Life-long deficits in social adaptation and the frontal lobes: New evidence, seventy-five years after Ackerly and Benton's landmark case report of JP.

The case of JP, reported by Ackerly and Benton in 1948 with a detailed follow-up by Ackerly in 1964, stands as the index case of developmental prefrontal damage and its impact on social adaptation. Although the 1948 case report included findings from a 1933 pneumoencephalogram and exploratory craniotomy, a definitive cause was never established for JP's prefrontal damage. Etiologies were never determined for the left-sided seizures that occurred when JP was age four, nor for the progressive anterograde amnesia that JP developed in middle age. Given Ackerly's thoroughness and long-term follow-up of his patient, it was hoped that a brain cutting would have been done, though no report of a post-mortem examination was published. The lead author of this paper (SB) set out to discover what had happened to JP after Ackerly's 1964 report and whether a brain cutting had in fact occurred. Using a variety of investigative approaches, it was discovered that a post-mortem brain examination had taken place. Those present at the brain cutting were identified, and the still-living witnesses to the brain cutting were interviewed. Previously unpublished, relevant materials were uncovered from archival sources. A film of the brain cutting, as well as photos, were located. A film of Ackerly interviewing JP prior to JP's death at age sixty-four also was found. The authors studied autopsy findings in the newly discovered video and still images. These findings were judged consistent with massive perinatal hemorrhagic damage to both frontal lobes. JP's left-sided seizures were likely due to activation of a focus from his congenital brain damage. The anterograde amnesia that was documented when JP was twenty-five and that was noted to worsen when he was forty-nine remains unexplained but may have been related to slowly progressive hydrocephalus. This paper expands what is known about the case of JP, making it the only report of a person with congenital frontal injury followed for their entire life including post-mortem brain examination.

The cost-effectiveness of interventions in diabetes: a review of published economic evaluations in the UK setting, with an eye on the future.

AIM: To synthesise key outcomes data from cost-effectiveness studies in diabetes, in the UK setting, and describe a narrative for the evidence-base, in order to understand the direction that future health economics research in this field could be heading. METHODS: The peer-reviewed literature was searched at http://www.pubmed.com for health economics analyses in diabetes in the UK setting published between 1995 and 2008, using the keywords: "costs", "cost-effectiveness", "diabetes", "UK". Studies on screening for diabetes or prevention of diabetes were excluded, along with studies that looked purely at cost of diabetes treatment or monitoring. RESULTS: There were over 350 hits on MEDLINE. A total of 23 articles were identified and reviewed. 18 studies were in type 2, two in type 1 and three studies in both types 1 and type 2 diabetes. All studies evaluated treatment from the perspective of the NHS, with the time horizons varying from 12 months to patient lifetimes. 13 studies estimated quality-adjusted life expectancy (QALE). The majority of studies used health economics modelling techniques to project clinical benefit and cost outcomes beyond the context of clinical trials, with Markov-type models predominating. The United Kingdom Prospective Study of Diabetes was the most frequently cited source of clinical effectiveness and cost data. Most studies were funded by the pharmaceutical industry and evaluated more expensive products, rather than cheaper generic therapies such as human insulin and metformin monotherapy. CONCLUSION: Treatment-to-target in patients with diabetes in the UK is generally cost-effective and sometimes cost-saving vs. standard care. Ongoing health economics analysis in diabetes is essential as new clinical data are published. Future analysis of clinical and cost outcomes in diabetes could be expected to look beyond the impact of interventions on HbA1c in isolation, as manufacturers seek to differentiate innovative products in the market. Furthermore, it is anticipated that the competitiveness in the market for interventions in diabetes will lead to future cost-effectiveness analysis taking more interest in comparisons of off-patent medication and generic, fixed-dose combination therapies.

Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study.

OBJECTIVE: To assess the cost-effectiveness of intensive versus conventional therapy for 8 years as applied in the Steno-2 study in patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS: A Markov model was developed to incorporate event and risk data from Steno-2 and account Danish-specific costs to project life expectancy, quality-adjusted life expectancy (QALE), and lifetime direct medical costs expressed in year 2005 Euros. Clinical and cost outcomes were projected over patient lifetimes and discounted at 3% annually. Sensitivity analyses were performed. RESULTS: Intensive treatment was associated with increased life expectancy, QALE, and lifetime costs compared with conventional treatment. Mean +/- SD undiscounted life expectancy was 18.1 +/- 7.9 years with intensive treatment and 16.2 +/- 7.3 years with conventional treatment (difference 1.9 years). Discounted life expectancy was 13.4 +/- 4.8 years with intensive treatment and 12.4 +/- 4.5 years with conventional treatment. Lifetime costs (discounted) for intensive and conventional treatment were euro45,521 +/- 19,697 and euro41,319 +/- 27,500, respectively (difference euro4,202). Increased costs with intensive treatment were due to increased pharmacy and consultation costs. Discounted QALE was 1.66 quality-adjusted life-years (QALYs) higher for intensive (10.2 +/- 3.6 QALYs) versus conventional (8.6 +/- 2.7 QALYs) treatment, resulting in an incremental cost-effectiveness ratio of euro2,538 per QALY gained. This is considered a conservative estimate because accounting prescription of generic drugs and capturing indirect costs would further favor intensified therapy. CONCLUSIONS: From a health care payer perspective in Denmark, intensive therapy was more cost-effective than conventional treatment. Assuming that patients in both arms were treated in a primary care setting, intensive therapy became dominant (cost- and lifesaving).

