Predictors and moderators of the response of adults with intellectual disabilities and depression to behavioural activation and guided self-help therapies.

BACKGROUND: No previous studies have reported predictors and moderators of outcome of psychological therapies for depression experienced by adults with intellectual disabilities (IDs). We investigated baseline variables as outcome predictors and moderators based on a randomised controlled trial where behavioural activation was compared with guided self-help. METHODS: This study was an exploratory secondary data analysis of data collected during a randomised clinical trial. Participants (n = 161) were randomised to behavioural activation or guided self-help and followed up for 12 months. Pre-treatment variables were included if they have previously been shown to be associated with an increased risk of having depression in adults with IDs or have been reported as a potential predictor or moderator of outcome of treatment for depression with psychological therapies. The primary outcome measure, the Glasgow Depression Scale for Adults with Learning Disabilities (GDS-LD), was used as the dependant variable in mixed effects regression analyses testing for predictors and moderators of outcome, with baseline GDS-LD, treatment group, study centre and antidepressant use as fixed effects, and therapist as a random effect. RESULTS: Higher baseline anxiety (mean difference in outcome associated with a 1 point increase in anxiety 0.164, 95% confidence interval [CI] 0.031, 0.297; P = 0.016), lower performance intelligence quotient (IQ) (mean difference in outcome associated with a 1 point increase in IQ 0.145, 95% CI 0.009, 0.280; P = 0.037) and hearing impairment (mean difference 3.449, 95% CI 0.466, 6.432; P = 0.024) were predictors of poorer outcomes, whilst greater severity of depressive symptoms at baseline (mean difference in outcome associated with 1 point increase in depression -0.160, 95% CI -0.806, -0.414; P < 0.001), higher expectation of change (mean difference in outcome associated with a 1 point increase in expectation of change -1.013, 95% CI -1.711, -0.314; p 0.005) and greater percentage of therapy sessions attended (mean difference in outcome with 1 point increase in percentage of sessions attended -0.058, 95% CI -0.099, -0.016; P = 0.007) were predictors of more positive outcomes for treatment after adjusting for randomised group allocation. The final model included severity of depressive and anxiety symptoms, lower WASI performance IQ subscale, hearing impairment, higher expectation of change and percentage of therapy sessions attended and explained 35.3% of the variance in the total GDS-LD score at 12 months (R2  = 0.353, F4, 128  = 17.24, P < 0.001). There is no evidence that baseline variables had a moderating effect on outcome for treatment with behavioural activation or guided self-help. CONCLUSIONS: Our results suggest that baseline variables may be useful predictors of outcomes of psychological therapies for adults with IDs. Further research is required to examine the value of these potential predictors. However, our findings suggest that therapists consider how baseline variables may enable them to tailor their therapeutic approach when using psychological therapies to treat depression experienced by adults with IDs.

Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement: updated reporting guidance for health economic evaluations.

Health economic evaluations are comparative analyses of alternative courses of action in terms of their costs and consequences. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, published in 2013, was created to ensure health economic evaluations are identifiable, interpretable, and useful for decision making. It was intended as guidance to help authors report accurately which health interventions were being compared and in what context, how the evaluation was undertaken, what the findings were, and other details that may aid readers and reviewers in interpretation and use of the study. The new CHEERS 2022 statement replaces previous CHEERS reporting guidance. It reflects the need for guidance that can be more easily applied to all types of health economic evaluation, new methods and developments in the field, as well as the increased role of stakeholder involvement including patients and the public. It is also broadly applicable to any form of intervention intended to improve the health of individuals or the population, whether simple or complex, and without regard to context (such as health care, public health, education, social care, etc). This summary article presents the new CHEERS 2022 28-item checklist and recommendations for each item. The CHEERS 2022 statement is primarily intended for researchers reporting economic evaluations for peer reviewed journals as well as the peer reviewers and editors assessing them for publication. However, we anticipate familiarity with reporting requirements will be useful for analysts when planning studies. It may also be useful for health technology assessment bodies seeking guidance on reporting, as there is an increasing emphasis on transparency in decision making.

Development of a core capability framework for qualified health professionals to optimise care for people with osteoarthritis: an OARSI initiative.

