Primary lateral sclerosis natural history study - planning, designing, and early enrollment.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Re-evaluating the merits of decentralization as a core strategy for effective delivery of drug-resistant tuberculosis care in Pakistan.

Decentralized, person-centred models of care delivery for drug-resistant tuberculosis (DR-TB) continue to be under-resourced in high-burden TB countries. The implementation of such models-made increasingly urgent by the COVID-19 pandemic-are key to addressing gaps in DR-TB care. We abstracted data of rifampicin-resistant (RR)/multidrug-resistant tuberculosis (MDR-TB) patients initiated on treatment at 11 facilities between 2010 and 2017 in Sindh and Balochistan provinces of Pakistan. We analysed trends in treatment outcomes relating to programme expansion to peri-urban and rural areas and estimated driving distance from patient residence to treatment facility. Among the 5586 RR/MDR-TB patients in the analysis, overall treatment success decreased from 82% to 66% between 2010 and 2017, as the programme expanded. The adjusted risk ratio for unfavourable outcomes was 1.013 (95% confidence interval 1.005-1.021) for every 20 km of driving distance. Our analysis suggests that expanding DR-TB care to centralized hubs added to increased unfavourable outcomes for people accessing care in peri-urban and rural districts. We propose that as enrolments increase, expanding DR-TB services close to or within affected communities is essential.

Patient preference for virtual versus in-person visits in neuromuscular clinical practice.

INTRODUCTION/AIMS: It is unknown if patients with neuromuscular diseases prefer in-person or virtual telemedicine visits. We studied patient opinions and preference on virtual versus in-person visits, and the factors influencing such preferences. METHODS: Telephone surveys, consisting of 11 questions, of patients from 10 neuromuscular centers were completed. RESULTS: Five hundred and twenty surveys were completed. Twenty-six percent of respondents preferred virtual visits, while 50% preferred in-person visits. Sixty-four percent reported physical interaction as "very important." For receiving a new diagnosis, 55% preferred in-person vs 35% reporting no preference. Forty percent were concerned about a lack of physical examination vs 20% who were concerned about evaluating vital signs. Eighty four percent reported virtual visits were sufficiently private. Sixty eight percent did not consider expenses a factor in their preference. Although 92% were comfortable with virtual communication technology, 55% preferred video communications, and 19% preferred phone calls. Visit preference was not significantly associated with gender, diagnosis, disease severity, or symptom management. Patients who were concerned about a lack of physical exam or assessment of vitals had significantly higher odds of selecting in-person visits than no preference. DISCUSSION: Although neither technology, privacy, nor finance burdened patients in our study, more patients preferred in-person visits than virtual visits and 40% were concerned about a lack of physical examination. Interactions that occur with in-person encounters had high importance for patients, reflecting differences in the perception of the patient-physician relationship between virtual and in-person visits.

Vitamin D status of children with paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS).

Coronavirus disease 2019 (COVID-19) has caused mild illness in children, until the emergence of the novel hyperinflammatory condition paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS). PIMS-TS is thought to be a post-SARS-CoV-2 immune dysregulation with excessive inflammatory cytokine release. We studied 25 hydroxyvitamin D (25OHD) concentrations in children with PIMS-TS, admitted to a tertiary paediatric hospital in the UK, due to its postulated role in cytokine regulation and immune response. Eighteen children (median (range) age 8·9 (0·3-14·6) years, male = 10) met the case definition. The majority were of Black, Asian and Minority Ethnic (BAME) origin (89 %, 16/18). Positive SARS-CoV-2 IgG antibodies were present in 94 % (17/18) and RNA by PCR in 6 % (1/18). Seventy-eight percentage of the cohort were vitamin D deficient (< 30 nmol/l). The mean 25OHD concentration was significantly lower when compared with the population mean from the 2015/16 National Diet and Nutrition Survey (children aged 4-10 years) (24 v. 54 nmol/l (95 % CI -38·6, -19·7); P < 0·001). The paediatric intensive care unit (PICU) group had lower mean 25OHD concentrations compared with the non-PICU group, but this was not statistically significant (19·5 v. 31·9 nmol/l; P = 0·11). The higher susceptibility of BAME children to PIMS-TS and also vitamin D deficiency merits contemplation. Whilst any link between vitamin D deficiency and the severity of COVID-19 and related conditions including PIMS-TS requires further evidence, public health measures to improve vitamin D status of the UK BAME population have been long overdue.

