Predictors and outcomes of sustained, intermittent or never achieving remission in patients with recent onset inflammatory polyarthritis:Results from the Norfolk Arthritis Register

Objectives: Early remission is the current treatment strategy for patients with inflammatory polyarthritis (IP) and RA. Our objective was to identify baseline factors associated with achieving remission: sustained (SR), intermittent (IR) or never (NR) over a 5-year period in patients with early IP.  Methods: Clinical and demographic data of patients with IP recruited to the Norfolk Arthritis Register (NOAR) were obtained at baseline and years 1, 2, 3 and 5. Remission was defined as no tender or swollen joints (out of 51). Patients were classified as NR or PR, respectively, if they were in remission at: no assessment or ⩾3 consecutive assessments after baseline, and IR otherwise. Ordinal regression and a random effects model, respectively, were used to examine the association between baseline factors, remission group and HAQ scores over time.  Results: A total of 868 patients (66% female) were included. Of these, 54%, 34% and 12% achieved NR, IR and SR, respectively. In multivariate analysis, female sex (odds ratio, OR 0.47, 95% CI: 0.35, 0.63), higher tender joint count (OR = 0.94, 95% CI: 0.93, 0.96), higher HAQ (OR = 0.59, 95% CI: 0.48, 0.74), being obese (OR = 0.70, 95% CI: 0.50, 0.99), hypertensive (OR = 0.67, 95% CI: 0.50, 0.90) or depressed (OR = 0.74, 95% CI: 0.55, 1.00) at baseline were independent predictors of being in a lower remission group. IR and SR were associated with lower HAQ scores over time and lower DAS28 at year 5.  Conclusion: Women with higher tender joint count and disability at baseline, depression, obesity and hypertension were less likely to achieve remission. This information could help when stratifying patients for more aggressive therapy

Beyond checklists: Using clinic ethnography to assess the enabling environment for tuberculosis infection prevention control in South Africa

Sub-optimal implementation of infection prevention and control (IPC) measures for airborne infections is associated with a rise in healthcare-acquired infections. Research examining contributing factors has tended to focus on poor infrastructure or lack of health care worker compliance with recommended guidelines, with limited consideration of the working environments within which IPC measures are implemented. Our analysis of compromised tuberculosis (TB)-related IPC in South Africa used clinic ethnography to elucidate the enabling environment for TB-IPC strategies. Using an ethnographic approach, we conducted observations, semi-structured interviews, and informal conversations with healthcare staff in six primary health clinics in KwaZulu-Natal, South Africa between November 2018 and April 2019. Qualitative data and fieldnotes were analysed deductively following a framework that examined the intersections between health systems ‘hardware’ and ‘software’ issues affecting the implementation of TB-IPC. Clinic managers and front-line staff negotiate and adapt TB-IPC practices within infrastructural, resource and organisational constraints. Staff were ambivalent about the usefulness of managerial oversight measures including IPC protocols, IPC committees and IPC champions. Challenges in implementing administrative measures including triaging and screening were related to the inefficient organisation of patient flow and information, as well as inconsistent policy directives. Integration of environmental controls was hindered by limitations in the material infrastructure and behavioural norms. Personal protective measures, though available, were not consistently applied due to limited perceived risk and the lack of a collective ethos around health worker and patient safety. In one clinic, positive organisational culture enhanced staff morale and adherence to IPC measures. ‘Hardware’ and ‘software’ constraints interact to impact negatively on the capacity of primary care staff to implement TB-IPC measures. Clinic ethnography allowed for multiple entry points to the ‘problematic’ of compromised TB-IPC, highlighting the importance of capturing dimensions of the ‘enabling environment’, currently not assessed in binary checklists

Beyond checklists: Using clinic ethnography to assess the enabling environment for tuberculosis infection prevention control in South Africa

