Bayesian estimation in NONMEM.

Bayesian estimation is a powerful but underutilized tool for answering drug development questions. In this tutorial, the principles of Bayesian model development, assessment, and prior selection will be outlined. An example pharmacokinetic (PK) model will be used to demonstrate the implementation of Bayesian modeling using the nonlinear mixed-effects modeling software NONMEM.

Model-based meta-analysis using latent variable modeling to set benchmarks for new treatments of systemic lupus erythematosus.

Several investigational agents are under evaluation in systemic lupus erythematosus (SLE) clinical trials but quantitative frameworks to enable comparison of their efficacy to reference benchmark treatments are lacking. To benchmark SLE treatment effects and identify clinically important covariates, we developed a model-based meta-analysis (MBMA) within a latent variable model framework for efficacy end points and SLE composite end point scores (BILAG-based Composite Lupus Assessment and Systemic Lupus Erythematosus Responder Index) using aggregate-level data on approved and investigational therapeutics. SLE trials were searched using PubMed and www.clinicaltrials.gov for treatment name, SLE and clinical trial as search criteria that resulted in four data structures: (1) study and investigational agent, (2) dose and regimen, (3) baseline descriptors, and (4) outcomes. The final dataset consisted of 25 studies and 81 treatment arms evaluating 16 different agents. A previously developed (K Goteti et al. 2022) SLE latent variable model of data from placebo arms (placebo + standard of care treatments) was used to describe aggregate SLE end points over time for the various SLE placebo and treatment arms in a Bayesian MBMA framework. Continuous dose-effect relationships using a maximum effect model were included for anifrolumab, belimumab, CC-220 (iberdomide), epratuzumab, lulizumab pegol, and sifalimumab, whereas the remaining treatments were modeled as discrete dose effects. The final MBMA model was then used to benchmark these compounds with respect to the maximal efficacy on the latent variable compared to the placebo. This MBMA illustrates the application of latent variable models in understanding the trajectories of composite end points in chronic diseases and should enable model-informed development of new investigational agents in SLE.

Population model-based analysis of the memory B-cell response following belimumab therapy in the treatment of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell hyperactivity and breach of tolerance. Autoreactive memory B cells, which have a decreased activation threshold and the ability to survive in absence of antigen, are believed to contribute to chronicity in autoimmune diseases like SLE. Belimumab, the first approved biological treatment of active SLE and lupus nephritis, reduces B cells dependent on B-lymphocyte stimulator protein (BLyS) for survival, whereas memory B cells are spared; several studies reported circulating memory B-cell concentrations increase following BLyS neutralization. This analysis investigated the effect of dose, demographics, and disease status on memory B-cell response after starting belimumab treatment. Population pharmacodynamic models were fitted to a pooled dataset from seven belimumab SLE trials. The optimal model was selected using maximum likelihood methods and was then refit to the data using Bayesian analysis and used to simulate memory B-cell response by belimumab dose and covariate subgroups. At the belimumab approved doses (10 mg/kg intravenously every 4 weeks, 200 mg subcutaneously every week), circulatory memory B cells increase in the first 4-8 weeks after belimumab initiation, typically returning to baseline levels over 76 weeks. The model analysis suggested belimumab stimulates memory B-cell transition from lymphoid and/or inflamed tissues into the circulation, rather than inhibiting trafficking in the reverse direction. Baseline BLyS and anti-double-stranded deoxyribonucleic acid antibody concentrations were statistically identifiable covariates of memory B-cell response, although their impact on predicting size and response duration was small.

Bayesian PBPK modeling using R/Stan/Torsten and Julia/SciML/Turing.Jl.

Physiologically-based pharmacokinetic (PBPK) models are mechanistic models that are built based on an investigator's prior knowledge of the in vivo system of interest. Bayesian inference incorporates an investigator's prior knowledge of parameters while using the data to update this knowledge. As such, Bayesian tools are well-suited to infer PBPK model parameters using the strong prior knowledge available while quantifying the uncertainty on these parameters. This tutorial demonstrates a full population Bayesian PBPK analysis framework using R/Stan/Torsten and Julia/SciML/Turing.jl.