OBJECTIVE: Develop a generic trans-disciplinary, skills-based capability framework for health professionals providing care for people with OA. DESIGN: e-Delphi survey. An international inter-professional Delphi Panel (researchers; clinicians; consumer representatives) considered a draft framework (adapted from elsewhere) of 131 specific capabilities mapped to 14 broader capability areas across four domains (A: person-centred approaches; B: assessment, investigation and diagnosis; C: management, interventions and prevention; D: service and professional development). Over three rounds, the Panel rated their agreement (Likert or numerical rating scales) on whether each specific capability in Domains B and C was essential (core) for all health professionals when providing care for all people with OA. Those achieving consensus (≥80% of Panel) rating of ≥ seven out of ten (Round 3) were retained. Generic domains (A and D) were included in the final framework and amended based on Panel comments. RESULTS: 173 people from 31 countries, spanning 18 disciplines and including 26 consumer representatives, participated. The final framework comprised 70 specific capabilities across 13 broad areas i) communication; ii) person-centred care; iii) history-taking; iv) physical assessment; v) investigations and diagnosis; vi) interventions and care planning; vii) prevention and lifestyle interventions; viii) self-management and behaviour change; ix) rehabilitative interventions; x) pharmacotherapy; xi) surgical interventions; xii) referrals and collaborative working; and xiii) evidence-based practice and service development). CONCLUSION: Experts agree that health professionals require an array of skills in person-centred approaches; assessment, investigation and diagnosis; management, interventions and prevention; and service and professional development to provide optimal care for people with OA.

Health professionals and students encounter multi-level barriers to implementing high-value osteoarthritis care: a multi-national study.

OBJECTIVE: Consistent evidence-practice gaps in osteoarthritis (OA) care are observed in primary care settings globally. Building workforce capacity to deliver high-value care requires a contemporary understanding of barriers to care delivery. We aimed to explore barriers to OA care delivery among clinicians and students. DESIGN: A cross-sectional, multinational study sampling clinicians (physiotherapists, primary care nurses, general practitioners (GPs), GP registrars; total possible denominator: n = 119,735) and final-year physiotherapy and medical students (denominator: n = 2,215) across Australia, New Zealand and Canada. Respondents answered a survey, aligned to contemporary implementation science domains, which measured barriers to OA care using categorical and free-text responses. RESULTS: 1886 clinicians and 1611 students responded. Items within the domains 'health system' and 'patient-related factors' represented the most applicable barriers experienced by clinicians (25-42% and 20-36%, respectively), whereas for students, 'knowledge and skills' and 'patient-related factors' (16-24% and 19-28%, respectively) were the most applicable domains. Meta-synthesis of qualitative data highlighted skills gaps in specific components of OA care (tailoring exercise, nutritional/overweight management and supporting positive behaviour change); assessment, measurement and monitoring; tailoring care; managing case complexity; and translating knowledge to practice (especially among students). Other barriers included general infrastructure limitations (particularly related to community facilities); patient-related factors (e.g., beliefs and compliance); workforce-related factors such as inconsistent care and a general knowledge gap in high-value care; and system and service-level factors relating to financing and time pressures, respectively. CONCLUSIONS: Clinicians and students encounter barriers to delivery of high-value OA care in clinical practice/training (micro-level); within service environments (meso-level); and within the health system (macro-level).

Type 2 diabetes remission: economic evaluation of the DiRECT/Counterweight-Plus weight management programme within a primary care randomized controlled trial.

AIM: The Counterweight-Plus weight management programme achieved 46% remission of Type 2 diabetes at 1 year in the DiRECT trial. We estimated the implementation costs of the Counterweight-Plus programme and its 1-year cost-effectiveness in terms of diabetes remission, compared with usual care, from the UK National Health Service (NHS) perspective. METHODS: Within-trial total costs included programme set-up and running costs (practitioner appointment visits, low-energy formula diet sachets and training), oral anti-diabetes and anti-hypertensive medications, and healthcare contacts. Total costs were calculated for aggregated resource use for each participant and 95% confidence intervals (CI) were based on 1000 non-parametric bootstrap iterations. RESULTS: One-year programme costs under trial conditions were estimated at £1137 per participant (95% CI £1071, £1205). The intervention led to a significant cost-saving of £120 (95% CI £78, £163) for the oral anti-diabetes drugs and £14 (95% CI £7.9, £22) for anti-hypertensive medications compared with the control. Deducting the cost-savings of all healthcare contacts from the intervention cost resulted an incremental cost of £982 (95% CI £732, £1258). Cost per 1 year of diabetes remission was £2359 (95% CI £1668, £3250). CONCLUSIONS: Remission of Type 2 diabetes within 1-year can be achieved at a cost below the annual cost of diabetes (including complications). Providing a reasonable proportion of remissions can be maintained over time, with multiple medical gains expected, as well as immediate social benefits, there is a case for shifting resources within diabetes care budgets to offer support for people with Type 2 diabetes to attempt remission. (Clinical Trial Registry No.: ISRCTN03267836).

