Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

BACKGROUND: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals. METHODS: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID). RESULTS: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy. CONCLUSIONS: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks. TRIAL REGISTRATION NUMBER: NCT04225312.

Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis.

BACKGROUND: Natalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals. METHODS: The NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses. RESULTS: Until December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, p<0.001), leading to very low trough drug levels in three patients on extended treatment intervals. No natalizumab ADAs were detected during intravenous or SC treatment. None of the participants on natalizumab SC showed evidence of MS disease activity. CONCLUSIONS: Natalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab.

Race, ethnicity and COVID-19 vaccination: a qualitative study of UK healthcare staff.

OBJECTIVE: COVID-19-related inequities experienced by racial and ethnic minority groups including healthcare professionals mirror wider health inequities, which risk being perpetuated by lower uptake of vaccination. We aim to better understand lower uptake among racial and ethnic minority staff groups to inform initiatives to enhance uptake. DESIGN: Twenty-five semi-structured interviews were conducted (October 2020-January 2021) with UK-based healthcare staff. Data were inductively and thematically analysed. RESULTS: Vaccine decision-making processes were underpinned by an overarching theme, 'weighing up risks of harm against potential benefits to self and others'. Sub-themes included 'fear of harm', 'moral/ethical objections', 'potential benefits to self and others', 'information and misinformation', and 'institutional or workplace pressure'. We identified ways in which these were weighted more heavily towards vaccine hesitancy for racial and ethnic minority staff groups influenced by perceptions about institutional and structural discrimination. This included suspicions and fear around institutional pressure to be vaccinated, racial injustices in vaccine development and testing, religious or ethical concerns, and legitimacy and accessibility of vaccine messaging and communication. CONCLUSIONS: Drawing on a critical race perspective, we conclude that acknowledging historical and contemporary abuses of power is essential to avoid perpetuating and aggravating mistrust by de-contextualising hesitancy from the social processes affecting hesitancy, undermining efforts to increase vaccine uptake.

The Journey towards resilience following a traumatic birth: A grounded theory.

Statistics have shown that up to 30% of women experience birth as traumatising. However, most women do not go on to develop post-traumatic stress disorder (PTSD), and instead appear to be resilient. Research is still sparse in the field of traumatic birth and resilience, and it is not known how women develop resilience after a traumatic birth. OBJECTIVES: The aim of this study was to understand the process of fostering resilience after a traumatic birth. METHOD: Semi-structured interviews were conducted with eight female participants aged 30 to 50 years who experienced a traumatic birth. A constructivist grounded theory was used to analyse interviews. RESULTS: Two main themes were identified which were developed into an emergent model: 1) the feeling of powerlessness during a traumatic birth; and 2) the journey towards resilience. The powerlessness of a traumatic birth was related to a perceived lack of voice and abandonment by healthcare professionals. The model revealed that women's journey towards resilience was aided by both internal and external resources that included healing self-care and ownership of the role of mother; and drawing upon faith, spirituality and supportive relationships. DISCUSSION: The findings suggest resilience is a process whereby women draw upon internal and external resources or both at different points in their journey. The implications of the findings include training healthcare professionals in communication to avoid trauma during labour; and prompting women to identify and utilise both internal and external resources to help them to overcome any trauma.

A randomized controlled trial of suicide prevention training for primary care providers: a study protocol.

BACKGROUND: Suicide is a national public health crisis and a critical patient safety issue. It is the 10th leading cause of death overall and the second leading cause of death among adolescents and young adults (15-34 years old). Research shows 80% of youth who died by suicide saw their primary care provider within the year of their death. It is imperative that primary care providers develop the knowledge and skills to talk with patients about distress and suicidal thoughts, and to assess and respond in the context of the ongoing patient - primary care provider relationship. METHODS: This study examines the effectiveness of simulation on suicide prevention training for providers-in-training by comparing two conditions: 1) a control group that receives online teaching on suicide prevention in primary care via brief online videos and 2) an experimental group that includes the same online teaching videos plus two standardized patient (SP) interactions (face-to-face and telehealth, presentation randomized). All SP interactions are video-recorded. The primary analysis is a comparison of the two groups' suicide prevention skills using an SP "test case" at 6-month follow-up. DISCUSSION: The primary research question examines the impact of practice (through SP simulation) over and above online teaching alone on suicide prevention skills demonstrated at follow-up. We will assess moderators of outcomes, differences among SP simulations (i.e., face-to-face vs. telehealth modalities), and whether the experimental group's suicide prevention skills improve over the three SP experiences. TRIAL REGISTRATION: The study was registered on Clinical Trials Registry ( clinicaltrials.gov ) on December 14, 2016. The Trial Registration Number is NCT02996344 .