Flexible and efficient Bayesian pharmacometrics modeling using Stan and Torsten, Part I.

Stan is an open-source probabilistic programing language, primarily designed to do Bayesian data analysis. Its main inference algorithm is an adaptive Hamiltonian Monte Carlo sampler, supported by state-of-the-art gradient computation. Stan's strengths include efficient computation, an expressive language that offers a great deal of flexibility, and numerous diagnostics that allow modelers to check whether the inference is reliable. Torsten extends Stan with a suite of functions that facilitate the specification of pharmacokinetic and pharmacodynamic models and makes it straightforward to specify a clinical event schedule. Part I of this tutorial demonstrates how to build, fit, and criticize standard pharmacokinetic and pharmacodynamic models using Stan and Torsten.

An unusual and challenging cause of small bowel bleeding: Isolated gastrointestinal blue rubber bleb nevus syndrome.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disease that presents as cutaneous and extra-cutaneous vascular malformations, most commonly affecting the gastrointestinal (GI) tract. We report a case of adult onset BRBNS in an African American male with vascular lesions isolated to the jejunum without any cutaneous manifestations. Physicians should recognize that BRBNS can present without skin involvement and may have complications from visceral organ involvement. Treatment of BRBNS is mainly symptomatic and aims at preserving the GI tract as much as possible. BRBNS may also present as delayed recurrence after surgical or endoscopic interventions.

Trainee participation during screening colonoscopy does not affect ADR at subsequent surveillance, but may result in early follow-up.

Background and study aims Training future endoscopists is essential to meet rising demands for screening and surveillance colonoscopies. Studies have shown conflicting results regarding the influence of trainees on adenoma detection rates (ADR). It is unclear whether trainee participation during screening adversely affects ADR at subsequent surveillance and whether it alters surveillance recommendations. Patients and methods A retrospective analysis of average-risk screening colonoscopies and surveillance exams over a subsequent 10-year period was performed. The initial inclusion criteria were met by 5208 screening and 2285 surveillance exams. Patients with poor preparation were excluded. The final analysis included 7106 procedures, including 4922 screening colonoscopies and 2184 surveillance exams. Data were collected from pathology and endoscopy electronic databases. The primary outcome was the ADR with and without trainee participation. Surveillance recommendations were analyzed as a secondary outcome. Results Trainees participated in 1131 (23 %) screening and in 232 (11 %) surveillance exams. ADR did not significantly differ ( P  = 0.19) for screening exams with trainee participation (19.5 %) or those without (21.4 %). ADRs were higher at surveillance exams with (22.4 %) and without (27.5 %) trainee participation. ADR at surveillance was not adversely affected by trainee participation during the previous colonoscopy. Shorter surveillance intervals were given more frequently if trainees participated during the initial screening procedure ( P  = 0.0001). Conclusions ADR did not significantly differ in screening or surveillance colonoscopies with or without trainee participation. ADR at surveillance was not adversely affected by trainee participation during the previous screening exam. However, trainee participation may result in shorter surveillance recommendations.

Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates.

Peripheral neuropathy (PN) is a common long-term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine-citrulline-monomethylauristatin E antibody-drug conjugates (ADCs) developed at Genentech. A pooled time-to-event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ≥ 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored. The time-to-event analysis suggested that the development of PN risk increased with ADC exposure, treatment duration, body weight, and previously reported PN. This model can be used to inform clinical strategies such as adaptations to dosing regimen and/or treatment duration as well as inform clinical eligibility to reduce the incidence of grade ≥ 2 PN.

Clostridium difficile in Inflammatory Bowel Disease: A Retrospective Study.

