User involvement in medical device development: An empirical study

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Changes in population, medical interventions and new technology opportunities, as well as public and political expectations, are all contributing factors to the pressure facing the healthcare system to change. Healthcare in the UK is beginning to move away from its traditional boundaries, for example hospitals and towards patient empowerment and collaboration. Consequently the target users for medical devices have also changed, with new users and user groups emerging. Further to this user involvement is emphatically becoming a part of healthcare delivery in the UK, recognised for bringing improvement in the quality, acceptance and in turn success of a medical device. The changing target market has given rise to the need to understand the newly created user groups and finding new ways to elicit their requirements has become vital for the success of medical devices. This research intends to draw upon and capture the importance of user requirements research, by investigating the early stages of Medical Device Development (MDD) giving particular attention to the conceptualisation of the user within this process. The research shall assess the possible links between user requirement elements, to benefit the healthcare system and investigate how user requirements methodologies that have been proven in other fields can be successfully deployed in the medical device development lifecycle. User requirements methodologies identified within the disciplines of information technology, ergonomics, psychology and design theories relating to medical device design, will be collectively assessed for their capacity to collaborate. The research methodology began with undertaking a systematic review of the literature, which facilitated the construction of a single theoretical conceptual framework of user involvement in medical device development, representative of a superior model of user requirements capture. To validate this framework empirical research followed. This was divided into exploratory, explanatory and interpretive data collection phases, with a view to extract; what the current process of MDD is in industry, why and how users are currently deployed in MDD, and the users perceived experience of involvement. The exploratory study showed that manufacturers were aware of their users and extracting the user requirements effectively was seen as the main competitive differentiator. However, manufacturers were not always aware of the best methods to capture user needs, especially with business objectives and obligatory requirements repeatedly taking precedence over optional user involvement methods. The explanatory study showed that not every department has an equal role to play in terms of user involvement in terms of methods to elicit requirements. However there was consensus across the departments to acknowledge their customers and their feedback to ensure they feel valued. Further to this communicating information to potential new devices users was carried out well in advance of the product coming to market. The customer focus was something not only addressed in the design of the device, but the service that followed. The interpretive study emphasised the importance of understanding the user’s needs and to understand that these needs do change over time. Educating users on disease and self-management was considered important, but realisation by patient user of their responsibility was vital in the successful use of a medical device. The original contributions of this study include its endeavour in taking a multidisciplinary approach to account for users and user involvement methods, and apply to specifically the early stages of the medical device development process. The research developed naturally to transcend and collaborate between these theories, as well as represent various voices within the research to really emphasise the multidisciplinary and multi-user approach it took. This research made a further innovative contribution by developing a framework to the problem of inadequate user involvement in the medical device development process. This could prove very beneficial for medical device manufacturers considering user involvement may become a regulatory requirement, meaning all medical device manufacturers would need to incorporate and document user involvement by law

Antimycobacterial potential of green synthesized silver nano particles from selected Himalayan flora

Mycobacterium tuberculosis (Mtb) is a persistent threat to human life and a challenge to global public health. The pathogen’s antibioticresistance has become a serious problem, prompting the development of nanotechnology-based medicines to prevent multidrug resistance in microorganisms. The present study aimed to synthesize silver nanoparticles (AgNPs), using leaves extracts of Achillea millefolium, Artemisia campestris and Hedera nepalensis to analyze their antimycobacterial potential. The biosynthesized silver nanoparticlesnwere harvested and characterized through UV visible spectroscopy,nField Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive X-ray spectroscopy (EDX). The FESEM analysis showed, that selected plant-based silver nanoparticles were spherical in shape with a diameter ranging from 50 nm to 80 nm. Energy Dispersive X-ray spectroscopy revealed that constitute elements of silver nanoparticles are Ag, C, O, Cl and Ca. The biosynthesized AgNPs exhibited significant antibacterial potential against Mycobacterium tuberculosis. At a concentration of 50 μL Hedera nepalensis exhibited the highest growth inhibition at 97.33%, followed by Artemisia at 95%, whereas the percentage growth inhibition of Achillea millefolium at 50 μL concentration was 72.33% as compared to the Rifampicin (RIF) i.e., 40%. Fluorescence microscopy confirmed visible growth inhibition in both experimental and controlled cultures. Hedra nepalensis and Artemisia campestris showed promising potential to inhibit the growth of mycobacteria populations, indicating their potential for the development of novel nanomedicine to treat tuberculosis effectively

