A cross-sectional survey of the perspectives of older people in the Scottish Highlands on the management of their chronic pain.

BACKGROUND: Although there is evidence of suboptimal outcomes in older people with chronic pain, little emphasis has been placed on those in remote and rural settings. OBJECTIVE: To describe the perspectives of older people in the Scottish Highlands on their chronic pain management. DESIGN: Cross-sectional survey. SETTING: NHS Highland, the most remote and rural geographical health board in Scotland. SUBJECTS: Home-dwelling members of the public aged ≥70 years. METHODS: Anonymised questionnaires were mailed to a random sample of 1800 older people. Questionnaire items were demographics, nature of any chronic pain, management regimens and perceived effectiveness. Validated scales were the Pain Disability Questionnaire and the Tampa Scale for Kinesiophobia. RESULTS: Adjusted response rate was 39.3% (709/1755). One-quarter (25.0%, n = 177) were experiencing chronic pain, being more likely to live in deprived areas (P < 0.05). Median pain intensity was 6 (IQR 4-7, 10 high), causing distress (median 5, IQR 3-7). Respondents largely consulted GPs (66.1%, n = 117) with a minority (16.4%, n = 29) referred to a specialist pain clinic and few consulting other health professionals. Over three quarters (78.0%, n = 138) were receiving prescribed medicines, most commonly paracetamol, alone (35.6%, n = 63) or in combination with opioids (16.4%, n = 29). One-third (31.6%, n = 56) expressed a desire for more effective medicines; few reported using any non-pharmacological therapies. The median scores for the Pain Disability Questionnaire and Tampa Scale for Kinesiophobia were 74 (IQR 34-104.5, 150 high) and 40 (IQR 35-45, 68 high). CONCLUSIONS: Evidence of provision of appropriate integrated and person-centred chronic pain care is lacking.

A pragmatic application of endobronchial ultrasound-guided transbronchial needle aspiration: a single institution experience.

BACKGROUND: Endobronchial ultrasound-guided trans-bronchial needle aspiration (EBUS-TBNA) is minimally invasive technique used for diagnosis and/or staging of benign and malignant pulmonary and non-pulmonary disease. Previous studies have established the utility of EBUS-TBNA in narrowly defined indications and populations. In this pragmatic 'real world' study we have analysed the use of EBUS-TBNA for a variety of clinical presentations and its clinical application in conjunction with other invasive investigations. METHODS: All EBUS-TBNA procedures performed at Sir Charles Gardiner Hospital in 2012-2014 were reviewed retrospectively, using relevant hospital databases. RESULTS: A total of 327 patients underwent 337 EBUS-TBNA procedures. EBUS-TBNA procedures were used to diagnose a wide spectrum of benign and malignant conditions. The main application was in the diagnosis and staging of malignant conditions (70.6%), and in the diagnosis of benign conditions such as sarcoidosis 40 (12.2%), and silicoanthracosis 17 (5.2%). EBUS-TBNA was sufficient to diagnose and stage the disease as a single stand-alone invasive procedure in 191 (59.2%) patients. EBUS-TBNA was the final invasive procedure undertaken in 283 (87.6%) patients. Only 13.3% of non small cell lung cancer (NSCLC) patients who had EBUS-TBNA as a first investigation required multiple procedures compared to 51.1% of all NSCLC patients undergoing EBUS-TBNA. Overall sensitivity, specificity, NPV and diagnostic accuracy for EBUS-TBNA were 89.7, 100, 85.1 and 89.9%, respectively and three minor complications (0.9%) occurred as a result of the procedure. CONCLUSIONS: EBUS-TBNA was undertaken for a wide variety of clinical conditions. Good diagnostic accuracy and safety profiles were demonstrated for the procedure, supporting its application as a first line investigation in the diagnosis and/or staging of a range of malignant and benign conditions. Our study was unique in its documentation of the use of EBUS-TBNA in a real-world setting in conjunction with other invasive modalities. EBUS-TBNA was utilised as a stand alone invasive procedure in more than half of the patients. Importantly, in NSCLC, when EBUS-TBNA was performed as primary diagnostic and staging investigation, less patients underwent subsequent invasive procedures.

Model-based trajectory tracking of a compliant continuum robot.