AIM: To investigate the epidemiology and risk factors of Clostridium difficile infections (CDI) in patients with inflammatory bowel disease (IBD). METHODS: This is a retrospective study of patients diagnosed with IBD. 1006 charts were screened and 654 patients met the inclusion criteria. Patients were divided into 2 cohorts based on the presence of prior diagnosis of CDI. Statistical analysis with Pearson's chi-squared and two-sample t-test was performed. RESULTS: The incidence of CDI among IBD patients was 6.7%. There was equal prevalence of CDI among Crohn's disease (CD) (n = 21, 49%) and ulcerative colitis (UC) (n = 22, 51%). IBD patients acquired CDI at a mean age of 42.7 years, with 56% of infections acquired in the community and only 28% associated with healthcare. Only 30% of IBD patients with CDI had prior antibiotic use, and 16% had prior steroid use. IBD patients were significantly more likely to require biologic therapy (57% versus 37%, p < 0.01) and have extraintestinal manifestations of IBD (43% versus 28%, p < 0.02). CONCLUSIONS: IBD patients are more susceptible to CDI at a younger age and often lack traditional risk factors. IBD patients with at least one CDI were more likely to require biologic therapy and had greater rates of extraintestinal manifestations.

A model of fracture risk used to examine the link between bone mineral density and the impact of different therapeutic mechanisms on fracture outcomes in patients with osteoporosis.

A hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005-2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture rate and bone mineral density (BMD) for both treatment and placebo arms. The search resulted in a metadata set comprised of 21 studies investigating the effects of various bisphosphonates, teriparatide, denosumab, and raloxifene in 65,254 patients over a cumulative 56.75 years of study. The IPD was used to augment an AD in a model-based meta-analysis (MBMA) hierarchical modeling approach. The resulting model predicts the probability of fracture events in patients with osteoporosis. The object of model building using this approach was to promote understanding of the impact of therapeutic drug effects on the probability of fracture together with, or independent of their effects on BMD. Candidate models were evaluated by deviance information criteria and posterior predictive check. The model with covariates for lumbar spine BMD with interaction with a drug effect on BMD, and patient body mass index, years post-menopause, fracture measure method (clinical or radiological) and an additional drug effect outperformed those models without interaction and without additional drug effects. The model quantitatively supports the widely held notion that changes in bone microarchitecture, which cannot be measured by areal BMD elicited by therapy contribute in a significant way to a reduction in fracture. Furthermore, this model can be used to simulate fracture risk in a clinical cohort similar to those contained in the MBMA.

Small Intestinal Angioectasia: Characterization, Risk Factors, and Rebleeding.

BACKGROUND: Gastrointestinal angioectasias (AEs) represent the most common vascular malformation within the gastrointestinal tract. This study sought to characterize epidemiologic/comorbid risk factors for AEs, rebleeding, and patterns of anatomic distribution within the small intestine. STUDY: This retrospective observational cohort study included 158 patients with AEs on capsule endoscopy (CE) from 2007 to 2015. Epidemiologic/comorbid data were collected and incorporated into final analysis. Each AE was categorized by location using a small bowel transit time-based quartile system. Rebleeding was evaluated following CE. Multivariate logistic regression was applied to statistically significant factors on univariate analysis to determine independent risk factors for rebleeding. RESULTS: Most lesions were found in the first quartile (67.1%). Rebleeding occurred in 46 (29.7%) of the 156 patients for whom data were available. Rates of rebleeding were significantly higher among older patients (74.4 vs. 67.7 y, P=0.001), those with active bleeding on CE (41.3% vs. 16.5%, P=0.001), those with a history of aortic stenosis (21.7% vs. 9.2%, P=0.033), and those with AEs presents in quartile 3 (26.1% vs. 8.3%, P=0.003). Age, active bleeding on CE, and AE presence in quartile 3 were independently associated with rebleeding in multivariate analysis (P=0.009, 0.023, and 0.008, respectively). CONCLUSIONS: These data help improve our knowledge of AEs regarding risk factors for rebleeding, and utilizes a novel small bowel transit time-based quartile localization method that may simplify future research and comparisons of anatomic distribution and behavior of small bowel AEs.

