (MDD) explored the intra-individual variations in HR parameters and their relationship with depression severity. METHODS: Data from 510 participants (Number of observations of the HR parameters = 6666) were collected from three centres in the Netherlands, Spain, and the UK, as a part of the remote assessment of disease and relapse-MDD study. We analysed the relationship between depression severity, assessed every 2 weeks with the Patient Health Questionnaire-8, with HR parameters in the week before the assessment, such as HR features during all day, resting periods during the day and at night, and activity periods during the day evaluated with a wrist-worn Fitbit device. Linear mixed models were used with random intercepts for participants and countries. Covariates included in the models were age, sex, BMI, smoking and alcohol consumption, antidepressant use and co-morbidities with other medical health conditions. RESULTS: Decreases in HR variation during resting periods during the day were related with an increased severity of depression both in univariate and multivariate analyses. Mean HR during resting at night was higher in participants with more severe depressive symptoms. CONCLUSIONS: Our findings demonstrate that alterations in resting HR during all day and night are associated with depression severity. These findings may provide an early warning of worsening depression symptoms which could allow clinicians to take responsive treatment measures promptly.

Obesity during the COVID-19 pandemic: both cause of high risk and potential effect of lockdown? A population-based electronic health record study.

OBJECTIVES: Obesity is a modifiable risk factor for coronavirus disease 2019 (COVID-19)-related mortality. We estimated excess mortality in obesity, both 'direct', through infection, and 'indirect', through changes in health care, and also due to potential increasing obesity during lockdown. STUDY DESIGN: The study design of this study is a retrospective cohort study and causal inference methods. METHODS: In population-based electronic health records for 1,958,638 individuals in England, we estimated 1-year mortality risk ('direct' and 'indirect' effects) for obese individuals, incorporating (i) pre-COVID-19 risk by age, sex and comorbidities, (ii) population infection rate and (iii) relative impact on mortality (relative risk [RR]: 1.2, 1.5, 2.0 and 3.0). Using causal inference models, we estimated impact of change in body mass index (BMI) and physical activity during 3-month lockdown on 1-year incidence for high-risk conditions (cardiovascular diseases, diabetes, chronic obstructive pulmonary disease and chronic kidney disease), accounting for confounders. RESULTS: For severely obese individuals (3.5% at baseline), at 10% population infection rate, we estimated direct impact of 240 and 479 excess deaths in England at RR 1.5 and 2.0, respectively, and indirect effect of 383-767 excess deaths, assuming 40% and 80% will be affected at RR = 1.2. Owing to BMI change during the lockdown, we estimated that 97,755 (5.4%: normal weight to overweight, 5.0%: overweight to obese and 1.3%: obese to severely obese) to 434,104 individuals (15%: normal weight to overweight, 15%: overweight to obese and 6%: obese to severely obese) would be at higher risk for COVID-19 over one year. CONCLUSIONS: Prevention of obesity and promotion of physical activity are at least as important as physical isolation of severely obese individuals during the pandemic.

Long-term follow-up of a randomized controlled trial of a text-message diabetes self-management support programme, SMS4BG.

AIMS: To determine the long-term effectiveness of an individually tailored text-message diabetes self-management support programme, SMS4BG, on glycaemic control at 2 years in adults with diabetes with an HbA1c concentration > 64 mmol/mol (8%). METHODS: We conducted a 2-year follow-up of a two-arm, parallel, randomized controlled trial across health services in New Zealand. Participants were English-speaking adults with type 1 or 2 diabetes and with an HbA1c >64 mmol/mol (8%). In the main trial participants randomized to the intervention group (N=183) received up to 9 months of an automated tailored text-message programme in addition to usual care. Participants in the control group (N=183) received usual care for 9 months. In this follow-up study, 293 (80%) of 366 randomized participants in the main trial were included. The primary outcome measure was change in glycaemic control (HbA1c ) from baseline to 2 years. Mixed-effect models were used to compare the group differences at 3, 6, 9 and 24 months, adjusted for baseline HbA1c and stratification factors (health district category, diabetes type and ethnicity). RESULTS: The decrease in HbA1c at 2 years was significantly greater in the intervention group [mean (sd) -10 (18) mmol/mol or -0.9 (1.6)%] compared with the control group [mean (sd) -1 (20) mmol/mol or -0.1 (1.8)%], with an adjusted mean difference of -9 mmol/mol (95% CI -14, -5) or -0.8% (95% CI -1.2, -0.4; P<0.0001). CONCLUSIONS: Improvements in glycaemic control resulting from a text-message diabetes self-management support programme were sustained at 2 years after randomization. These findings support the implementation of SMS4BG in current practice.

