Current and future economic burden of diabetes among working-age adults in Asia: conservative estimates for Singapore from 2010-2050

Abstract Background Diabetes not only imposes a huge health burden but also a large economic burden worldwide. In the working-age population, cost of lost productivity can far exceed diabetes-related medical cost. In this study, we aimed to estimate the current and future indirect and excess direct costs of diagnosed type 2 diabetes among the working-age population in Singapore. Methods A previously-published epidemiological model of diabetes was adapted to forecast prevalence among working-age patients with diagnosed type 2 diabetes in the absence of interventions. The current methodology of the American Diabetes Association was adopted to estimate the costs of diabetes for this population. Diabetes-related excess direct medical costs were obtained from a local cost study while indirect costs were calculated using the human capital approach applied to local labor force statistics. These cost were estimated conservatively from a societal perspective on a per patient basis and projected to the overall Singapore population from 2010 to 2050. Results In 2010, total economic costs per working-age patient were estimated to be US$5,646 (US$4,432-US$10,612), of which 42$7,791 (US$5,741-US$12,756) in 2050, with the share of indirect costs rising to 65 %. Simultaneous increases in prevalence imply that the total economic costs of diabetes for the entire working-age population will increase by 2.4 fold from US$787 million in 2010 to US$1,867 million in 2050. Conclusions By current projections, diabetes in Singapore represents a growing economic burden. Among the working-age population, the impact of productivity loss will become increasingly significant. Prevention efforts to reduce overall prevalence should also engage stakeholders outside the health sector who ultimately bear the indirect burden of disease

Behaviour change physiotherapy intervention to increase physical activity following hip and knee replacement (PEP-TALK): study protocol for a pragmatic randomised controlled trial.

INTRODUCTION: While total hip replacement (THR) and total knee replacement (TKR) successfully reduce pain associated with chronic joint pathology, this infrequently translates into increased physical activity. This is a challenge given that over 50% of individuals who undergo these operations are physically inactive and have medical comorbidities such as hypertension, heart disease, diabetes and depression. The impact of these diseases can be reduced with physical activity. This trial aims to investigate the effectiveness of a behaviour change physiotherapy intervention to increase physical activity compared with usual rehabilitation after THR or TKR. METHODS AND ANALYSIS: The PEP-TALK trial is a multicentre, open-labelled, pragmatic randomised controlled trial. 260 adults who are scheduled to undergo a primary unilateral THR or TKR and are moderately inactive or inactive, with comorbidities, will be recruited across eight sites in England. They will be randomised post-surgery, prior to hospital discharge, to either six, 30 min weekly group-based exercise sessions (control), or the same six weekly, group-based, exercise sessions each preceded by a 30 min cognitive behaviour approach discussion group. Participants will be followed-up to 12 months by postal questionnaire. The primary outcome is the University of California, Los Angeles (UCLA) Physical Activity Score at 12 months. Secondary outcomes include: physical function, disability, health-related quality of life, kinesiophobia, perceived pain, self-efficacy and health resource utilisation. ETHICS AND DISSEMINATION: Research ethics committee approval was granted by the NRES Committee South Central (Oxford B - 18/SC/0423). Dissemination of results will be through peer-reviewed, scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN29770908

P181 Musculoskeletal pain and prognosis of acute coronary syndrome and cerebrovascular accident: a linked electronic health record cohort study