Patient-Selected Strategies for Post Cardiac Rehabilitation Exercise Adherence in Heart Failure.

PURPOSE: The aim of this study was to evaluate the use of patient-selected exercise adherence strategies following cardiac rehabilitation (CR). DESIGN: Twenty patients with heart failure (HF) were recruited and randomly assigned to the intervention or control group at completion of CR. METHODS: The intervention included the use of six adherence strategies (logs, graphs, pedometers, phone follow-up, education, and a letter from CR staff), which were provided for 6 weeks post CR and during home-based exercise. After 6 weeks, the intervention group selected strategies to continue, and only those were provided for the last 6 weeks. At 12 weeks, patients were retested. FINDINGS: Patients with HF demonstrated improvement in distance walked and less HF symptoms and adhered to exercise at levels recommended during CR. CONCLUSION: Inclusion of patient-selected adherence strategies supports continued exercise and helps to sustain physiological improvements. CLINICAL RELEVANCE: Results from this study have implications for CR programs serving HF patients and provide insight into adherence strategies.

Chk1 KA1 domain auto-phosphorylation stimulates biological activity and is linked to rapid proteasomal degradation.

The DNA damage-activated protein kinase Chk1 is known to undergo auto-phosphorylation, however the sites and functional significance of this modification remain poorly understood. We have identified two novel Chk1 auto-phosphorylation sites, threonines 378 and 382 (T378/382), located in a highly conserved motif within the C-terminal Kinase Associated 1 (KA1) domain. T378/382 occur within optimal consensus Chk1 phosphorylation motifs and substitution with phospho-mimetic aspartic acid residues results in a constitutively active mutant Chk1 kinase (Chk1-DD) that arrests cell cycle progression in G2 phase of the cell cycle in the absence of DNA damage. Remarkably, the mutant Chk1-DD protein is also subject to very rapid proteasomal degradation, with a half-life approximately one tenth that of wild-type Chk1. Consistent with this, T378/T382 auto-phosphorylation also accelerates the proteasomal degradation of constitutively active Chk1 KA1 domain structural mutants. T378/382 auto-phosphorylation and accelerated degradation of wild-type Chk1 occurs at low levels during unperturbed growth, but surprisingly, is not augmented in response to genotoxic stress. Taken together, these observations demonstrate that Chk1 T378/T382 auto-phosphorylation within the KA1 domain is linked to kinase activation and rapid proteasomal degradation, and suggest a non-canonical mechanism of regulation.

Development of a questionnaire to evaluate patients' awareness of cardiovascular disease risk in England's National Health Service Health Check preventive cardiovascular programme.

BACKGROUND: The National Health Service (NHS) Health Check is a cardiovascular disease (CVD) risk assessment and management programme in England aiming to increase CVD risk awareness among people at increased risk of CVD. There is no tool to assess the effectiveness of the programme in communicating CVD risk to patients. AIMS: The aim of this paper was to develop a questionnaire examining patients' CVD risk awareness for use in health service research evaluations of the NHS Health Check programme. METHODS: We developed an 85-item questionnaire to determine patients' views of their risk of CVD. The questionnaire was based on a review of the relevant literature. After review by an expert panel and focus group discussion, 22 items were dropped and 2 new items were added. The resulting 65-item questionnaire with satisfactory content validity (content validity indices≥0.80) and face validity was tested on 110 NHS Health Check attendees in primary care in a cross-sectional study between 21 May 2014 and 28 July 2014. RESULTS: Following analyses of data, we reduced the questionnaire from 65 to 26 items. The 26-item questionnaire constitutes four scales: Knowledge of CVD Risk and Prevention, Perceived Risk of Heart Attack/Stroke, Perceived Benefits and Intention to Change Behaviour and Healthy Eating Intentions. Perceived Risk (Cronbach's α=0.85) and Perceived Benefits and Intention to Change Behaviour (Cronbach's α=0.82) have satisfactory reliability (Cronbach's α≥0.70). Healthy Eating Intentions (Cronbach's α=0.56) is below minimum threshold for reliability but acceptable for a three-item scale. CONCLUSIONS: The resulting questionnaire, with satisfactory reliability and validity, may be used in assessing patients' awareness of CVD risk among NHS Health Check attendees.