Implementation of the Western Australian Osteoporosis Model of Care: a fracture liaison service utilising emergency department information systems to identify patients with fragility fracture to improve current practice and reduce re-fracture rates: a 12-month analysis.

Fracture liaison service linked to an emergency department database effectively identifies patients with OP, improves best practice care, reduces recurrent fractures, and improves quality of life (QoL). The next step is to establish cost-effectiveness. This should be seen as the standard model of care. INTRODUCTION: The Western Australian Osteoporosis Model of Care recommends implementation of a fracture liaison service (FLS) to manage patients with minimal trauma fractures (MTFs). This study evaluates the efficacy of a FLS linked to a tertiary hospital emergency department information system (EDIS) in reducing recurrent fractures. METHODS: Patients aged ≥ 50 years with MTF identified from EDIS were invited to the FLS. Patient outcomes were compared to routine care (retrospective group-same hospital, and prospective group-other hospital) at 3- and 12-month follow-up. RESULTS: Two hundred forty-one of 376 (64.1%) eligible patients participated in the FLS with 12 months of follow-up. Absolute risk of recurrent MTF at 12 months was reduced by 9.2 and 10.2% compared with the prospective and retrospective controls, respectively. After age/sex adjustment, FLS participants had less MTF at 12 months vs. the retrospective controls, OR 0.38 (95%CI 0.18-0.79), but not the prospective controls, OR 0.40 (95%CI 0.16-1.01). FLS patients were more likely to receive the 'best practice' care, i.e. awareness of osteoporosis, investigations, and treatment (all p < 0.05). 'Fallers' (OR 0.48 (95%CI 0.24, 0.96)) and fall rates were lower in the FLS (p = 0.001) compared to the prospective control. FLS experienced the largest improvement in QoL from 3 to 12 months as measured by the EuroQoL 5-domain (EQ-5D) UK weighted score (+ 15 vs. - 11 vs. - 16%, p < 0.001) and EQ-5D Health State visual analogue scale (+ 29 vs. - 2 vs. + 1%, p < 0.001). CONCLUSION: Patients managed in a linked EDIS-FLS were more likely to receive the 'best practice' care and had lower recurrent MTF and improved QoL.

Correction to: Effectiveness of a new model of primary care management on knee pain and function in patients with knee osteoarthritis: Protocol for THE PARTNER STUDY.

After the publication of this protocol [1], our collaborator Prima Health solutions advised us of their intent to withdraw from the study.

Use of The Global Alliance for Musculoskeletal Health survey module for estimating the population prevalence of musculoskeletal pain: findings from the Solomon Islands.

BACKGROUND: Musculoskeletal (MSK) conditions are common and the biggest global cause of physical disability. The objective of the current study was to estimate the population prevalence of MSK-related pain using a standardized global MSK survey module for the first time. METHODS: A MSK survey module was constructed by the Global Alliance for Musculoskeletal Health Surveillance Taskforce and the Global Burden of Disease MSK Expert Group. The MSK module was included in the 2015 Solomon Islands Demographic and Health Survey. The sampling design was a two-stage stratified, nationally representative sample of households. RESULTS: A total of 9214 participants aged 15-49 years were included in the analysis. The age-standardized four-week prevalence of activity-limiting low back pain, neck pain, and hip and/or knee pain was 16.8, 8.9, and 10.8%, respectively. Prevalence tended to increase with age, and be higher in those with lower levels of education. CONCLUSIONS: Prevalence of activity-limited pain was high in all measured MSK sites. This indicates an important public health issue for the Solomon Islands that needs to be addressed. Efforts should be underpinned by integration with strategies for other non-communicable diseases, aging, disability, and rehabilitation, and with other sectors such as social services, education, industry, and agriculture. Primary prevention strategies and strategies aimed at self-management are likely to have the greatest and most cost-effective impact.

Patients' perceived health service needs for osteoarthritis (OA) care: a scoping systematic review.