Exenatide versus insulin glargine in patients with type 2 diabetes in the UK: a model of long-term clinical and cost outcomes.

OBJECTIVES: The aim of this study was to evaluate the long-term clinical and economic outcomes associated with exenatide or insulin glargine, added to oral therapy in individuals with type 2 diabetes inadequately controlled with combination oral agents in the UK setting. METHODS: A published and validated computer simulation model of diabetes was used to project long-term complications, life expectancy, quality-adjusted life expectancy and direct medical costs. Probabilities of diabetes-related complications were derived from published sources. Treatment effects and patient characteristics were extracted from a recent randomised controlled trial comparing exenatide with insulin glargine. Simulations incorporated published quality of life utilities and UK-specific costs from 2004. Pharmacy costs for exenatide were based on 20, 40, 60, 80 and 100% of the US value (as no price for the UK was available at the time of analysis). Future costs and clinical benefits were discounted at 3.5% annually. Sensitivity analyses were performed. RESULTS: In the base-case analysis exenatide was associated with improvements in life expectancy of 0.057 years and in quality-adjusted life expectancy of 0.442 quality-adjusted life years (QALYs) versus insulin glargine. Long-term projections demonstrated that exenatide was associated with a lower cumulative incidence of most cardiovascular disease (CVD) complications and CVD-related death than insulin glargine. Using the range of cost values, evaluation results showed that exenatide is likely to fall in a range between dominant (cost and life saving) at 20% of the US price and cost-effective (with an ICER of 22,420 pounds per QALY gained) at 100% of the US price, versus insulin glargine. CONCLUSIONS: Based on the findings of a recent clinical trial, long-term projections indicated that exenatide is likely to be associated with improvement in life expectancy and quality-adjusted life expectancy compared to insulin glargine. The results from this modelling analysis suggest that that exenatide is likely to represent good value for money by generally accepted standards in the UK setting in individuals with type 2 diabetes inadequately controlled on oral therapy.

A French cost-consequence analysis of the renoprotective benefits of irbesartan in patients with type 2 diabetes and hypertension.

OBJECTIVES: We performed a cost-consequence analysis in a French setting of the renoprotective benefit of irbesartan in hypertensive type 2 diabetes patients over a 25-year period. RESEARCH DESIGN AND METHODS: A previously published Markov model simulated progression from microalbuminuria to overt nephropathy, doubling of serum creatinine, end-stage renal disease and death. Three treatment strategies with analogous blood pressure control were compared: (A) control--conventionally medicated antihypertensive therapy (excluding angiotensin converting enzyme inhibitors, other angiotensin-2-receptor antagonists and dihydropyridine calcium channel blockers) initiated at microalbuminuria; (B) early irbesartan--(300 mg daily added to control, initiated with microalbuminuria) and (C) late irbesartan--(300 mg daily, initiated with overt nephropathy). Probabilities came from the Irbesartan in Reduction of Microalbuminuria-2 study, Irbesartan in Diabetic Nephropathy Trial and other sources. Clinical and economic outcomes were projected over 25 years. Annual discount rates were 3%. RESULTS: Compared to control, early use of irbesartan added (mean +/- standard deviation) 1.51 +/- 0.08 undiscounted life years (discounted: 0.94 +/- 0.05 years), while late irbesartan added 0.07 +/- 0.01 (0.04 +/- 0.01) years/patient. Early irbesartan added 1.03 +/- 0.06 discounted quality-adjusted life years (QALYs), while late irbesartan added 0.06 +/- 0.01 QALYs. Early and late irbesartan treatments were projected to save 22,314 +/- 1273 euro and 6619 +/- 820 euro/patient, respectively versus control. Sensitivity analysis showed that even over short time horizons both irbesartan treatments were superior to the control group. CONCLUSIONS: In France, early irbesartan treatment improved quality and length of life and reduced costs in hypertensive patients with type 2 diabetes and microalbuminuria. Late irbesartan therapy is beneficial, but earlier irbesartan leads to better outcomes.

Counting the costs of overweight and obesity: modeling clinical and cost outcomes.