Introduction: Compliant mechanisms, especially continuum robots, are becoming integral to advancements in minimally invasive surgery due to their ability to autonomously navigate natural pathways, significantly reducing collision severity. A major challenge lies in developing an effective control strategy to accurately reflect their behavior for enhanced operational precision. Methods: This study examines the trajectory tracking capabilities of a tendon-driven continuum robot at its tip. We introduce a novel feedforward control methodology that leverages a mathematical model based on Cosserat rod theory. To mitigate the computational challenges inherent in such models, we implement an implicit time discretization strategy. This approach simplifies the governing equations into space-domain ordinary differential equations, facilitating real-time computational efficiency. The control strategy is devised to enable the robot tip to follow a dynamically prescribed trajectory in two dimensions. Results: The efficacy of the proposed control method was validated through experimental tests on six different demand trajectories, with a motion capture system employed to assess positional accuracy. The findings indicate that the robot can track trajectories with an accuracy within 9.5%, showcasing consistent repeatability across different runs. Discussion: The results from this study mark a significant step towards establishing an efficient and precise control methodology for compliant continuum robots. The demonstrated accuracy and repeatability of the control approach significantly enhance the potential of these robots in minimally invasive surgical applications, paving the way for further research and development in this field.

A qualitative exploration of chronic pain management of older adults in remote and rural settings.

BACKGROUND: The World Health Organization predicts that the number of older adults will nearly double between 2015 and 2050. Older adults are at a higher risk of developing medical conditions such as chronic pain. However, there is little information about chronic pain and its management in older adults especially those residing in remote and rural areas. AIM: To explore views, experiences, and behavioural determinants of older adults regarding chronic pain management in remote and rural settings in Scottish Highlands. METHOD: Qualitative one-to-one telephone interviews were conducted with older adults with chronic pain residing in remote and rural areas in the Scottish Highlands. The interview schedule was developed by the researchers, validated, and piloted prior to use. All interviews were audio-recorded, transcribed, and independently thematically-analysed by two researchers. Interviews continued until data saturation. RESULTS: Fourteen interviews were conducted with three key themes emerging: views and experiences with chronic pain, need to enhance pain management, and perceived barriers to pain management. Overall, pain was reported as severe and negatively impacted lives. Majority of interviewees used medicines for pain relief but noted that their pain was still poorly controlled. Interviewees had limited expectation for improvement since they considered their condition a normal consequence of ageing. Residing in remote and rural areas was perceived to complicate access to services with many having to travel long distances to see a health professional. CONCLUSION: Chronic pain management in remote and rural areas remains a significant issue among older adults interviewed. Thus, there is a need to develop approaches to improve access to related information and services.

Postgraduate career intentions of medical students and recent graduates in Malawi: a qualitative interview study.

BACKGROUND: In 2004, the Malawian Ministry of Health declared a human resource crisis and launched a six year Emergency Human Resources Programme. This included salary supplements for key health workers and a tripling of doctors in training. By 2010, the number of medical graduates had doubled and significantly more doctors were working in rural district hospitals. Yet there has been little research into the views of this next generation of doctors in Malawi, who are crucial to the continuing success of the programme. The aim of this study was to explore the factors influencing the career plans of medical students and recent graduates with regard to four policy-relevant aspects: emigration outside Malawi; working at district level; private sector employment and postgraduate specialisation. METHODS: Twelve semi-structured interviews were conducted with fourth year medical students and first year graduates, recruited through purposive and snowball sampling. Key informant interviews were also carried out with medical school faculty. Recordings were transcribed and analysed using a framework approach. RESULTS: Opportunities for postgraduate training emerged as the most important factor in participants' career choices, with specialisation seen as vital to career progression. All participants intended to work in Malawi in the long term, after a period of time outside the country. For nearly all participants, this was in the pursuit of postgraduate study rather than higher salaries. In general, medical students and young doctors were enthusiastic about working at district level, although this is curtailed by their desire for specialist training and frustration with resource shortages. There is currently little intention to move into the private sector. CONCLUSIONS: Future resourcing of postgraduate training opportunities is crucial to preventing emigration as graduate numbers increase. The lesser importance put on salary by younger doctors may be an indicator of the success of salary supplements. In order to retain doctors at district levels for longer, consideration should be given to the introduction of general practice/family medicine as a specialty. Returning specialists should be encouraged to engage with younger colleagues as role models and mentors.

Evaluation of a shared approach to interprofessional learning about stroke self-management.

This article describes an evaluation of interprofessional training in a stroke self-management program (SSMP) for health and social care professionals. Sixty-six practitioners from 8 teams and 11 professions received training. The aim was to evaluate the impact of the interprofessional training on participants' beliefs and attitudes to self-management and collaboration and knowledge sharing throughout the stroke pathway. Methods included contextual mapping of the stroke pathway, before and after questionnaires, analysis of practitioners' case reflections on their use of the SSMP and semi-structured interviews. Overall, practitioners' attitudes and beliefs about self-management had changed post-training, and the majority felt the program could be used successfully throughout the stroke pathway. Practitioners felt that the interprofessional training had led to a more consistent approach to supporting self-management and had improved communication between teams about patients/goals. The project provided the opportunity for interprofessional teams to explore beliefs and attitudes to changes in practice together.