Abstract Background/Aims There is some evidence of an increased risk of cardiovascular disease in patients with painful musculoskeletal conditions, but it is unclear if musculoskeletal pain also worsens its prognosis. The aim was to determine whether patients with musculoskeletal pain have poorer prognosis following acute coronary syndrome (ACS) or cerebrovascular accident (CVA). Methods Data were obtained from national primary care electronic health records (Clinical Practice Research Datalink; CPRD) with linkage to hospital admissions and mortality records. Patients aged 45 years and over with ACS or CVA recorded in primary care and as the primary reason for hospital admission within ±30 days were included. Patients were grouped by consultations in primary care for painful musculoskeletal conditions (by recency/severity and by condition) in the 24 months prior to ACS or CVA. Severe musculoskeletal pain was defined as prescription of strong analgesia or relevant secondary care referral in the 6 months before ACS or CVA. Short-term outcomes included length of hospital stay, mortality during admission or within 30 days of discharge, and readmission within 30 days of discharge. Management outcomes included procedures during admission and prescriptions for anti-hypertensives, anti-platelets and anti-coagulants in the 3 months following admission. Longer term outcomes included further ACS or CVA and mortality in those who survived &amp;gt;30 days after discharge. Results There were 171,670 patients with ACS (36% females; median age 70 years) and 138,512 patients with CVA (49% females; median age 76 years); 30% of patients in each cohort consulted for a painful musculoskeletal condition prior to admission for ACS or CVA. An increased prevalence of cardiovascular risk factors was observed for patients with severe musculoskeletal pain compared to those without pain for comorbidities such as obesity (ACS 26% vs 16%, CVA 25% vs 15%), diabetes (ACS 24% vs 17%, CVA 23% vs 17%) and lifestyle characteristics such as current/ex-smoker (ACS 58% vs 52%, CVA 52% vs 46%), respectively. Patients with severe musculoskeletal pain had similar lengths of stay, rates of readmission and further ACS/CVA after adjustment for sociodemographic characteristics and comorbidities than those without musculoskeletal pain. They were more likely to receive a procedure during admission for ACS (adjusted risk ratio [aRR] 1.15, 95% confidence interval [CI] 1.03-1.28). Prescriptions for ACS (severe pain aRR 1.01, 95% CI 1.00-1.02; inflammatory condition aRR 1.01, 95% CI 1.00-1.02) and CVA (inflammatory condition aRR 1.04, 95% CI 1.01-1.06) were higher in the 3 months post-admission for those with musculoskeletal pain. Conclusion Musculoskeletal pain did not independently worsen the prognosis following hospitalisation for incident ACS or CVA. The findings are reassuring, but also highlight the need for closer surveillance due to the complexities of patients with severe musculoskeletal presenting with incident ACS or CVA. Disclosure K.J. Mason: None. K.P. Jordan: None. F.A. Achana: None. J. Bailey: None. Y. Chen: None. M. Frisher: None. A.L. Huntley: None. C.D. Mallen: None. M.A. Mamas: None. M. Png: None. S. Tatton: None. S. White: None. J.J. Edwards: None. </jats:sec

Negative-pressure wound therapy compared with standard dressings following surgical treatment of major trauma to the lower limb: the WHiST RCT.

BACKGROUND: Major trauma is the leading cause of death in people aged  72 hours after injury and inability to complete questionnaires. INTERVENTIONS: Incisional negative-pressure wound therapy (n = 785), in which a non-adherent absorbent dressing covered with a semipermeable membrane is connected to a pump to create a partial vacuum over the wound, versus standard dressings not involving negative pressure (n = 763). Trial participants and the treating surgeon could not be blinded to treatment allocation. MAIN OUTCOME MEASURES: Deep surgical site infection at 30 days was the primary outcome measure. Secondary outcomes were deep infection at 90 days, the results of the Disability Rating Index, health-related quality of life, the results of the Patient and Observer Scar Assessment Scale and resource use collected at 3 and 6 months post surgery. RESULTS: A total of 98% of participants provided primary outcome data. There was no evidence of a difference in the rate of deep surgical site infection at 30 days. The infection rate was 6.7% (50/749) in the standard dressing group and 5.8% (45/770) in the incisional negative-pressure wound therapy group (intention-to-treat odds ratio 0.87; 95% confidence interval 0.57 to 1.33; p = 0.52). There was no difference in the deep surgical site infection rate at 90 days: 13.2% in the standard dressing group and 11.4% in the incisional negative-pressure wound therapy group (odds ratio 0.84, 95% confidence interval 0.59 to 1.19; p = 0.32). There was no difference between the two groups in disability, quality of life or scar appearance at 3 or 6 months. Incisional negative-pressure wound therapy did not reduce the cost of treatment and was associated with a low probability of cost-effectiveness. LIMITATIONS: Owing to the emergency nature of the surgery, we anticipated that some patients who were randomised would subsequently be unable or unwilling to participate. However, the majority of the patients (85%) agreed to participate. Therefore, participants were representative of the population with lower-limb fractures associated with major trauma. CONCLUSIONS: The findings of this study do not support the use of negative-pressure wound therapy in patients having surgery for major trauma to the lower limbs. FUTURE WORK: Our work suggests that the use of incisional negative-pressure wound therapy dressings in other at-risk surgical wounds requires further investigation. Future research may also investigate different approaches to reduce postoperative infections, for example the use of topical antibiotic preparations in surgical wounds and the role of orthopaedic implants with antimicrobial coatings when fixing the associated fracture. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12702354 and UK Clinical Research Network Portfolio ID20416. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 38. See the NIHR Journals Library for further project information