OBJECTIVE: To identify and synthesise evidence regarding patients' perceived health service needs related to osteoarthritis (OA). DESIGN: A comprehensive systematic scoping review of MEDLINE, PsycINFO, EMBASE and CINAHL (1990-2016) was performed to capture information regarding patient perceived health service needs related to OA. Risk of bias and quality of included articles were assessed. Relevant data were extracted and collated to provide a systematic review of the existing literature. RESULTS: Of the 1384 identified manuscripts, 21 were relevant to areas of patient perceived need, including needs related to medical care, pharmacologic therapy, physiotherapy and exercise therapy and alternative medicine. Key findings included (1) Symptom control drove the need for both conventional and complementary services. (2) An individualized relationship was sought with a practitioner knowledgeable in OA care and who adopted a holistic approach, whether providing conventional or alternative therapies. (3) Medications were required to obtain symptomatic relief, with use tempered by recognition of potential side effects and financial cost. (4) The need for allied health services was recognised, although patient and system issues were barriers to uptake. (5) Patient's attitudes towards joint replacement, orthoses and physical aids were influenced by patient preferences and previous healthcare experiences. CONCLUSION: Patient perceived needs are similar to those suggested by clinical guideline recommendations. Better aligning patient perceived needs with healthcare requirements may improve OA outcomes and optimise healthcare system utilisation.

Systematic scoping review of patients' perceived needs of health services for osteoporosis.

Health service planners, administrators and providers need to understand the patients' perspective of health services related to osteoporosis to optimise health outcomes. The aims of this study were to systematically identify and review the literature regarding patients' perceived health service needs relating to osteoporosis and osteopenia. A systematic scoping review was performed of publications in MEDLINE, EMBASE, CINAHL and PsycINFO (1990-2016). Descriptive data regarding study design and methodology were extracted and risk of bias assessed. Aggregates of patients' perceived needs of osteoporosis health services were categorised. Thirty-three studies (19 quantitative and 14 qualitative) from 1027 were relevant. The following areas of perceived need emerged: (1) patients sought healthcare from doctors to obtain information and initiate management. They were dissatisfied with poor communication, lack of time and poor continuity of care. (2) Patients perceived a role for osteoporosis pharmacotherapy but were concerned about medication administration and adverse effects. (3) Patients believed that exercise and vitamin supplementation were important, but there is a lack of data examining the needs for other non-pharmacological measures such as smoking cessation and alcohol. (4) Patients wanted diagnostic evaluation and ongoing surveillance of their bone health. This review identified patients' needs for better communication with their healthcare providers. It also showed that a number of important cornerstones of therapy for osteoporosis, such as pharmacotherapy and exercise, are identified as important by patients, as well as ongoing surveillance of bone health. Understanding patients' perceived needs and aligning them with responsive and evidence-informed service models are likely to optimise patient outcomes.

Development and validation of a cost-utility model for Type 1 diabetes mellitus.

AIMS: To develop a health economic model to evaluate the cost-effectiveness of new interventions for Type 1 diabetes mellitus by their effects on long-term complications (measured through mean HbA1c ) while capturing the impact of treatment on hypoglycaemic events. METHODS: Through a systematic review, we identified complications associated with Type 1 diabetes mellitus and data describing the long-term incidence of these complications. An individual patient simulation model was developed and included the following complications: cardiovascular disease, peripheral neuropathy, microalbuminuria, end-stage renal disease, proliferative retinopathy, ketoacidosis, cataract, hypoglycemia and adverse birth outcomes. Risk equations were developed from published cumulative incidence data and hazard ratios for the effect of HbA1c , age and duration of diabetes. We validated the model by comparing model predictions with observed outcomes from studies used to build the model (internal validation) and from other published data (external validation). We performed illustrative analyses for typical patient cohorts and a hypothetical intervention. RESULTS: Model predictions were within 2% of expected values in the internal validation and within 8% of observed values in the external validation (percentages represent absolute differences in the cumulative incidence). CONCLUSIONS: The model utilized high-quality, recent data specific to people with Type 1 diabetes mellitus. In the model validation, results deviated less than 8% from expected values.

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Gender differences in the relationships between lean body mass, fat mass and peak bone mass in young adults.