An Integrated Kinematic Modeling and Experimental Approach for an Active Endoscope.

Continuum robots are a type of robotic device that are characterized by their flexibility and dexterity, thus making them ideal for an active endoscope. Instead of articulated joints they have flexible backbones that can be manipulated remotely, usually through tendons secured onto structures attached to the backbone. This structure makes them lightweight and ideal to be miniaturized for endoscopic applications. However, their flexibility poses technical challenges in the modeling and control of these devices, especially when closed-loop control is needed, as is the case in medical applications. There are two main approaches in the modeling of continuum robots, the first is to theoretically model the behavior of the backbone and the interaction with the tendons, while the second is to collect experimental observations and retrospectively apply a model that can approximate their apparent behavior. Both approaches are affected by the complexity of continuum robots through either model accuracy/computational time (theoretical method) or missing complex system interactions and lacking expandability (experimental method). In this work, theoretical and experimental descriptions of an endoscopic continuum robot are merged. A simplified yet representative mathematical model of a continuum robot is developed, in which the backbone model is based on Cosserat rod theory and is coupled to the tendon tensions. A robust numerical technique is formulated that has low computational costs. A bespoke experimental facility with precise automated motion of the backbone via the precise control of tendon tension, leads to a robust and detailed description of the system behavior provided through a contactless sensor. The resulting facility achieves a real-world mean positioning error of 3.95% of the backbone length for the examined range of tendon tensions which performs favourably to existing approaches. Moreover, it incorporates hysteresis behavior that could not be predicted by the theoretical modeling alone, reinforcing the benefits of the hybrid approach. The proposed workflow is theoretically grounded and experimentally validated allowing precise prediction of the continuum robot behavior, adhering to realistic observations. Based on this accurate estimation and the fact it is geometrically agnostic enables the proposed model to be scaled for various robotic endoscopes.

A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice.

BACKGROUND: The spread of SARS-CoV-2 has caused a worldwide pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection and may enable the relaxation of social-distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection; therefore, it is desirable that any new vaccine candidates elicit a robust immune response in older adults. METHODS: Here, we use in-depth immunophenotyping to characterize the innate and adaptive immune response induced upon intramuscular administration of the adenoviral vectored ChAdOx1 nCoV-19 (AZD-1222) COVID-19 vaccine candidate in mice. FINDINGS: A single vaccination generates spike-specific Th1 cells, Th1-like Foxp3+ regulatory T cells, polyfunctional spike-specific CD8+ T cells. and granzyme-B-producing CD8 effectors. Spike-specific IgG and IgM are generated from both the early extrafollicular antibody response and the T follicular helper cell-supported germinal center reaction, which is associated with the production of virus-neutralizing antibodies. A single dose of this vaccine generated a similar type of immune response in aged mice but of a reduced magnitude than in younger mice. We report that a second dose enhances the immune response to this vaccine in aged mice. CONCLUSIONS: This study shows that ChAdOx1 nCoV-19 induces both cellular and humoral immunity in adult and aged mice and suggests a prime-boost strategy is a rational approach to enhance immunogenicity in older persons. FUNDING: This study was supported by BBSRC, Lister institute of Preventative Medicine, EPSRC VaxHub, and Innovate UK.

Follicular Regulatory T Cells Can Access the Germinal Center Independently of CXCR5.

The germinal center (GC) response is critical for generating high-affinity humoral immunity and immunological memory, which forms the basis of successful immunization. Control of the GC response is thought to require follicular regulatory T (Tfr) cells, a subset of suppressive Foxp3+ regulatory T cells located within GCs. Relatively little is known about the exact role of Tfr cells within the GC and how they exert their suppressive function. A unique feature of Tfr cells is their reported CXCR5-dependent localization to the GC. Here, we show that the lack of CXCR5 on Foxp3+ regulatory T cells results in a reduced frequency, but not an absence, of GC-localized Tfr cells. This reduction in Tfr cells is not sufficient to alter the magnitude or output of the GC response. This demonstrates that additional, CXCR5-independent mechanisms facilitate Treg cell homing to the GC.

Enhancing the oral bioavailability of the poorly soluble drug dicumarol with a bioadhesive polymer.