DNAscan: personal computer compatible NGS analysis, annotation and visualisation.

BACKGROUND: Next Generation Sequencing (NGS) is a commonly used technology for studying the genetic basis of biological processes and it underpins the aspirations of precision medicine. However, there are significant challenges when dealing with NGS data. Firstly, a huge number of bioinformatics tools for a wide range of uses exist, therefore it is challenging to design an analysis pipeline. Secondly, NGS analysis is computationally intensive, requiring expensive infrastructure, and many medical and research centres do not have adequate high performance computing facilities and cloud computing is not always an option due to privacy and ownership issues. Finally, the interpretation of the results is not trivial and most available pipelines lack the utilities to favour this crucial step. RESULTS: We have therefore developed a fast and efficient bioinformatics pipeline that allows for the analysis of DNA sequencing data, while requiring little computational effort and memory usage. DNAscan can analyse a whole exome sequencing sample in 1 h and a 40x whole genome sequencing sample in 13 h, on a midrange computer. The pipeline can look for single nucleotide variants, small indels, structural variants, repeat expansions and viral genetic material (or any other organism). Its results are annotated using a customisable variety of databases and are available for an on-the-fly visualisation with a local deployment of the gene.iobio platform. DNAscan is implemented in Python. Its code and documentation are available on GitHub: https://github.com/KHP-Informatics/DNAscan . Instructions for an easy and fast deployment with Docker and Singularity are also provided on GitHub. CONCLUSIONS: DNAscan is an extremely fast and computationally efficient pipeline for analysis, visualization and interpretation of NGS data. It is designed to provide a powerful and easy-to-use tool for applications in biomedical research and diagnostic medicine, at minimal computational cost. Its comprehensive approach will maximise the potential audience of users, bringing such analyses within the reach of non-specialist laboratories, and those from centres with limited funding available.

Multiple sclerosis - a review.

Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene-environment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein-Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of 'pre-symptomatic MS' being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.

Remote assessment of disease and relapse in major depressive disorder (RADAR-MDD): a multi-centre prospective cohort study protocol.

BACKGROUND: There is a growing body of literature highlighting the role that wearable and mobile remote measurement technology (RMT) can play in measuring symptoms of major depressive disorder (MDD). Outcomes assessment typically relies on self-report, which can be biased by dysfunctional perceptions and current symptom severity. Predictors of depressive relapse include disrupted sleep, reduced sociability, physical activity, changes in mood, prosody and cognitive function, which are all amenable to measurement via RMT. This study aims to: 1) determine the usability, feasibility and acceptability of RMT; 2) improve and refine clinical outcome measurement using RMT to identify current clinical state; 3) determine whether RMT can provide information predictive of depressive relapse and other critical outcomes. METHODS: RADAR-MDD is a multi-site prospective cohort study, aiming to recruit 600 participants with a history of depressive disorder across three sites: London, Amsterdam and Barcelona. Participants will be asked to wear a wrist-worn activity tracker and download several apps onto their smartphones. These apps will be used to either collect data passively from existing smartphone sensors, or to deliver questionnaires, cognitive tasks, and speech assessments. The wearable device, smartphone sensors and questionnaires will collect data for up to 2-years about participants' sleep, physical activity, stress, mood, sociability, speech patterns, and cognitive function. The primary outcome of interest is MDD relapse, defined via the Inventory of Depressive Symptomatology- Self-Report questionnaire (IDS-SR) and the World Health Organisation's self-reported Composite International Diagnostic Interview (CIDI-SF). DISCUSSION: This study aims to provide insight into the early predictors of major depressive relapse, measured unobtrusively via RMT. If found to be acceptable to patients and other key stakeholders and able to provide clinically useful information predictive of future deterioration, RMT has potential to change the way in which depression and other long-term conditions are measured and managed.

Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity.

BACKGROUND: The term 'metabolically healthy obese (MHO)' is distinguished using body mass index (BMI), yet BMI is a poor index of adiposity. Some epidemiological data suggest that MHO carries a lower risk of cardiovascular disease (CVD) or mortality than being normal weight yet metabolically unhealthy. OBJECTIVES: We aimed to undertake a detailed phenotyping of individuals with MHO by using imaging techniques to examine ectopic fat (visceral and liver fat deposition) and myocardial function. We hypothesised that metabolically unhealthy individuals (irrespective of BMI) would have adverse levels of ectopic fat and myocardial dysfunction compared with MHO individuals. SUBJECTS: Individuals were categorised as non-obese or obese (BMI ⩾30 kg m(-2)) and as metabolically healthy or unhealthy according to the presence or absence of metabolic syndrome. METHODS: Sixty-seven individuals (mean±s.d.: age 49±11 years) underwent measurement of (i) visceral, subcutaneous and liver fat using magnetic resonance imaging and proton magnetic resonance spectroscopy, (ii) components of metabolic syndrome, (iii) cardiorespiratory fitness and (iv) indices of systolic and diastolic function using tissue Doppler echocardiography. RESULTS: Cardiorespiratory fitness was similar between all groups; abdominal and visceral fat was highest in the obese groups. Compared with age- and BMI-matched metabolically healthy counterparts, the unhealthy (lean or obese) individuals had higher liver fat and decreased early diastolic strain rate, early diastolic tissue velocity and systolic strain indicative of subclinical systolic and diastolic dysfunction. The magnitude of dysfunction correlated with the number of components of metabolic syndrome but not with BMI or with the degree of ectopic (visceral or liver) fat deposition. CONCLUSIONS: Myocardial dysfunction appears to be related to poor metabolic health rather than simply BMI or fat mass. These data may partly explain the epidemiological evidence on CVD risk relating to the different obesity phenotypes.

Risk Factors, Epidemiology and Treatment Strategies for Metabolic Bone Disease in Patients with Neurological Disease.

Metabolic bone disease is a major public health concern, especially when it manifests as hip fracture which carries significant morbidity and mortality. Individuals with neurological disease are at higher risk of osteopenia, osteoporosis and fragility fracture compared to age-matched controls, yet this is under-appreciated by these patients. Clinician attention to this topic is therefore of importance and should address the bone health of men as well as women, a group in whom it may be an under-recognised problem. Evidence for optimal management of bone health in neurological disease remains to be defined, but a growing literature provides some useful guidance. This review focuses on two conditions, multiple sclerosis and Parkinson's disease, where research has been active over recent years. In neuroinflammation, shared immunological pathways between bone and brain are a current domain of interest and it will be intriguing to interrogate the action of emerging immunotherapies on these dual compartments.

Atraumatic needles for lumbar puncture: why haven't neurologists changed?

Diagnostic lumbar puncture is a key procedure in neurology; however, it is commonly complicated by post-lumbar puncture headache. Atraumatic needle systems can dramatically reduce the incidence of this iatrogenic complication. However, only a minority of neurologists use such needles. In this paper, we discuss possible reasons why neurologists have not switched to new technology, looking more at diffusion of innovation rather than lack of evidence. We suggest ways to overcome this failure to adopt change, ranging from local interventions to patient empowerment.

Clusterin regulates ß-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.

Although the mechanism of Aß action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aß neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aß/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aß toxicity and DKK1 upregulation and, conversely, Aß increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aß mediates neurotoxicity, we measured the effects of Aß and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aß neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aß-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aß-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aß induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aß in neurodegenerative diseases.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study.

BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality.

BACKGROUND: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. METHODS: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. RESULTS: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l(-1) increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l(-1) increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. CONCLUSIONS: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.