From PLOS via Jisc Publications RouterHistory: collection 2022, received 2022-05-04, accepted 2022-10-12, epub 2022-11-09Acknowledgements: We acknowledge the important contributions of Gimenne Zwama, Thandeka Smith and Zama Khanyile in conducting and documenting the ethnographic fieldwork in KZN. We are grateful to the health clinic managers and health workers for their time, interest, and motivation to participate in this study. We thank our colleagues from the Umoya omuhle project for the rich inter-disciplinary discussions and exchange of ideas.Publication status: PublishedFunder: Economic and Social Research Council; funder-id: http://dx.doi.org/10.13039/501100000269; Grant(s): ES/P008011/1Funder: Bloomsbury Set, Research England; Grant(s): CCF17-7779Funder: Economic and Social Research Council; Grant(s): ES/P008011/1Funder: Wellcome Trust Strategic Core Award; Grant(s): Africa Health Research Institute, ref. 201433/A/16/ASub-optimal implementation of infection prevention and control (IPC) measures for airborne infections is associated with a rise in healthcare-acquired infections. Research examining contributing factors has tended to focus on poor infrastructure or lack of health care worker compliance with recommended guidelines, with limited consideration of the working environments within which IPC measures are implemented. Our analysis of compromised tuberculosis (TB)-related IPC in South Africa used clinic ethnography to elucidate the enabling environment for TB-IPC strategies. Using an ethnographic approach, we conducted observations, semi-structured interviews, and informal conversations with healthcare staff in six primary health clinics in KwaZulu-Natal, South Africa between November 2018 and April 2019. Qualitative data and fieldnotes were analysed deductively following a framework that examined the intersections between health systems ‘hardware’ and ‘software’ issues affecting the implementation of TB-IPC. Clinic managers and front-line staff negotiate and adapt TB-IPC practices within infrastructural, resource and organisational constraints. Staff were ambivalent about the usefulness of managerial oversight measures including IPC protocols, IPC committees and IPC champions. Challenges in implementing administrative measures including triaging and screening were related to the inefficient organisation of patient flow and information, as well as inconsistent policy directives. Integration of environmental controls was hindered by limitations in the material infrastructure and behavioural norms. Personal protective measures, though available, were not consistently applied due to limited perceived risk and the lack of a collective ethos around health worker and patient safety. In one clinic, positive organisational culture enhanced staff morale and adherence to IPC measures. ‘Hardware’ and ‘software’ constraints interact to impact negatively on the capacity of primary care staff to implement TB-IPC measures. Clinic ethnography allowed for multiple entry points to the ‘problematic’ of compromised TB-IPC, highlighting the importance of capturing dimensions of the ‘enabling environment’, currently not assessed in binary checklists

Tuberculosis infection prevention and control: why we need a whole systems approach.

Infection prevention and control (IPC) measures to reduce transmission of drug-resistant and drug-sensitive tuberculosis (TB) in health facilities are well described but poorly implemented. The implementation of TB IPC has been assessed primarily through quantitative and structured approaches that treat administrative, environmental, and personal protective measures as discrete entities. We present an on-going project entitled Umoya omuhle ("good air"), conducted in two provinces of South Africa, that adopts an interdisciplinary, 'whole systems' approach to problem analysis and intervention development for reducing nosocomial transmission of Mycobacterium tuberculosis (Mtb) through improved IPC. We suggest that TB IPC represents a complex intervention that is delivered within a dynamic context shaped by policy guidelines, health facility space, infrastructure, organisation of care, and management culture. Methods drawn from epidemiology, anthropology, and health policy and systems research enable rich contextual analysis of how nosocomial Mtb transmission occurs, as well as opportunities to address the problem holistically. A 'whole systems' approach can identify leverage points within the health facility infrastructure and organisation of care that can inform the design of interventions to reduce the risk of nosocomial Mtb transmission

The photochemical mediated ring contraction of 4H-1,2,6-thiadiazines to afford 1,2,5-thiadiazol-3(2H)-one 1-oxides