This article investigates the effect of particle size and the incorporation of a bioadhesive polymer, poly(fumaric-co-sebacic) anhydride p(FA:SA), on the relative bioavailability of dicumarol. A novel method was used to reduce particle size of the drug, and encapsulated formulations were fabricated using a phase inversion technique to produce nanospheres and microspheres with varying size. Groups of Yorkshire swine were catheterized and gavaged after fasting for 12 h with each formulation in a 50 mg/mL suspension. Blood was collected at different time points, from 0 to 96 h, and pharmacokinetic analysis revealed that formulations incorporating the smaller drug particles showed the highest bioavailability: micronized drug with 7% p(FA:SA) 17:83 polymer had 190% relative bioavailability, and phase inverted p(FA:SA) 17:83 microspheres with 31% (w/w) loading had 198% relative bioavailability to spray dried formulation. Formulations with larger drug particles achieved 71% relative bioavailability. A nonadhesive formulation, fabricated with poly(lactic acid) (PLA), showed 91% relative bioavailability. Both particle size and polymer composition play a role in oral absorption of dicumarol.

The development of an analytical method for urinary metabolites of the riot control agent 2-chlorobenzylidene malononitrile (CS).

The analysis of biomedical samples such as urine and blood can provide evidence of exposure to chemicals for a range of applications including occupational exposure monitoring, detection of drugs of abuse, performance enhancement in sport and investigations of poisoning and incapacitation. This paper reports the development of an analytical method for two suspected urinary metabolites of the riot control agent 2-chlorobenzylidene malononitrile (CS): 2-chlorohippuric acid and 2-chlorobenzyl-N-acetylcysteine. 2-Chlorohippuric acid was identified in all 2h post-exposure samples from a set of urine samples taken from army recruits exposed to low levels of thermally dispersed CS during training. 2-Chlorobenzyl-N-acetylcysteine, a metabolite known to be formed in the rat, was not identified in any of the samples. The lower limit of detection (LLOD) for 2-chlorohippuric acid and 2-chlorobenzyl-N-acetylcysteine was 1ng/ml and 0.5ng/ml in pooled urine from the pre-exposed subjects. 2-Chlorohippuric acid was rapidly excreted but was detectable in the urine of 17 of the 19 subjects tested 20h after exposure.

Immune response to two different dosing schedules of the anthrax vaccine precipitated (AVP) vaccine.

A pilot study compared the immune response of regular (0, 3, 6, 32 weeks) and extended (0, 10, 13, 32 weeks) schedules of the UK anthrax vaccine (anthrax vaccine precipitated, AVP). Concentrations of antibodies to protective antigen (PA) were higher (p<0.05) among recipients of the extended (n=7) versus regular schedule (n=6) at week 32, and 2 weeks after the second and third vaccinations. Toxin neutralisation assay levels and anti-lethal factor antibodies followed patterns similar to anti-PA antibodies. Extending the interval between the first two AVP vaccinations may produce a stronger immune response, but persistence of this effect needs further study.

Psychiatric disorders amongst adults with learning disabilities - prevalence and relationship to ability level.

OBJECTIVES: To determine the prevalence of psychiatric disorders in adults with learning disabilities, and the relationship with severity of learning disabilities. METHOD: The study is population-based. Detailed psychiatric assessments on 207 adults with learning disabilities living in Leicestershire, UK. were conducted by a learning disabilities psychiatrist, using the Present Psychiatric State - Learning Disabilities; and Disability Assessment Schedule. Diagnostic criteria are clearly defined. Developmental assessments were undertaken using the Vineland Scale (survey form). RESULTS: Psychiatric disorders were found in 49.2%, and rates for most individual disorders were higher than those found in the general population. Comparison with the two previous population-based studies shows the ascertained rates were broadly similar to those reported by Corbett but higher than those reported by Lund. Adults with more severe learning disabilities had higher rates of additional psychiatric disorders. CONCLUSIONS: The results may be explained by a combination of the genetic, physical, psychological and social factors associated with learning disabilities also being aetiological to psychiatric disorders. The high prevalence rates of psychiatric disorders demonstrate the importance of health service provision for adults with learning disabilities.

Cross-reactivity of Schistosoma mansoni cytosolic superoxide dismutase, a protective vaccine candidate, with host superoxide dismutase and identification of parasite-specific B epitopes.