Barriers to Treatment for Female Problem Gamblers: A UK Perspective.

There is a paucity of research in the UK which examines problem gambling and that which does exist is mainly quantitative, focuses on male samples and fails to look at treatment seeking populations or obstacles preventing problem gamblers from seeking treatment. This paper presents findings from part of a larger qualitative study that explored the experience of treatment for female problem gamblers. Data were collected using semi-structured interviews with eight women who had received individual cognitive-behavioural therapy in the National Health Service for their gambling problem. An interpretative phenomenological analysis approach was applied in the research process, identifying three main themes, of which the subtheme 'Barriers to Treatment' is examined here. Internal and external barriers to treatment organically emerged in all female participants' accounts and appear to have an impact on service utilisation. Input directly from gamblers can be combined with findings from other studies to devise better ways of reaching female problem gamblers. A better understanding of barriers to treatment can also provide valuable direction for future research and suggest applications in clinical service provision and treatment planning.

Testing of a Model with Latino Patients That Explains the Links Among Patient-Perceived Provider Cultural Sensitivity, Language Preference, and Patient Treatment Adherence.

INTRODUCTION: Disparities in treatment adherence based on race and ethnicity are well documented but poorly understood. Specifically, the causes of treatment nonadherence among Latino patients living in the USA are complex and include cultural and language barriers. PURPOSE: The purpose of this study was to examine whether patients' perceptions in patient-provider interactions (i.e., trust in provider, patient satisfaction, and patient sense of interpersonal control in patient-provider interactions) mediate any found association between patient-perceived provider cultural sensitivity (PCS) and treatment adherence among English-preferred Latino (EPL) and Spanish-preferred Latino (SPL) patients. METHODS: Data from 194 EPL patients and 361 SPL patients were obtained using questionnaires. A series of language-specific structural equation models were conducted to test the relationship between patient-perceived PCS and patient treatment adherence and the examined mediators of this relationship among the Latino patients. RESULTS: No significant direct effects of patient-perceived PCS on general treatment adherence were found. However, as hypothesized, several significant indirect effects emerged. Preferred language appeared to have moderating effects on the relationships between patient-perceived PCS and general treatment adherence. CONCLUSION: These results suggest that interventions to promote treatment adherence among Latino patients should likely include provider training to foster patient-defined PCS, trust in provider, and patient satisfaction with care. Furthermore, this training needs to be customized to be suitable for providing care to Latino patients who prefer speaking Spanish and Latino patients who prefer speaking English.

Integrated care pilot in north-west London: a mixed methods evaluation.

INTRODUCTION: This paper provides the results of a year-long evaluation of a large-scale integrated care pilot in north-west London. The pilot aimed to integrate care across primary, acute, community, mental health and social care for people with diabetes and/or those aged 75+ through care planning, multidisciplinary case reviews, information sharing and project management support. METHODS: The evaluation team conducted qualitative studies of change at organisational, clinician and patient levels (using interviews, focus groups and a survey); and quantitative analysis of change in service use and patient-level clinical outcomes (using patient-level datasets and a matched control study). RESULTS: The pilot had successfully engaged provider organisations, created a shared strategic vision and established governance structures. However, the engagement of clinicians was variable and there was no evidence to date of significant reductions in emergency admissions. There was some evidence of changes in care processes. CONCLUSION: Although the pilot has demonstrated the beginnings of large-scale change, it remains in the early stages and faces significant challenges as it seeks to become sustainable for the longer term. It is critical that National Health Service managers and clinicians have realistic expectations of what can be achieved in a relatively short period of time.

Rising obesity-related hospital admissions among children and young people in England: national time trends study.