Change practice now! Using atraumatic needles to prevent post lumbar puncture headache.

BACKGROUND AND PURPOSE: Lumbar puncture (LP) is a key diagnostic procedure in medicine. Post lumbar puncture headache (PLPHA) is a well recognized complication of LP. Evidence suggests that using atraumatic needles for diagnostic LP (ATNLP) reduces risk of PLPHA. However, clinicians in Europe and the USA routinely use traumatic needles for diagnostic LP (TNLP). The occurrence of PLPHA following ATNLP and TNLP was compared in a clinical setting. Further, a survey was performed exploring use of ATNLP amongst UK neurologists. METHODS: Service development study. Patients were followed up 2 and 7 days after LP using blinded telephone assessment. A questionnaire was developed to assess use of ATNLP amongst UK neurologists. Frequency, onset, duration and severity of PLPHA were recorded as were use of analgesia, general practitioner consultations, hospital readmissions, days off work due to PLPHA and cost. Neurologists were asked about their familiarity with, and use of, ATNLP. RESULTS: One hundred and nine participants attending the Royal London Hospital were included, and 74 attendees of the Association of British Neurologists 2012 conference completed an on-site questionnaire. ATNLP reduced the rate of PLPHA (27.1% vs. 60.4%; P < 0.01). In those participants who developed PLPHA symptoms were short lived (mean 50 h vs. 94 h, P = 0.02) and less severe after ATNLP. Use of ATNLP led to significant cost savings. Only one in five UK neurologists regularly use ATNLP stating lack of training and availability of atraumatic needles as main reasons. CONCLUSIONS: ATNLP significantly reduces the risk of PLPHA. Training is required 3 to facilitate a change from TNLP to ATNLP amongst clinicians.

Household carbon monoxide (CO) concentrations in a large African city: An unquantified public health burden?

Carbon monoxide (CO) is a poisonous gas produced by incomplete combustion of carbon-based fuels that is linked to mortality and morbidity. Household air pollution from burning fuels on poorly ventilated stoves can lead to high concentrations of CO in homes. There are few datasets available on household concentrations of CO in urban areas of sub-Saharan African countries. CO was measured every minute over 24 h in a sample of homes in Nairobi, Kenya. Data on household characteristics were gathered by questionnaire. Metrics of exposure were summarised and analysis of temporal changes in concentration was performed. Continuous 24-h data were available from 138 homes. The mean (SD), median (IQR) and maximum 24-h CO concentration was 4.9 (6.4), 2.8 (1.0-6.3) and 44 ppm, respectively. 50% of homes had detectable CO concentrations for 847 min (14h07m) or longer during the 24-h period, and 9% of homes would have activated a CO-alarm operating to European specifications. An association between a metric of total CO exposure and self-reported exposure to vapours >15 h per week was identified, however this were not statistically significant after adjustment for the multiple comparisons performed. Mean concentrations were broadly similar in homes from a more affluent area and an informal settlement. A model of typical exposure suggests that cooking is likely to be responsible for approximately 60% of the CO exposure of Nairobi schoolchildren. Household CO concentrations are substantial in Nairobi, Kenya, despite most homes using gas or liquid fuels. Concentrations tend to be highest during the evening, probably associated with periods of cooking. Household air pollution from cooking is the main source of CO exposure of Nairobi schoolchildren. The public health impacts of long-term CO exposure in cities in sub-Saharan Africa may be considerable and should be studied further.

Structural and dynamic requirements for optimal activity of the essential bacterial enzyme dihydrodipicolinate synthase.