Evaluation of a multidisciplinary team model of care in paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS)

BackgroundCoronavirus disease (COVID-19) pandemic has seen the emergence of a novel paediatric condition Paediatric Inflammatory Multisystem Syndrome Temporally associated with Severe acute respiratory syndrome coronavirus 2 (PIMS-TS). Royal College of Paediatric and Child Health guidance for the management of PIMS-TS recommends early discussion with relevant specialists in a multi-disciplinary team (MDT) setting.A regional MDT panel including representatives from cardiology, general paediatrics, infectious diseases, intensive care, rheumatology, research and pharmacy was established in May 2020 at pace with the evolution of PIMS -TS. Daily clinical decision support was provided using a video conference platform for all regional paediatric units.ObjectivesWe describe the evaluation of the newly configured PIMS-TS MDT, using a mixed-methods survey to capture user experience and feedback.MethodsEvaluation was conducted in July 2020. All users of the MDT service including chairpersons, panel members and referring clinicians were invited to complete the online survey. A 28-point questionnaire based on validated MDT evaluation methodology was developed and included 5 domains relevant to the PIMS-TS MDT: 1. Meeting organisation and process 2. Meeting infrastructure and logistics 3. Clinical decisions 4. Working and culture 5. Meeting feedback.ResultsSurvey response rate was 75%. Results from each domain is as below:Meeting organisation and process: – Users (90%) were aware of referral criteria, referral processes (86%) and MDT configuration including chairperson (90%) and panel members (75%). Majority were not aware (27%) or uncertain (25%) of specific meeting structure and protocols.Infrastructure & logistics: Majority (63%) found accessing videoconference platform straightforward (90%), with only (18%) reporting quality issues. Notably, nearly half the MDT users (49%) reported capacity and time restraints affecting their ability to attend the MDT.Clinical decisions: Clarity of clinical recommendations was acknowledged by majority (90%). Two thirds (65%) were aware of case referral proforma, nonetheless, majority were unsure or not aware of processes around post-MDT documentation in patient records.Working and culture: There was 98% agreement that MDT facilitated constructive discussion, supported learning and research and had positively impacted patient care.Meeting feedback: Rapid access to specialist expertise and complex decision-making support was universally acknowledged. Areas highlighted for improvement pertained to time and capacity constraints limiting participation, and to embed an MDT culture which encouraged inclusive, supportive behaviours and a collaborative team ethos.ConclusionsOur evaluation of the new PIMS-MDT demonstrates the process of agile adaptation to change followed by continuous learning and improvement, required to create efficient healthcare systems. User survey feedback identified excellent practice of achieving region-wide standardised care but also highlighted time and capacity constraints and the importance of fostering a supportive culture, which were subsequently incorporated in developing the MDT processes. Rapid implementation of system-wide changes at unprecedented scale and pace has been the norm during the COVID-19 pandemic, but this must be coupled with iterative cycles of learning and improvement to ensure optimal care.

Paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS) and Vitamin D deficiency

BackgroundCoronavirus disease 2019 (COVID-19), has caused mild illness in children, until the emergence of the novel hyperinflammatory condition PIMS-TS: Paediatric Inflammatory Multisystem Syndrome Temporally associated with Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PIMS-TS is thought to be a post- SARS-CoV-2 immune dysregulation with excessive inflammatory cytokine release.ObjectivesThere has been a long-standing interest in the role of 25 hydroxyvitamin D (25OHD) in cytokine-storm induced critical illnesses due to the premise of its anti-inflammatory actions including regulation of cytokine release. Vitamin D deficiency in critically ill individuals in intensive care has been linked to poor cardiovascular outcome and increased mortality.We report the vitamin D status of children with PIMS-TS admitted to a single tertiary paediatric hospital in the Midlands region of the United Kingdom (U.K).MethodsWe studied 25OHD levels in children admitted to a tertiary paediatric hospital in the U.K., fulfilling the case definition of PIMS-TS detailed by the Royal College of Paediatrics and Child Health. Children were managed either on paediatric intensive care unit (PICU group) or on the wards (non-PICU group). 25OHD concentrations were measured by quantitative liquid chromatography tandem mass spectrometry. Statistical analysis used a two-sample t-test, assuming unequal variances.ResultsFifty children [median (range) age 8.8 (0.99 to 14.6) years, male = 24] met the case definition. The majority were of Black, Asian and Minority Ethnic (BAME) origin [78%, 39/50]. SARS-CoV-2 IgG antibodies were confirmed in 64% (32/50) and SARS-CoV-2 RNA detected by PCR in 6% (3/50) of the study population. Of those patients without serology or PCR data available, the majority had a confirmed Covid 19 positive contact.Eighty-two percent of the cohort were vitamin D deficient (<30nmol/L). The mean 25OHD concentration was significantly lower when compared to the population mean from the 2015/16 National Diet and Nutrition Survey, a cohort of healthy children with no medical conditions, aged 4–10 years [22 vs 54nmol/L (95% CI: 15.9, 24.1);p<0.001]. Children from BAME backgrounds had reduced vitamin D levels compared to children from a white background [mean 25OHD concentration 17.7 vs 28.2;p=0.12]. The PICU group had lower mean 25OHD concentrations compared to the non-PICU group, although this was not statistically significant [16.9 vs 28 nmol/L;p=0.071].ConclusionsPIMS-TS has seen an over-representation of children from BAME background, who are also at greatest risk of vitamin D deficiency. Whilst any link between vitamin D deficiency and the severity of COVID-19 and related conditions, including PIMS-TS, requires further evidence, public health measures to improve vitamin D status of the U.K BAME population has been long overdue. Given the safety profile of vitamin D supplementation and the over-representation of BAME individuals with vitamin D deficiency and PIMS-TS, mandated year-round supplementation of all high-risk children should be the way forward.