OBJECTIVE: To describe the trends in hospital admissions associated with obesity as a primary diagnosis and comorbidity, and bariatric surgery procedures among children and young people in England. DESIGN: National time trends study of hospital admissions data between 2000 and 2009. PARTICIPANTS: Children and young people aged 5 to 19 years who were admitted to hospital with any diagnosis of obesity. MAIN OUTCOME MEASURES: Age- and sex-specific admission rates per million children. RESULTS: Between 2000 and 2009, age- and sex-specific hospital admission rates in 5-19 year olds for total obesity-related diagnoses increased more than four-fold from 93.0 (95% CI 86.0 to 100.0) per million children to 414.0 (95% CI 410.7 to 417.5) per million children, largely due to rising admissions where obesity was mentioned as a co-morbidity. The median age of admission to hospital over the study period was 14.0 years; 5,566 (26.7%) admissions were for obesity and 15,319 (73.3%) mentioned obesity as a comorbidity. Admissions were more common in girls than boys (56.2% v 43.8%). The most common reasons for admission where obesity was a comorbid condition were sleep apnoea, asthma, and complications of pregnancy. The number of bariatric surgery procedures has risen from 1 per year in 2000 to 31 in 2009, with the majority were performed in obese girls (75.6%) aged 13-19 years. CONCLUSIONS: Hospital admission rates for obesity and related comorbid conditions have increased more than four-fold over the past decade amongst children and young people. Although some of the increase is likely to be due to improved case ascertainment, conditions associated with obesity in children and young people are imposing greater challenges for health care providers in English hospitals. Most inpatient care is directed at dealing with associated conditions rather than primary assessment and management of obesity itself.

Factors affecting the motivation of healthcare professionals providing care to Emiratis with type 2 diabetes.

OBJECTIVE: We aimed to identify facilitators of and barriers to healthcare professionals' motivation in a diabetes centre in the United Arab Emirates (UAE). DESIGN: A qualitative research approach was employed using semistructured interviews to assess perception of and attitudes regarding healthcare professionals' motivation in providing good quality diabetes care. SETTING: A diabetes centre located in Abu-Dhabi, UAE. PARTICIPANTS: Healthcare professionals including specialist physicians, dieticians, podiatrists, health educators and nurses were recruited through purposive sampling. MAIN OUTCOME MEASURES: After data collection, the audiotaped interviews were transcribed verbatim and subjected to content analysis. RESULTS: Nine semistructured interviews were conducted with healthcare professionals of various professional backgrounds. Important facilitators and barriers related to patient, professional, organization and cultural factors were identified. Barriers that related to heavy workload, disjointed care, lack of patient compliance and awareness, and cultural beliefs and attitudes about diabetes were common. Key facilitators included the patient's role in achieving therapeutic outcomes as well as compliance, cooperation and communication. CONCLUSION: This qualitative study provides some unique insights about factors affecting healthcare professionals' motivation in providing good quality care. To improve the motivation of healthcare professionals in the management of diabetes and therefore the quality of diabetes care, several steps are needed. Importantly, the role of primary care should be reinforced and strengthened regarding the management of type 2 diabetes mellitus, privacy of the consultation time should be highly protected and regulated, and awareness of the Emirate culture and its impact on health should be disseminated to the healthcare professionals providing care to Emirates with diabetes. Also, greater emphasis should be placed on educating Emiratis with diabetes on, and involving them in, the management of their condition.

Spinal cord lesions in patients with clinically isolated syndrome: a powerful tool in diagnosis and prognosis.

OBJECTIVE: Spinal cord (SC) lesions are frequently found in multiple sclerosis (MS), but are rare in healthy aging and cerebrovascular patients. Our aim was to analyze the contribution of SC involvement in clinically isolated syndrome (CIS) in diagnosing MS according the McDonald 2010 criteria and in predicting conversion to clinically definite MS (CDMS). METHODS: We prospectively followed monofocal, relapsing onset CIS patients with either SC or brain symptom onset (including optic neuritis). MRI of the brain and SC were performed shortly after onset and patients were followed for 24 to 119 months (median 64 months). SC MRI findings were assessed for their contribution to the McDonald 2010 diagnostic criteria and their effect on conversion to CDMS. RESULTS: One hundred twenty-one patients were included (63 spinal CIS). Based on the brain scan only, 36 patients fulfilled the McDonald criteria; by including SC findings, 6 additional patients fulfilled these criteria. To diagnose 1 additional nonspinal CIS patient, the number needed to scan is 7. In nonspinal CIS patients that did not fulfill McDonald brain MRI criteria (n = 42), presence of an SC lesion was associated with a higher risk of conversion to CDMS (odds ratio: 14.4; 95% confidence interval: 2.6-80.0) and shorter time to conversion to CDMS (hazard ratio: 51.4; 95% confidence interval: 5.5-476.3). CONCLUSIONS: Presence of SC lesions facilitates diagnosing MS and is predictive for conversion to CDMS, especially in patients with nonspinal CIS who do not fulfill brain MRI criteria. We therefore recommend performing an SC scan in patients with nonspinal CIS who do not fulfill McDonald brain MRI criteria.