Modeling and simulation for medical product development and evaluation: highlights from the FDA-C-Path-ISOP 2013 workshop.

Medical-product development has become increasingly challenging and resource-intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative [1]. Priorities identified included the need for improved modeling and simulation tools, further emphasized in FDA's 2011 Strategic Plan for Regulatory Science [Appendix]. In an effort to support and advance model-informed medical-product development (MIMPD), the Critical Path Institute (C-Path) [www.c-path.org], FDA, and International Society of Pharmacometrics [www.go-isop.org] co-sponsored a workshop in Washington, D.C. on September 26, 2013, to examine integrated approaches to developing and applying model- MIMPD. The workshop brought together an international group of scientists from industry, academia, FDA, and the European Medicines Agency to discuss MIMPD strategies and their applications. A commentary on the proceedings of that workshop is presented here.

Exposure-response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes.

AIMS: To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure-response (E-R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM). METHODS: Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1-100 mg once daily, duration ≤12 weeks) were used to develop E-R models for efficacy (glycosylated haemoglobin [HbA1c ], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E-R. RESULTS: The efficacy model predicted maximal decreases in FPG and HbA1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl(-1) ) and 10-25 mg every day empagliflozin targeted 80-90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation. CONCLUSIONS: E-R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy.

Quality and efficiency in small practices transitioning to patient centered medical homes: a randomized trial.

BACKGROUND: There is growing evidence that even small and solo primary care practices can successfully transition to full Patient Centered Medical Home (PCMH) status when provided with support, including practice redesign, care managers, and a revised payment plan. Less is known about the quality and efficiency outcomes associated with this transition. OBJECTIVE: Test quality and efficiency outcomes associated with 2-year transition to PCMH status among physicians in intervention versus control practices. DESIGN: Randomized Controlled Trial. PARTICIPANTS: Eighteen intervention practices with 43 physicians and 14 control practices with 24 physicians; all from adult primary care practices. INTERVENTIONS: Modeled on 2008 NCQA PPC®-PCMH™, intervention practices received 18 months of tailored practice redesign support; 2 years of revised payment, including up to $2.50 per member per month (PMPM) for achieving quality targets and up to $2.50 PMPM for PPC-PCMH recognition; and 18 months of embedded care management support. Controls received yearly participation payments. MAIN MEASURES: Eleven clinical quality indicators from the 2009 HEDIS process and health outcomes measures derived from patient claims data; Ten efficiency indicators based on Thomson Reuter efficiency indexes and Emergency Department (ED) Visit Ratios; and a panel of costs of care measures. KEY RESULTS: Compared to control physicians, intervention physicians significantly improved TWO of 11 quality indicators: hypertensive blood pressure control over 2 years (intervention +23 percentage points, control -2 percentage points, p =0.02) and breast cancer screening over 3 years (intervention +3.5 percentage points, control -0.4 percentage points, p =0.03). Compared to control physicians, intervention physicians significantly improved ONE of ten efficiency indicators: number of care episodes resulting in ED visits was reduced (intervention -0.7 percentage points, control + 0.5 percentage points, p = 0.002), with 3.8 fewer ED visits per year, saving approximately $1,900 in ED costs per physician, per year. There were no significant cost-savings on any of the pre-specified costs of care measures. CONCLUSIONS: In a randomized trial, we observed that some indicators of quality and efficiency of care in general adult primary care practices transitioning to PCMH status can be significantly, but modestly, improved over 2 years, although most indicators did not improve and there were no cost-savings compared with control practices. For the most part, quality and efficiency of care provided in unsupported control practices remained unchanged or worsened during the trial.

A novel model-based meta-analysis to indirectly estimate the comparative efficacy of two medications: an example using DPP-4 inhibitors, sitagliptin and linagliptin, in treatment of type 2 diabetes mellitus.