Dihydrodipicolinate synthase (DHDPS) is an essential enzyme involved in the lysine biosynthesis pathway. DHDPS from E. coli is a homotetramer consisting of a 'dimer of dimers', with the catalytic residues found at the tight-dimer interface. Crystallographic and biophysical evidence suggest that the dimers associate to stabilise the active site configuration, and mutation of a central dimer-dimer interface residue destabilises the tetramer, thus increasing the flexibility and reducing catalytic efficiency and substrate specificity. This has led to the hypothesis that the tetramer evolved to optimise the dynamics within the tight-dimer. In order to gain insights into DHDPS flexibility and its relationship to quaternary structure and function, we performed comparative Molecular Dynamics simulation studies of native tetrameric and dimeric forms of DHDPS from E. coli and also the native dimeric form from methicillin-resistant Staphylococcus aureus (MRSA). These reveal a striking contrast between the dynamics of tetrameric and dimeric forms. Whereas the E. coli DHDPS tetramer is relatively rigid, both the E. coli and MRSA DHDPS dimers display high flexibility, resulting in monomer reorientation within the dimer and increased flexibility at the tight-dimer interface. The mutant E. coli DHDPS dimer exhibits disorder within its active site with deformation of critical catalytic residues and removal of key hydrogen bonds that render it inactive, whereas the similarly flexible MRSA DHDPS dimer maintains its catalytic geometry and is thus fully functional. Our data support the hypothesis that in both bacterial species optimal activity is achieved by fine tuning protein dynamics in different ways: E. coli DHDPS buttresses together two dimers, whereas MRSA dampens the motion using an extended tight-dimer interface.

Cerebrospinal fluid and urinary biomarkers in multiple sclerosis.

OBJECTIVES: Biomarkers with the potential for longitudinal measurements are needed in multiple sclerosis (MS). Urine is easy to collect, and repeated sampling is possible. METHODS: 39 paired CSF and urine samples were taken. Oligoclonal bands (OCBs) were measured in CSF. Kappa and lambda free light chain (FLC), neopterin and ubiquitin C-terminal hydrolase-L1 (UCHL1) were measured in CSF and urine. RESULTS: 16/39 samples had OCBs unique to the CSF. CSF FLC levels (P < 0.0001) were higher in OCB-positive subjects, with no difference in urinary FLC. CSF and urinary FLC did not correlate. There were a significant correlation between total CSF FLC and CSF neopterin in MS samples (correlation coefficient = 0.588, P = 0.016) and a strong correlation between CSF lambda FLC and CSF neopterin in MS samples (correlation coefficient = 0.875, P < 0.001). There was a strong correlation between urinary neopterin/creatinine levels and urinary total FLC/protein levels (correlation coefficient = 0.452, P = 0.004). Only three CSF samples (8%) had detectable levels of UCHL1. 18/38 (48%) (8/15 MS and 10/23 control) urine samples had detectable levels of UCLH1. CONCLUSIONS: This study confirms the relationship between CSF OCBs and CSF FLCs, highlighting the importance of intrathecal B- and plasma-cell activation in MS. There is a relationship between CSF FLC and CSF neopterin in MS, highlighting the multifaceted immune activation seen in MS. Correlations in the OCB-positive group highlight the multifaceted immune activation seen in MS. Further studies are required to evaluate CSF and urinary biomarkers.

An example of governance for AI in health services from Aotearoa New Zealand.

Artificial Intelligence (AI) is undergoing rapid development, meaning that potential risks in application are not able to be fully understood. Multiple international principles and guidance documents have been published to guide the implementation of AI tools in various industries, including healthcare practice. In Aotearoa New Zealand (NZ) we recognised that the challenge went beyond simply adapting existing risk frameworks and governance guidance to our specific health service context and population. We also deemed prioritising the voice of Maori (the indigenous people of Aotearoa NZ) a necessary aspect of honouring Te Tiriti (the Treaty of Waitangi), as well as prioritising the needs of healthcare service users and their families. Here we report on the development and establishment of comprehensive and effective governance over the development and implementation of AI tools within a health service in Aotearoa NZ. The implementation of the framework in practice includes testing with real-world proposals and ongoing iteration and refinement of our processes.

Did it hurt? COVID-19 vaccination experience in people with multiple sclerosis.