Ceramic Stereolithography of Bioactive Glasses: Influence of Resin Composition on Curing Behavior and Green Body Properties

Herein we report on the preparation of a bioactive glass (BAG)-based photocurable resin for the additive manufacturing of BAG scaffolds with high filler loadings. The preparation of glass/ceramics resins for stereolithography with high filler loading is always a challenge, especially for fillers with a high refractive index variance. Various photocurable resin compositions with and without bioactive glass fillers have been investigated to see the influence of bioactive glass on physical properties of the resin and resulting green body. The effect of concentration of monomers, reactive diluent, light absorber (Sudan orange G dye), photoinitiator (PI), non-reactive diluent, and fillers (BAG) on rheology and photocuring behavior of the resin and tomography of the resulting 3D structures have been investigated. The BAG contents affect the rheology of resin and influence the rate of the polymerization reaction. The resin compositions with 55–60% BAG, 10% PEG-200 (diluent), 1% of PI and 0.015% of the dye were found to be suitable compositions for the stereolithographic fabrication. A higher percentage of PI caused over-curing, while a higher amount of dye decreased the cure depth of the resin. The micro-computed tomography (µ-CT) and scanning electron microscopic (SEM) images of the resulting green bodies display a relatively dense glass scaffold without any visible cracks and good interlayer connection and surface finishing. These properties play an important role in the mechanical behavior of 3D scaffolds. This study will be helpful to prepare high density glass/ceramic slurries and optimize their printing properties

Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families

The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 × 10−8, permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 × 10−8, permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies

Pregnancy and neonatal outcomes of COVID-19: The PAN-COVID study

Objective To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. Methods Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. Results Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3–1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. Conclusions Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians’ threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Diversity of culturable thermophilic bacteria in hotspring of Kotli Azad Jammu and Kashmir

Hot water springs are unique areas populated by mesophiles, thermotolerant, and hyperthermophiles. They are source of diversity of thermophiles, mainly belonging to archaea and bacteria domains. The diversity of thermophiles gives an outline of the huge biological potential that can be exploited for industrial applications.To this end, this study was aimed to isolate and characterize the unexplored thermophilic microorganisms from hot water spring in Tatapani, Tehsil & District Kotli AJK, Pakistan. Around 10 bacterial isolates were identified using morphological, biochemical, physiological and molecular attributes. Sequencing of the 16S rDNA gene of the isolates followed by BLAST search revealed that the strain MBT008 has 100% similarity with Anoxybacillus kamchatkensis. MBT012 showed 99.57% similarity with A. mongoliensis, MBT014 was affiliated with A. tengchongensis with 99.43% similarity, MBT009 showed 99.83% homology with A. gonensis and MBT018, 98.70% similarity with A. karvacharensis. The presence of all this microbial divesrity in one common source is of immense importance related to envioronmental and industrial aspects in general and extraction of thermostable enzymes from these thermophiles specifically opens new horizons in the field of industrial biotechnology. These thermophiles are revealing new capabilities and are being manipulated by biotechnologists in utilizing them in different unique ways

Diversity of culturable thermophilic bacteria from Tata Pani hotspring of Kotli Azad Jammu and Kashmir

Hot water springs are unique areas populated by mesophiles, thermotolerant and hyperthermophiles. They are the source of diversity of thermophiles, mainly belonging to archaea and bacteria domains. The diversity of thermophiles gives an outline of the huge biological potential that can be exploited for industrial applications.To this end, this study was aimed to isolate and characterise the unexplored thermophilic microorganisms from hot water spring in Tatapani, Tehsil & District Kotli AJK, Pakistan. Around 10 bacterial isolates were identified using morphological, biochemical, physiological and molecular attributes. Sequencing of the 16S rDNA gene of the isolates followed by BLAST search revealed that the strain MBT008 has 100% similarity with Anoxybacillus kamchatkensis. MBT012 showed 99.57% similarity with A. mongoliensis, MBT014 was affiliated with A. tengchongensis with 99.43% similarity, MBT009 showed 99.83% homology with A. gonensis and MBT018, 98.70% similarity with A. karvacharensis. The presence of all this microbial diversity in one common source is of immense importance related to envioronmental and industrial aspects in general and extraction of thermostable enzymes from these thermophiles specifically opens new horizons in the field of industrial biotechnology. These thermophiles are revealing new capabilities and are being manipulated by biotechnologists in utilizing them in different unique ways