OBJECTIVES: To develop a longitudinal statistical model to indirectly estimate the comparative efficacies of two drugs, using model-based meta-analysis (MBMA). Comparison of two oral dipeptidyl peptidase (DPP)-4 inhibitors, sitagliptin and linagliptin, for type 2 diabetes mellitus (T2DM) treatment was used as an example. DESIGN: Systematic review with MBMA. DATA SOURCES: MEDLINE, EMBASE, http://www.ClinicalTrials.gov, Cochrane review of DPP-4 inhibitors for T2DM, sitagliptin trials on Food and Drug Administration website to December 2011 and linagliptin data from the manufacturer. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Double-blind, randomised controlled clinical trials, ≥12 weeks' duration, that analysed sitagliptin or linagliptin efficacies as changes in glycated haemoglobin (HbA1c) levels, in adults with T2DM and HbA1c >7%, irrespective of background medication. MODEL DEVELOPMENT AND APPLICATION: A Bayesian model was fitted (Markov Chain Monte Carlo method). The final model described HbA1c levels as function of time, dose, baseline HbA1c, washout status/duration and ethnicity. Other covariates showed no major impact on model parameters and were not included. For the indirect comparison, a population of 1000 patients was simulated from the model with a racial composition reflecting the average racial distribution of the linagliptin trials, and baseline HbA1c of 8%. RESULTS: The model was developed using longitudinal data from 11 234 patients (10 linagliptin, 15 sitagliptin trials), and assessed by internal evaluation techniques, demonstrating that the model adequately described the observations. Simulations showed both linagliptin 5 mg and sitagliptin 100 mg reduced HbA1c by 0.81% (placebo-adjusted) at week 24. Credible intervals for participants without washout were -0.88 to -0.75 (linagliptin) and -0.89 to -0.73 (sitagliptin), and for those with washout, -0.91 to -0.76 (linagliptin) and -0.91 to -0.75 (sitagliptin). CONCLUSIONS: This study demonstrates the use of longitudinal MBMA in the field of diabetes treatment. Based on an example evaluating HbA1c reduction with linagliptin versus sitagliptin, the model used seems a valid approach for indirect drug comparisons.

A randomized, controlled trial of implementing the patient-centered medical home model in solo and small practices.

BACKGROUND: Transition to a Patient-Centered Medical Home (PCMH) is challenging in primary care, especially for smaller practices. OBJECTIVE: To test the effectiveness of providing external supports, including practice redesign, care management and revised payment, compared to no support in transition to PCMH among solo and small (<2-10 providers) primary care practices over 2 years. DESIGN: Randomized Controlled Trial. PARTICIPANTS: Eighteen supported practices (intervention) and 14 control practices (controls). INTERVENTIONS: Intervention practices received 6 months of intensive, and 12 months of less intensive, practice redesign support; 2 years of revised payment, including cost of National Council for Quality Assurance's (NCQA) Physician Practice Connections(®)-Patient-Centered Medical Home™ (PPC(®)-PCMH™) submissions; and 18 months of care management support. Controls received yearly participation payments plus cost of PPC(®)-PCMH™. MAIN MEASURES: PPC(®)-PCMH™ at baseline and 18 months, plus intervention at 7 months. KEY RESULTS: At 18 months, 5 % of intervention practices and 79% of control practices were not recognized by NCQA; 10% of intervention practices and 7% of controls achieved PPC(®)-PCMH™ Level 1; 5% of intervention practices and 0% of controls achieved PPC(®)-PCMH™ Level 2; and 80% of intervention practices and 14% of controls achieved PPC(®)-PCMH™ Level 3. Intervention practices were 27 times more likely to improve PPC(®)-PCMH™ by one level, irrespective of practice size (p < 0.001) 95% CI (5-157). Among intervention practices, a multilevel ordinal piecewise model of change showed a significant and rapid 7-month effect (p(time7) = 0.01), which was twice as large as the sustained effect over subsequent 12 months (p(time18) = 0.02). Doubly multivariate analysis of variance showed significant differential change by condition across PPC(®)-PCMH™ standards over time (p(time x group)=0.03). Intervention practices improved eight of nine standards, controls improved three of nine (p(PPC1) = 0.009; p(PPC2) = 0.005; p(PPC3) = 0.007). CONCLUSIONS: Irrespective of size, practices can make rapid and sustained transition to a PCMH when provided external supports, including practice redesign, care management and payment reform. Without such supports, change is slow and limited in scope.