BACKGROUND: Current guidelines recommend vaccination against SARS-CoV2 for people with multiple sclerosis (pwMS). The long-term review of the safety and effectiveness of COVID-19 vaccines in pwMS is limited. METHODS: Service re-evaluation. PwMS using the MS service at Barts Health National Health Service Trust were sent questionnaires via email to report symptoms following first and second COVID-19 vaccinations (n = 570). A retrospective review of electronic health records was conducted for clinical and safety data post-vaccination(s); cut-off was end of September 2021. Separate logistic regressions were carried out for symptoms experienced at each vaccination. Two sets of regressions were fitted with covariates: (i) Disease-modifying therapy type and (ii) patient characteristics for symptoms experienced. RESULTS: 193/570 pwMS responded. 184 pwMS had both vaccinations. 144 received the AZD1222 and 49 the BNT162b2 vaccine. 87% and 75% of pwMS experienced any symptoms at first and second vaccinations, respectively. The majority of symptoms resolved within a short timeframe. No severe adverse effects were reported. Two pwMS subsequently died; one due to COVID-19 and one due to aspiration pneumonia. Males were at a reduced risk of reporting symptoms at first vaccination. There was evidence that pwMS in certain treatment groups were at reduced risk of reporting symptoms at second vaccination only. CONCLUSIONS: Findings are consistent with our preliminary data. Symptoms post-vaccination were similar to the non-MS population and were mostly temporary. It is important to inform the MS community of vaccine safety data.

Predictors of engagement with remote sensing technologies for symptom measurement in Major Depressive Disorder.

BACKGROUND: Remote sensing for the measurement and management of long-term conditions such as Major Depressive Disorder (MDD) is becoming more prevalent. User-engagement is essential to yield any benefits. We tested three hypotheses examining associations between clinical characteristics, perceptions of remote sensing, and objective user engagement metrics. METHODS: The Remote Assessment of Disease and Relapse - Major Depressive Disorder (RADAR-MDD) study is a multicentre longitudinal observational cohort study in people with recurrent MDD. Participants wore a FitBit and completed app-based assessments every two weeks for a median of 18 months. Multivariable random effects regression models pooling data across timepoints were used to examine associations between variables. RESULTS: A total of 547 participants (87.8% of the total sample) were included in the current analysis. Higher levels of anxiety were associated with lower levels of perceived technology ease of use; increased functional disability was associated with small differences in perceptions of technology usefulness and usability. Participants who reported higher system ease of use, usefulness, and acceptability subsequently completed more app-based questionnaires and tended to wear their FitBit activity tracker for longer. All effect sizes were small and unlikely to be of practical significance. LIMITATIONS: Symptoms of depression, anxiety, functional disability, and perceptions of system usability are measured at the same time. These therefore represent cross-sectional associations rather than predictions of future perceptions. CONCLUSIONS: These findings suggest that perceived usability and actual use of remote measurement technologies in people with MDD are robust across differences in severity of depression, anxiety, and functional impairment.

In silico modeling of the Menkes copper-translocating P-type ATPase 3rd metal binding domain predicts that phosphorylation regulates copper-binding.

The Menkes (ATP7A) P(1B)-type ATPase is a transmembrane copper-translocating protein. It contains six similar high-affinity metal-binding domains (MBDs) in the N-terminal cytoplasmic tail that are important for sensing intracellular copper and regulating ATPase function through the transfer of copper between domains. Molecular characterization of copper-binding and transfer is predominantly dependent on NMR structures derived from E. coli expression systems. A limitation of these models is the exclusion of post-translational modifications. We have previously shown that the third copper-binding domain, MBD3, uniquely contains two phosphorylated residues: Thr-327, which is phosphorylated only in the presence of elevated copper; and Ser-339, which is constitutively phosphorylated independent of copper levels. Here, using molecular dynamic simulations, we have incorporated these phosphorylated residues into a model based on the NMR structures of MBD3. Our data suggests that constitutively phosphorylated Ser-339, which is in a loop facing the copper-binding site, may facilitate the copper transfer process by exposing the CxxC copper-binding region of MBD3. Copper-induced phosphorylation of Thr327 is predicted to stabilize this change in conformation. This offers new molecular insights into how cell signaling (phosphorylation) can affect MBD structure and dynamics and how this may in turn affect copper-binding and thus copper-translocation functions of ATP7A.