E.B. and C.G.T. are grateful to Heriot-Watt University and the EPSRC CRITICAT Centre for Doctoral Training (E.B. Ph.D. Studentship: EP/L016419/1, C.G.T Ph.D. Studentship: EP/LO14419/1) for funding and training. C.G.T. is grateful to the Heriot-Watt Annual Fund for financial support. P.A.K. and A.S.K. thank the University of Cyprus for the Internal Grant “Thiadiazine-Based Organic Photovoltaics”, and the Cyprus Research Promotion Foundation (Grant Nos. ΣΤΡΑΤΗΙΙ/0308/06, NEKYP/0308/02 ΥΓΕΙΑ/0506/19, and ΕΝΙΣΧ/0308/83). M.J.P. thanks the EPSRC for funding (Grant Nos. EP/T021675 and EP/V006746), and the Leverhulme Trust (Grant No. PG-2020-208). S.A.M. thanks the EPSRC for funding (Grant No. EP/T019867/1).1,2,6-Thiadiazines treated with visible light and 3O2 under ambient conditions are converted into difficult-to-access 1,2,5-thiadiazole 1-oxides (35 examples, yields of 39–100%). Experimental and theoretical studies reveal that 1,2,6-thiadiazines act as triplet photosensitizers that produce 1O2 and then undergo a chemoselective [3 + 2] cycloaddition to give an endoperoxide that ring contracts with selective carbon atom excision and complete atom economy. The reaction was optimized under both batch and continuous-flow conditions and is also efficient in green solvents.Publisher PDFPeer reviewe

The Campbells: lordship, literature and liminality

The Campbells have the potential to offer much to the theme of literature and borders, given that the kindred’s astonishing political success in the late medieval and early modern period depended heavily upon the ability to negotiate multiple frontiers: between Highlands and Lowlands; between Gaelic Scotland and Ireland, and, especially after the Reformation, with England and the matter of Britain. This paper will explore the literary dimension to Campbell expansionism, from the Book of the Dean of Lismore in the earlier sixteenth century, to poetry addressed to dukes of Argyll in the earlier eighteenth century. Particular attention will be paid to the literary proclivities of the household of the Campbells of Glenorchy on either side of what appears to be a major watershed in 1550; and to the agenda of the Campbell protégé John Carswell, first post-Reformation bishop of the Isles, and author of the first printed book in Gaelic in either Scotland or Ireland, Foirm na n-Urrnuidheadh (‘The Form of Prayers’), published at Edinburgh in 1567

Prime–boost vaccination with plasmid and adenovirus gene vaccines control HER2/neu(+ )metastatic breast cancer in mice

INTRODUCTION: Once metastasis has occurred, the possibility of completely curing breast cancer is unlikely, particularly for the 30 to 40% of cancers overexpressing the gene for HER2/neu. A vaccine targeting p185, the protein product of the HER2/neu gene, could have therapeutic application by controlling the growth and metastasis of highly aggressive HER2/neu(+ )cells. The purpose of this study was to determine the effectiveness of two gene vaccines targeting HER2/neu in preventive and therapeutic tumor models. METHODS: The mouse breast cancer cell line A2L2, which expresses the gene for rat HER2/neu and hence p185, was injected into the mammary fat pad of mice as a model of solid tumor growth or was injected intravenously as a model of lung metastasis. SINCP-neu, a plasmid containing Sindbis virus genes and the gene for rat HER2/neu, and Adeno-neu, an E1,E2a-deleted adenovirus also containing the gene for rat HER2/neu, were tested as preventive and therapeutic vaccines. RESULTS: Vaccination with SINCP-neu or Adeno-neu before tumor challenge with A2L2 cells significantly inhibited the growth of the cells injected into the mammary fat or intravenously. Vaccination 2 days after tumor challenge with either vaccine was ineffective in both tumor models. However, therapeutic vaccination in a prime–boost protocol with SINCP-neu followed by Adeno-neu significantly prolonged the overall survival rate of mice injected intravenously with the tumor cells. Naive mice vaccinated using the same prime–boost protocol demonstrated a strong serum immunoglobulin G response and p185-specific cellular immunity, as shown by the results of ELISPOT (enzyme-linked immunospot) analysis for IFNγ. CONCLUSION: We report herein that vaccination of mice with a plasmid gene vaccine and an adenovirus gene vaccine, each containing the gene for HER2/neu, prevented growth of a HER2/neu-expressing breast cancer cell line injected into the mammary fat pad or intravenously. Sequential administration of the vaccines in a prime–boost protocol was therapeutically effective when tumor cells were injected intravenously before the vaccination. The vaccines induced high levels of both cellular and humoral immunity as determined by in vitro assessment. These findings indicate that clinical evaluation of these vaccines, particularly when used sequentially in a prime–boost protocol, is justified

Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study

Objectives; Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods; Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results; The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (S.D.) HAQ-DI 1.1 (0.83)], with ‘grip’ and ‘activity’ being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = −0.53, P < 0.0001). Conclusion; The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS).

OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441