OBJECTIVE: To quantify changes in clinical and cost outcomes associated with increasing levels of body mass index (BMI) in a US setting. RESEARCH METHODS AND PROCEDURES: A semi-Markov model was developed to project and compare life expectancy (LE), quality-adjusted life expectancy (QALE) and direct medical costs associated with distinct levels of BMI in simulated adult cohorts over a lifetime horizon. Cohort definitions included age (20-65 years), gender, race, and BMI (24-45 kg m(-2)). Cohorts were exclusively male or female and either Caucasian or African-American. Mortality rates were adjusted according to these factors using published data. BMI progression over time was modeled. BMI-dependent US direct medical costs were derived from published sources and inflated to year 2004 values. A third party reimbursement perspective was taken. QALE and costs were discounted at 3% per annum. RESULTS: In young Caucasian cohorts LE decreased as BMI increased. However, in older Caucasian cohorts the BMI associated with greatest longevity was higher than 25 kg m(-2). A similar pattern was observed in young adult African-American cohorts. A survival paradox was projected in older African-American cohorts, with some BMI levels in the obese category associated with greatest longevity. QALE in all four race/gender cohorts followed similar patterns to LE. Sensitivity analyses demonstrated that simulating BMI progression over time had an important impact on results. Direct costs in all four cohorts increased with BMI, with a few exceptions. CONCLUSIONS: Optimal BMI, in terms of longevity, varied between race/gender cohorts and within these cohorts, according to age, contributing to the debate over what BMI level or distribution should be considered ideal in terms of mortality risk. Simulating BMI progression over time had a substantial impact on health outcomes and should be modeled in future health economic analyses of overweight and obesity.

Cost-effectiveness of irbesartan in diabetic nephropathy: a systematic review of published studies.

BACKGROUND: To review published studies on the cost-effectiveness of the use of irbesartan for treatment of advance overt nephropathy in patients with type 2 diabetes and hypertension. METHODS: Articles were identified based on a search of the PubMed databases using the keywords 'irbesartan', 'ESRD', 'cost-effectiveness', 'nephropathy' and 'costs', and by personal communication with the authors. Only studies published in the last 10 years were included. All costs data from the cost-effectiveness studies were inflated to 2003 Euros using published governmental conversion tables. RESULTS: Seven published studies were identified, spanning the following country settings: the US, Belgium and France, Germany, Hungary, Italy, Spain, and the UK. In each, the same pharmacoeconomic model was adapted using country-specific data to project and evaluate the clinical and cost outcomes of the treatment arms of the Irbesartan in Diabetic Nephropathy Trial (IDNT) (irbesartan, amlodipine or standard blood pressure control). Mean time to onset of ESRD was 8.23 years for irbesartan, 6.82 years for amlodipine and 6.88 years for the control (values were the same for Belgium, France, Germany, Hungary, Italy and Spain as transition probabilities for progression to ESRD were all derived from the IDNT). Mean cumulative incidence of ESRD was 36% with irbesartan, 49% with amlodipine and 45% with control treatment. Treatment with irbesartan was projected to improve life expectancy compared to both amlodipine and control in all seven published studies. Analysis of total lifetime costs showed that irbesartan treatment was cost saving compared to the other two treatment regimens, due to the associated reduction in ESRD cases. Cost savings with irbesartan became evident very early; after 2-3 years of treatment in most settings. CONCLUSIONS: Modelling studies based on the IDNT published to date suggest that irbesartan treatment in patients with type 2 diabetes, hypertension and advanced nephropathy is both life- and cost-saving compared to amlodipine or control.

Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections.

BACKGROUND: It has been proposed that infection by group A beta-hemolytic streptococci (GABHS) can trigger acute symptom exacerbations among patients with Tourette's syndrome (TS) or obsessive-compulsive disorder (OCD), via autoimmune mechanisms. OBJECTIVE: To examine the temporal relationship between newly acquired GABHS infections (and other immunologic indices) and acute exacerbations of tics and obsessive-compulsive symptoms. METHODS: Pediatric patients (7-17 years of age) with TS and/or OCD (N = 47) and healthy control subjects (N = 19) were prospectively monitored for newly acquired GABHS infections, nonspecific markers of acute inflammatory responses, and D8/17-reactive cells (a marker of rheumatic fever). Objective monthly ratings of tic and obsessive-compulsive symptom severity were used to determine the timing of symptom exacerbations. RESULTS: The overall rate of acute exacerbations of neuropsychiatric symptoms was 0.56 exacerbations per patient per year. The average rate of new GABHS infections, using a stringent definition, was 0.42 infections per subject per year among patients, compared with 0.28 infections per subject per year for control subjects. The association between symptom exacerbations and new GABHS infections among patients was no greater than that expected on the basis of chance. At baseline, patients demonstrated significantly higher levels of D8/17-reactive cells and neopterin, compared with control subjects, but there was no consistent pattern of change when exacerbation time points were compared with baseline or follow-up time points. CONCLUSIONS: The results suggest no clear relationship between new GABHS infections and symptom exacerbations in an unselected group of patients with TS and/or OCD.