Facilitating pharmacometric workflow with the metrumrg package for R.

metrumrg is an R package that facilitates workflow for the discipline of pharmacometrics. Support is provided for data preparation, modeling, simulation, diagnostics, and reporting. Existing tools and techniques are emphasized where available; original solutions are provided for otherwise unmet needs. In particular, metrumrg implements an R interface for the NONMEM(®) modeling software, optionally run in a distributed computing environment. The paradigm allows start-to-finish analyses in a single scripting language. Emphasis on text-based formats promotes traceability of results.

Interventions for preventing falls in older people living in the community.

BACKGROUND: Approximately 30% of people over 65 years of age living in the community fall each year. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To assess the effects of interventions designed to reduce the incidence of falls in older people living in the community. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (February 2012), CENTRAL (The Cochrane Library 2012, Issue 3), MEDLINE (1946 to March 2012), EMBASE (1947 to March 2012), CINAHL (1982 to February 2012), and online trial registers. SELECTION CRITERIA: Randomised trials of interventions to reduce falls in community-dwelling older people. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. We used a rate ratio (RaR) and 95% confidence interval (CI) to compare the rate of falls (e.g. falls per person year) between intervention and control groups. For risk of falling, we used a risk ratio (RR) and 95% CI based on the number of people falling (fallers) in each group. We pooled data where appropriate. MAIN RESULTS: We included 159 trials with 79,193 participants. Most trials compared a fall prevention intervention with no intervention or an intervention not expected to reduce falls. The most common interventions tested were exercise as a single intervention (59 trials) and multifactorial programmes (40 trials). Sixty-two per cent (99/159) of trials were at low risk of bias for sequence generation, 60% for attrition bias for falls (66/110), 73% for attrition bias for fallers (96/131), and only 38% (60/159) for allocation concealment.Multiple-component group exercise significantly reduced rate of falls (RaR 0.71, 95% CI 0.63 to 0.82; 16 trials; 3622 participants) and risk of falling (RR 0.85, 95% CI 0.76 to 0.96; 22 trials; 5333 participants), as did multiple-component home-based exercise (RaR 0.68, 95% CI 0.58 to 0.80; seven trials; 951 participants and RR 0.78, 95% CI 0.64 to 0.94; six trials; 714 participants). For Tai Chi, the reduction in rate of falls bordered on statistical significance (RaR 0.72, 95% CI 0.52 to 1.00; five trials; 1563 participants) but Tai Chi did significantly reduce risk of falling (RR 0.71, 95% CI 0.57 to 0.87; six trials; 1625 participants).Multifactorial interventions, which include individual risk assessment, reduced rate of falls (RaR 0.76, 95% CI 0.67 to 0.86; 19 trials; 9503 participants), but not risk of falling (RR 0.93, 95% CI 0.86 to 1.02; 34 trials; 13,617 participants).Overall, vitamin D did not reduce rate of falls (RaR 1.00, 95% CI 0.90 to 1.11; seven trials; 9324 participants) or risk of falling (RR 0.96, 95% CI 0.89 to 1.03; 13 trials; 26,747 participants), but may do so in people with lower vitamin D levels before treatment.Home safety assessment and modification interventions were effective in reducing rate of falls (RR 0.81, 95% CI 0.68 to 0.97; six trials; 4208 participants) and risk of falling (RR 0.88, 95% CI 0.80 to 0.96; seven trials; 4051 participants). These interventions were more effective in people at higher risk of falling, including those with severe visual impairment. Home safety interventions appear to be more effective when delivered by an occupational therapist.An intervention to treat vision problems (616 participants) resulted in a significant increase in the rate of falls (RaR 1.57, 95% CI 1.19 to 2.06) and risk of falling (RR 1.54, 95% CI 1.24 to 1.91). When regular wearers of multifocal glasses (597 participants) were given single lens glasses, all falls and outside falls were significantly