UNLABELLED: The relationships between fat mass and bone mass in young adults are unclear. In 1,183 young Australians, lean body mass had a strong positive relationship with total body bone mass in both genders. Fat mass was a positive predictor of total body bone mass in females, with weaker association in males. INTRODUCTION: Body weight and lean body mass are established as major determinants of bone mass, but the relationships between fat mass (including visceral fat) and peak bone mass in young adults are unclear. The aim of this study was to evaluate the associations between bone mass in young adults and three body composition measurements: lean body mass, fat mass and trunk-to-limb fat mass ratio (a surrogate measure of visceral fat). METHODS: Study participants were 574 women and 609 men aged 19-22 years from the Raine study. Body composition, total body bone mineral content (TBBMC), bone area and areal bone mineral density (TBBMD) were measured using DXA. RESULTS: In multivariate linear regression models with height, lean body mass, fat mass and trunk-to-limb fat mass ratio as predictor variables, lean mass was uniquely associated with the largest proportion of variance of TBBMC and TBBMD in males (semi-partial R(2) 0.275 and 0.345, respectively) and TBBMC in females (semi-partial R(2) 0.183). Fat mass was a more important predictor of TBBMC and TBBMD in females (semi-partial R(2) 0.126 and 0.039, respectively) than males (semi-partial R(2) 0.006 and 0.018, respectively). Trunk-to-limb fat mass ratio had a weak, negative association with TBBMC and bone area in both genders (semi-partial R(2) 0.004 to 0.034). CONCLUSIONS: Lean body mass has strong positive relationship with total body bone mass in both genders. Fat mass may play a positive role in peak bone mass attainment in women but the association was weaker in men; different fat compartments may have different effects.

Approaches to the detection of very small, common, and easily missed outbreaks that together contribute substantially to human Cryptosporidium infection.

Water supply-associated cryptosporidiosis outbreaks have decreased in England since the application of risk reduction measures to public water supplies. We hypothesized that smaller outbreaks were occurring which could be better detected by enhanced surveillance. Rolling analysis of detailed questionnaire data was applied prospectively in a population of 2·2 million in the south of England in 2009 and 2010. Detection of spatiotemporal clusters using SaTScan was later undertaken retrospectively. Together these approaches identified eight outbreaks, compared to an expectation of less than one based on national surveillance data. These outbreaks were small and associated with swimming pool use or, less commonly, direct (e.g. petting-farm) contact with animals. These findings suggest that frequent small-scale transmission in swimming pools is an important contributor to disease burden. Identification of swimming pool-level risk factors may inform preventative measures. These findings and the approaches described may be applicable to many other populations and to some other diseases.

Assessment of alendronate and dietary treatment in the management of feline idiopathic ionised hypercalcaemia and ionised hypercalcaemia associated with chronic kidney disease: 29 cases (2016-2022).

OBJECTIVES: This retrospective cohort multicentre study aimed to characterise the signalment, clinicopathologic data, complications and the association between treatment and outcome (the reduction in ionised calcium concentration) in cats with idiopathic or chronic kidney disease-associated ionised hypercalcaemia managed with alendronate and standard treatment or standard treatment alone, and to compare the outcome between the two groups. MATERIALS AND METHODS: Medical records for cats diagnosed with idiopathic or chronic kidney disease-associated ionised hypercalcaemia were retrospectively reviewed. Cats treated with alendronate and standard treatment were assigned to the alendronate group and cats treated with standard treatment alone were assigned to the control group. The standard treatment was defined as dietary modification and/or monitoring of ionised calcium concentrations and management of complications secondary to hypercalcaemia. The follow-up period was selected as 6 months. RESULTS: Twenty-nine cats were enrolled in the study. Nine cats were included in the control group and 20 cats in the alendronate group. A significant reduction in serum ionised calcium was observed in both groups between the baseline and the follow-up visit; however, this reduction did not differ significantly between both groups (the mean change in the ionised calcium concentration in alendronate and control group was -0.18 and -0.17, respectively). Suspected bisphosphate-related osteonecrosis of the jaw was reported in one cat receiving alendronate. CLINICAL SIGNIFICANCE: In this study, similar reduction in serum ionised calcium concentration was observed in cats with ionised hypercalcaemia treated with diet alone and in cats treated with diet and alendronate. These results should be interpreted with caution, as the study was underpowered for meaningful statistical comparison. Cats receiving alendronate should be monitored for the development of adverse reactions, including osteonecrosis of the jaw.

Predicted impact of extending the screening interval for diabetic retinopathy: the Scottish Diabetic Retinopathy Screening programme.