Schistosoma mansoni, an intravascular parasite, has evolved a number of immune evasion mechanisms to establish itself in the host, such as antioxidant enzymes. Our laboratory has demonstrated that the highest levels of certain antioxidant enzymes are found in adult worms, which are the least susceptible to immune killing. Vaccination of mice with naked DNA constructs containing the gene encoding Cu/Zn cytosolic superoxide dismutase (SmCT-SOD) showed significant levels of protection compared to a control group, and our data demonstrate that the adult worms are a target of the immune response that confers resistance in SmCT-SOD DNA-vaccinated mice. Because SmCT-SOD shows significant identity with the human homologue, we evaluated the reactivity of anti-SmCT-SOD antibodies derived from SmCT-SOD-immunized mice and rabbits and from S. mansoni-infected individuals to human superoxide dismutase (hSOD) and SmCT-SOD parasite-specific peptides to assess the potential for autoimmune responses from immunization with the recombinant molecule. In addition, we evaluated the ability of various SmCT-SOD adjuvant-delivered immunizations to induce cross-reactive antibodies. Both mouse and rabbit antibodies generated against SmCT-SOD recognized the denatured form of hSOD. The same antibodies did not recognize nondenatured hSOD. Sera from infected individuals with different clinical forms of schistosomiasis recognized SmCT-SOD but not hSOD. Antibodies from mice immunized with different SmCT-SOD-containing formulations of both DNA and protein were able to recognize SmCT-SOD-derived peptides but not soluble hSOD. All together, these findings serve as a basis for developing a subunit vaccine against schistosomiasis.

Human CD4+ T cells present within the microenvironment of human lung tumors are mobilized by the local and sustained release of IL-12 to kill tumors in situ by indirect effects of IFN-gamma.

By implanting nondisrupted pieces of human lung tumor biopsy tissues into SCID mice, it has been possible to establish viable grafts of the tumor, as well as the tumor-associated microenvironment, including inflammatory cells, fibroblasts, tumor vasculature, and the extracellular matrix. Using this xenograft model, we have evaluated and characterized the effects of a local and sustained release of human rIL-12 (rhIL-12) from biodegradable microspheres. In response to rhIL-12, the human CD45+ inflammatory cells present within the xenograft mediate the suppression or the complete arrest of tumor growth in SCID mice. Analysis of the cellular events reveals that human CD4+ and CD8+ T cells are induced by rhIL-12 to produce and secrete IFN-gamma. Serum levels of human IFN-gamma in mice bearing rhIL-12-treated tumor xenografts correlate directly with the degree of tumor suppression, while neutralizing Abs to human IFN-gamma abrogate the IL-12-mediated tumor suppression. Gene expression profiling of tumors responding to intratumoral rhIL-12 demonstrates an up-regulation of IFN-gamma and IFN-gamma-dependent genes not observed in control-treated tumors. Genes encoding a number of proinflammatory cytokines, chemokines (and their receptors), adhesion molecules, activation markers, and the inducible NO synthase are up-regulated following the introduction of rhIL-12, while genes associated with tumor growth, angiogenesis, and metastasis are decreased in expression. NO contributes to the tumor killing because an inhibitor of inducible NO synthase prevents IL-12-induced tumor suppression. Cell depletion studies reveal that the IL-12-induced tumor suppression, IFN-gamma production, and the associated changes in gene expression are all dependent upon CD4+ T cells.

Intratumoral IL-12 and TNF-alpha-loaded microspheres lead to regression of breast cancer and systemic antitumor immunity.

BACKGROUND: Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response. METHODS: BALB/c mice with established MT-901 tumors underwent resection or treatment with a single intratumoral injection of PLAM containing IL-12, TNF-alpha, or GM-CSF, alone or in combination. Two weeks later, lymph nodes and spleens were harvested, activated with anti-CD3 monoclonal antibodies (mAb) and rhIL-2, and assessed for antitumor reactivity by an interferon gamma (IFNgamma) release assay. Tumor-infiltrating lymphocyte (TIL) analysis was performed on days 2 and 5 after treatment by mechanically processing the tumors to create a single cell suspension, followed by three-color fluorescence-activated cell sorter (FACS) analysis. RESULTS: Intratumoral injection of cytokine-loaded PLAM significantly suppressed tumor growth, with the combination of IL-12 and TNF-alpha leading to increased infiltration by polymorphonuclear cells and CD8+ T-cells in comparison with controls. The induction of tumor-specific reactive T-cells in the nodes and spleens, as measured by IFN-gamma production, was highest with IL-12 and TNF-alpha. This treatment resulted in resistance to tumor rechallenge. CONCLUSIONS: A single intratumoral injection of IL-12 and TNF-alpha-loaded PLAM into a breast tumor leads to infiltration by polymorphonuclear cells and CD8+ T-cells with subsequent tumor regression. In addition, this local therapy induces specific antitumor T-cells in the lymph nodes and spleens, resulting in memory immune response.