reduced in the subgroup that regularly took part in outside activities. Conversely, there was a significant increase in outside falls in intervention group participants who took part in little outside activity.Pacemakers reduced rate of falls in people with carotid sinus hypersensitivity (RaR 0.73, 95% CI 0.57 to 0.93; three trials; 349 participants) but not risk of falling. First eye cataract surgery in women reduced rate of falls (RaR 0.66, 95% CI 0.45 to 0.95; one trial; 306 participants), but second eye cataract surgery did not.Gradual withdrawal of psychotropic medication reduced rate of falls (RaR 0.34, 95% CI 0.16 to 0.73; one trial; 93 participants), but not risk of falling. A prescribing modification programme for primary care physicians significantly reduced risk of falling (RR 0.61, 95% CI 0.41 to 0.91; one trial; 659 participants).An anti-slip shoe device reduced rate of falls in icy conditions (RaR 0.42, 95% CI 0.22 to 0.78; one trial; 109 participants). One trial (305 participants) comparing multifaceted podiatry including foot and ankle exercises with standard podiatry in people with disabling foot pain significantly reduced the rate of falls (RaR 0.64, 95% CI 0.45 to 0.91) but not the risk of falling.There is no evidence of effect for cognitive behavioural interventions on rate of falls (RaR 1.00, 95% CI 0.37 to 2.72; one trial; 120 participants) or risk of falling (RR 1.11, 95% CI 0.80 to 1.54; two trials; 350 participants).Trials testing interventions to increase knowledge/educate about fall prevention alone did not significantly reduce the rate of falls (RaR 0.33, 95% CI 0.09 to 1.20; one trial; 45 participants) or risk of falling (RR 0.88, 95% CI 0.75 to 1.03; four trials; 2555 participants).No conclusions can be drawn from the 47 trials reporting fall-related fractures.Thirteen trials provided a comprehensive economic evaluation. Three of these indicated cost savings for their interventions during the trial period: home-based exercise in over 80-year-olds, home safety assessment and modification in those with a previous fall, and one multifactorial programme targeting eight specific risk factors. AUTHORS' CONCLUSIONS: Group and home-based exercise programmes, and home safety interventions reduce rate of falls and risk of falling.Multifactorial assessment and intervention programmes reduce rate of falls but not risk of falling; Tai Chi reduces risk of falling.Overall, vitamin D supplementation does not appear to reduce falls but may be effective in people who have lower vitamin D levels before treatment.

Impact of point-of-care case management on readmissions and costs.

OBJECTIVE: To measure the impact of point-of-care case management by a team of diverse clinical specialists at a large medical group on 30-day readmissions and associated costs. STUDY DESIGN: An intent-to-treat, historical, baseline cohort comparison design. METHODS: A case management team employed by a managed care organization was integrated into the point of care at 4 medical offices of a medical group to provide services to health plan members who were medically hospitalized. Measures included case management process measures, 30-day readmissions and associated costs, and total savings. RESULTS: Among eligible members, 93% were enrolled in the case management program. In the baseline cohort, 17.60% of members were readmitted within 30 days, compared with 12.08% in the intervention group. Regression models identified case management intervention, prospective risk score, and Medicaid insurance coverage as significantly associated with readmissions and associated costs. Annual savings in 30-day inpatient utilization costs were $1040.74 per member, which considerably exceeded the costs of the program. CONCLUSIONS: Point-of-care case management can be an effective strategy for reducing readmissions and associated costs. Providing services at the point of care allows for greater convenience for members and increased collaboration with physicians. This strategy of a managed care organization collaborating with medical groups and hospitals has the potential to enhance outcomes in accountable care organizations and to support patientcentered medical homes.