AIMS/HYPOTHESIS: The aim of our study was to identify subgroups of patients attending the Scottish Diabetic Retinopathy Screening (DRS) programme who might safely move from annual to two yearly retinopathy screening. METHODS: This was a retrospective cohort study of screening data from the DRS programme collected between 2005 and 2011 for people aged ≥12 years with type 1 or type 2 diabetes in Scotland. We used hidden Markov models to calculate the probabilities of transitions to referable diabetic retinopathy (referable background or proliferative retinopathy) or referable maculopathy. RESULTS: The study included 155,114 individuals with no referable diabetic retinopathy or maculopathy at their first DRS examination and with one or more further DRS examinations. There were 11,275 incident cases of referable diabetic eye disease (9,204 referable maculopathy, 2,071 referable background or proliferative retinopathy). The observed transitions to referable background or proliferative retinopathy were lower for people with no visible retinopathy vs mild background retinopathy at their prior examination (respectively, 1.2% vs 8.1% for type 1 diabetes and 0.6% vs 5.1% for type 2 diabetes). The lowest probability for transitioning to referable background or proliferative retinopathy was among people with two consecutive screens showing no visible retinopathy, where the probability was <0.3% for type 1 and <0.2% for type 2 diabetes at 2 years. CONCLUSIONS/INTERPRETATION: Transition rates to referable diabetic eye disease were lowest among people with type 2 diabetes and two consecutive screens showing no visible retinopathy. If such people had been offered two yearly screening the DRS service would have needed to screen 40% fewer people in 2009.

Psr is involved in regulation of glucan production, and double deficiency of BrpA and Psr is lethal in Streptococcus mutans.

Streptococcus mutans, the primary causative agent of dental caries, contains two paralogues of the LytR-CpsA-Psr family proteins encoded by brpA and psr, respectively. Previous studies have shown that BrpA plays an important role in cell envelope biogenesis/homeostasis and affects stress responses and biofilm formation by Strep. mutans, traits critical to cariogenicity of this bacterium. In this study, a Psr-deficient mutant, TW251, was constructed. Characterization of TW251 showed that deficiency of Psr did not have any major impact on growth rate. However, when subjected to acid killing at pH 2.8, the survival rate of TW251 was decreased dramatically compared with the parent strain UA159. In addition, TW251 also displayed major defects in biofilm formation, especially during growth with sucrose. When compared to UA159, the biofilms of TW251 were mainly planar and devoid of extracellular glucans. Real-time-PCR and Western blot analyses revealed that deficiency of Psr significantly decreased the expression of glucosyltransferase C, a protein known to play a major role in biofilm formation by Strep. mutans. Transmission electron microscopy analysis showed that deficiency of BrpA caused alterations in cell envelope and cell division, and the most significant defects were observed in TW314, a Psr-deficient and BrpA-down mutant. No such effects were observed with Psr mutant TW251 under similar conditions. These results suggest that while there are similarities in functions between BrpA and Psr, distinctive differences also exist between these two paralogues. Like Bacillus subtilis but different from Staphylococcus aureus, a functional BrpA or Psr is required for viability in Strep. mutans.

A patient-centred approach to estimate total annual healthcare cost by body mass index in the UK Counterweight programme.

BACKGROUND: Previous studies, based on relative risks for certain secondary diseases, have shown greater healthcare costs in higher body mass index (BMI) categories. The present study quantifies the relationship between BMI and total healthcare expenditure, with the patient as the unit of analysis. METHODS: Analyses of cross-sectional data, collected over 18-months in 2002-2003, from 3324 randomly selected patients, in 65 general practices across UK. Healthcare costs estimated from primary care, outpatient, accident/emergency and hospitalisation attendances, weighted by unit costs taken from standard sources. RESULTS: In univariate analyses, significant associations (P<0.05) were found between total healthcare expenditure and all dependent variables (women>men, drinkernon-smokers, and increasing with greater physical activity, age and BMI. In multivariate analysis, age, sex, BMI, smoking and alcohol consumption remained significantly associated with healthcare cost, and together explained just 9% of the variance in healthcare expenditure. Adjusted total annual healthcare cost was £16 (95% CI £11-£21) higher per unit BMI. All cost categories were significantly (P<0.003) higher for those with BMI >40 compared with BMI <20 kg m(-2): prescription drugs (men: £390 versus £16; women: £211 versus £73), hospitalisation (men: £72 versus £0; women: £243 versus £107), primary care (men: £191 versus £69; women: £268 versus £153) and outpatient care (£234 versus £107 women only). CONCLUSIONS: Annual healthcare expenditure rose a mean of £16 per unit greater BMI, doubling between BMI 20-40 kg m(-2). This gradient may be an underestimate if the lower-BMI patients with heights and weights recorded had other costly diseases.

Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.

Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance.The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication. The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website (www.ispor.org/TaskForces/EconomicPubGuidelines.asp). We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in 5 years.

Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.

OBJECTIVES: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). METHODS: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. RESULTS: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). CONCLUSIONS: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. HIGHLIGHTS: Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.