MRI characteristics are predictive for CDMS in monofocal, but not in multifocal patients with a clinically isolated syndrome.

BACKGROUND: To diagnose multiple sclerosis (MS), evidence for dissemination in space and time is required. There is no clear definition on how symptoms and signs of a patient indicate clinical dissemination in space. To provide a uniform approach on this subject, a clinical classification system was described recently differentiating patients with mono- and multifocal clinical presentation. Here we assess the predictive value of clinically defined dissemination in space at first presentation for time to clinically definite MS (CDMS). METHODS: Four hundred and sixty-eight patients with a first episode suggestive of MS were classified as clinically mono- or multifocal by two neurologists blinded to magnetic resonance imaging (MRI) results. These patients were part of the BENEFIT study in which 292 patients were randomized to interferon beta-1b (IFNB-1b) and 176 to placebo. By using Kaplan-Meier statistics the risk for CDMS was studied in mono- and multifocal patients of the placebo group, both with and without taking into account MRI measures of potential prognostic relevance. RESULTS: Time to CDMS was similar in monofocal and multifocal patients. In monofocal patients, the risk for CDMS over 2 years was significantly higher when >or= 9 T2 lesions or at least one Gd-enhancing lesion were present at the first event or 3 or 6 months after the first event. In patients with multifocal presentation, these MRI measures had no significant added value in predicting time to CDMS. CONCLUSION: These data indicate that a carefully performed neurological assessment of symptoms and signs, combined with lesions on MRI, is important for defining the risk of conversion to CDMS. TRIAL REGISTRATION: The Benefit trial has been registered under NCT00185211 http://www.clinicaltrials.gov.

CCL5 and CCR5 genotypes modify clinical, radiological and pathological features of multiple sclerosis.

Chemokines mediate selective recruitment of leukocyte subsets into the CNS during inflammatory episodes. We hypothesised that functional polymorphisms in CCR5 and CCL5 influence perivascular leukocyte infiltration, inflammation, axonal loss, and remyelination, and disease course. Therefore, we determined genotypes at four possibly functional polymorphisms in CCR5 and CCL5 for 637 patients and 92 brain donors with multiple sclerosis (MS). For a subset of 192 patients, MRI data were available. We found that low-producer allele CCL5-403*G was associated with reduced risk of severe axonal loss, whereas high-producer allele CCL5-403*A was associated with a worse clinical disease course measured by the MS Functional Composite Score and MS Severity Score. Low-producer allele CCR5+303*G was associated with reduced T2 hyperintense and T1 hypointense lesion volumes on MRI, and high-producer allele CCR5+303*A with early age at onset. Furthermore, low-producer allele CCR5Delta32 was associated with reduced T2 lesion volume, lower black hole ratio on MRI, and with a higher percentage of lesions with signs of remyelination, histopathologically. In summary, our multifaceted study supports the notion that polymorphisms in CCL5 and CCR5 modify the course of MS.

The role of spinal cord imaging in the diagnosis of multiple sclerosis.

BACKGROUND: A 29-year-old male presented with fluctuating but progressive sensory disturbances comprising tingling and dysesthesia in his right leg. MRI of the brain showed white matter lesions initially thought to be caused by multiple sclerosis. INVESTIGATIONS: Neurological examination, cerebrospinal fluid examination, laboratory blood testing, brain and spinal MRI scans. DIAGNOSIS: Spinal cord schwannoma. MANAGEMENT: Surgical removal of the schwannoma. An algorithm is provided that clarifies the appropriate MRI work-up for cases where the clinical presentation is suggestive of multiple sclerosis.

Overdiagnosis of multiple sclerosis and magnetic resonance imaging criteria.

Retrospectively, we assessed the specificity of two proposed magnetic resonance imaging (MRI) criteria for multiple sclerosis (MS) in patients suspected to have MS but who ultimately receive another diagnosis. Brain MRIs of 28 patients mixed with 28 MRIs of MS patients from the same cohort of 377 consecutively referred patients were scored by a neuroradiologist masked to the final diagnosis. The criteria for dissemination in space incorporated in the McDonald International Panel showed good specificity (89%). However, the more sensitive criteria proposed by a Subcommittee of the American Academy of Neurology resulted in a lower specificity (29%), indicating an increased risk of a false-positive diagnosis.