Using a low-cost, real-time electronic immunization registry in Pakistan to demonstrate utility of data for immunization programs and evidence-based decision making to achieve SDG-3: Insights from analysis of Big Data on vaccines.

BACKGROUND: Despite the proliferation of digital interventions such as Electronic Immunization Registries (EIR), currently, there is little evidence regarding the use of EIR data to improve immunization outcomes in resource-constrained settings. To achieve the Sustainable Development Goal (SDG) of ensuring healthy lives and well-being for all ages, particularly for newborns and children under the age of 5 (goal 3b), it is essential to generate and use quality data for evidence-based decision making to overcome barriers inherent in immunization systems. In Pakistan, only 66 % of children receive all basic vaccinations, and in Sindh province, the number is even lower at 49 %. In 2012, IRD developed and piloted Zindagi Mehfooz (Safe Life; ZM) ElR, an Android-based platform that records and analyses individual-level child data in real-time. In 2017 in collaboration with Expanded Programme for Immunization (EPI) Sindh, ZM was scaled-up across the entire Sindh province and is currently being used by 2521 government vaccinators in 1539 basic health facilities, serving >48 million population. OBJECTIVE: The study aims to demonstrate how big immunization data from the ZM-EIR is being leveraged in Sindh, Pakistan for actionable decision making via three use cases (a) improving performance management of vaccinators to increase geographical coverage, (b) quantifying the impact of provincial accelerated outreach activities, and (c) examining the impact of the COVID-19 pandemic on routine immunization coverage to help devise a tailored approach for future efforts. METHODS: From October 2017 to April 2020, more than 2.9 million children and 0.9 million women have been enrolled, and more than 22 million immunization events have been recorded in the ZM-EIR. We extracted de-identified data from ZM-EIR for January 1, 2019 - April 20, 2020, period. Given the needs of each use case, monthly and daily indicators on vaccinator performance (attendance and compliance), daily immunization visits, and the number of antigens administered were calculated. Geo-coordinate data of antigen administration was extracted and displayed on geographic maps using QGIS. All generated reports were shared at fixed frequency with various stakeholders, such as partners at EPI-Sindh, for utilization in decision making and informing policy. RESULT: Our use-cases demonstrate the use of EIR data for data-driven decision making. From January - December 2019, the monthly monitoring of program indicators helped increase the vaccinator attendance from 44% to 88%, while an 85 % increase in geographical coverage was observed in a polio-endemic super high-risk union council (SHRUC) in Karachi. The analysis of daily average antigens administered during accelerated outreach efforts (AOE) as compared to routine activities showed an increase in average daily Pentavalent-3, Measles-1, and Measles-2 vaccines administered by 103%, 154%, and 180% respectively. These findings helped decide to continue the accelerated effort in high-risk areas (compared to the entire province) rather than discontinuing the activity due to high costs. During COVID-19 lockdown, the daily average number of child immunizations reduced from 16,649 to 4335 per day, a decline of 74% compared to 6 months preceding COVID-19 lockdown. ZM-EIR data is currently helping to shape the planning and implementation of critical strategies to mitigate the impact of the COVID-19 pandemic. CONCLUSION: The big data for vaccines generated through EIRs is a powerful tool to monitor immunization work-force and ensure chronically missed communities are identified and covered through targeted strategies. Geospatial data availability and analysis is changing the way EPI review meetings occur with stakeholders, taking data-driven decisions for better planning and resource allocation. In the fight against COVID-19 pandemic, as governments gradually begin to shift from containing the outbreak to strategizing a plan for sustaining the essential health services, the countries that will emerge most successful are likely the ones who can best use technology and real-time data for targeted efforts.