Benefits and harms of antenatal and newborn screening programmes in health economic assessments: the VALENTIA systematic review and qualitative investigation.

BACKGROUND: Health economic assessments are used to determine whether the resources needed to generate net benefit from an antenatal or newborn screening programme, driven by multiple benefits and harms, are justifiable. It is not known what benefits and harms have been adopted by economic evaluations assessing these programmes and whether they omit benefits and harms considered important to relevant stakeholders. OBJECTIVES: (1) To identify the benefits and harms adopted by health economic assessments in this area, and to assess how they have been measured and valued; (2) to identify attributes or relevance to stakeholders that ought to be considered in future economic assessments; and (3) to make recommendations about the benefits and harms that should be considered by these studies. DESIGN: Mixed methods combining systematic review and qualitative work. SYSTEMATIC REVIEW METHODS: We searched the published and grey literature from January 2000 to January 2021 using all major electronic databases. Economic evaluations of an antenatal or newborn screening programme in one or more Organisation for Economic Co-operation and Development countries were considered eligible. Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist. We identified benefits and harms using an integrative descriptive analysis and constructed a thematic framework. QUALITATIVE METHODS: We conducted a meta-ethnography of the existing literature on newborn screening experiences, a secondary analysis of existing individual interviews related to antenatal or newborn screening or living with screened-for conditions, and a thematic analysis of primary data collected with stakeholders about their experiences with screening. RESULTS: The literature searches identified 52,244 articles and reports, and 336 unique studies were included. Thematic framework resulted in seven themes: (1) diagnosis of screened for condition, (2) life-years and health status adjustments, (3) treatment, (4) long-term costs, (5) overdiagnosis, (6) pregnancy loss and (7) spillover effects on family members. Diagnosis of screened-for condition (115, 47.5%), life-years and health status adjustments (90, 37.2%) and treatment (88, 36.4%) accounted for most of the benefits and harms evaluating antenatal screening. The same themes accounted for most of the benefits and harms included in studies assessing newborn screening. Long-term costs, overdiagnosis and spillover effects tended to be ignored. The wide-reaching family implications of screening were considered important to stakeholders. We observed good overlap between the thematic framework and the qualitative evidence. LIMITATIONS: Dual data extraction within the systematic literature review was not feasible due to the large number of studies included. It was difficult to recruit healthcare professionals in the stakeholder's interviews. CONCLUSIONS: There is no consistency in the selection of benefits and harms used in health economic assessments in this area, suggesting that additional methods guidance is needed. Our proposed thematic framework can be used to guide the development of future health economic assessments evaluating antenatal and newborn screening programmes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42020165236. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127489) and is published in full in Health Technology Assessment; Vol. 28, No. 25. See the NIHR Funding and Awards website for further award information

An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity

We recently characterized Winnie mice carrying a missense mutation in Muc2, leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie, there was a fourfold increase in activated dendritic cells (DCs; CD11c+ major histocompatibility complex (MHC) class IIhi) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal TH17 signature genes Il17a, IL17f, Tgfb, and Ccr6, particularly in the distal colon. Winnie mesenteric lymph node leukocytes secreted multiple TH1, TH2, and TH17 cytokines on activation, with a large increase in interleukin-17A (IL-17A) progressively with age. A major source of mucosal IL-17A in Winnie was CD4+ T lymphocytes. Loss of T and B lymphocytes in Rag1-/- × Winnie (RaW) crosses did not prevent spontaneous inflammation but did prevent progression with age in the colon but not the cecum. Adoptive transfer of naive T cells into RaW mice caused more rapid and severe colitis than in Rag1-/-, indicating that the epithelial defect results in an intestinal microenvironment conducive to T-cell activation. Thus, the Winnie primary epithelial defect results in complex multicytokine-mediated colitis involving both innate and adaptive immune components with a prominent IL-23/TH17 response, similar to that of human ulcerative colitis

Utilisation of Mucin Glycans by the Human Gut Symbiont Ruminococcus gnavus Is Strain-Dependent

Commensal bacteria often have an especially rich source of glycan-degrading enzymes which allow them to utilize undigested carbohydrates from the food or the host. The species Ruminococcus gnavus is present in the digestive tract of ≥90% of humans and has been implicated in gut-related diseases such as inflammatory bowel diseases (IBD). Here we analysed the ability of two R. gnavus human strains, E1 and ATCC 29149, to utilize host glycans. We showed that although both strains could assimilate mucin monosaccharides, only R. gnavus ATCC 29149 was able to grow on mucin as a sole carbon source. Comparative genomic analysis of the two R. gnavus strains highlighted potential clusters and glycoside hydrolases (GHs) responsible for the breakdown and utilization of mucin-derived glycans. Transcriptomic and functional activity assays confirmed the importance of specific GH33 sialidase, and GH29 and GH95 fucosidases in the mucin utilisation pathway. Notably, we uncovered a novel pathway by which R. gnavus ATCC 29149 utilises sialic acid from sialylated substrates. Our results also demonstrated the ability of R. gnavus ATCC 29149 to produce propanol and propionate as the end products of metabolism when grown on mucin and fucosylated glycans. These new findings provide molecular insights into the strain-specificity of R. gnavus adaptation to the gut environment advancing our understanding of the role of gut commensals in health and disease

Cost-utility analysis of molnupiravir plus usual care versus usual care alone as early treatment for community-based adults with COVID-19 and increased risk of adverse outcomes in the UK PANORAMIC trial

This is the author accepted manuscript. The final version is available on open access from the Royal College of General Practitioners via the DOI in this recordData availability: Qualifying researchers who wish to access our data should submit a proposal with a valuable research question. Proposals will be assessed by a committee formed from the trial management group, including senior statistical and clinical representation. Data will be shared in accordance with the data sharing policy of Nuffield Department of Primary Care Health Sciences.BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over six months. DESIGN AND SETTING: Economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK National Health Service and personal social services perspective and a six-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] 445 to 453) and higher mean QALYs of 0.0055 (95% CI 0.004 to 0.007) than usual care (mean incremental cost per QALY of £81190). Sensitivity and subgroup analyses showed similar results, except those aged ≥75 years with a 55% probability of being cost-effective at a £30000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15000 per QALY threshold. CONCLUSION: Molnupiravir at the current cost of £513 per course is unlikely to be cost-effective relative to usual care over a six-month time horizon among mainly vaccinated COVID-19 patients at increased risk of adverse outcomes, except those aged ≥75 years.National Institute for Health and Care Research (NIHR

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

This is the final version. Available on open access from Elsevier via the DOI in this recordData sharing: Qualifying researchers who wish to access our data should submit a proposal with a valuable research question. Proposals will be assessed by a committee formed from the trial management group, including senior statistical and clinical representation. Data will be shared in accordance with the data sharing policy of Nuffield Department of Primary Care Health Sciences.BACKGROUND: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. METHODS: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.National Institute for Health Research (NIHR