How to design the cost‐effectiveness appraisal process of new healthcare technologies to maximise population health: A conceptual framework

This paper presents a conceptual framework to analyse the design of the cost‐effectiveness appraisal process of new healthcare technologies. The framework characterises the appraisal processes as a diagnostic test aimed at identifying cost‐effective (true positive) and non‐cost‐effective (true negative) technologies. Using the framework, factors that influence the value of operating an appraisal process, in terms of net gain to population health, are identified. The framework is used to gain insight into current policy questions including (a) how rigorous the process should be, (b) who should have the burden of proof, and (c) how optimal design changes when allowing for appeals, price reductions, resubmissions, and re‐evaluations. The paper demonstrates that there is no one optimal appraisal process and the process should be adapted over time and to the specific technology under assessment. Optimal design depends on country‐specific features of (future) technologies, for example, effect, price, and size of the patient population, which might explain the difference in appraisal processes across countries. It is shown that burden of proof should be placed on the producers and that the impact of price reductions and patient access schemes on the producer's price setting should be considered when designing the appraisal process.     

Diagnostic Specificity of Neurophysiological Endophenotypes in Schizophrenia and Bipolar Disorder

Background: The utility of an endophenotype depends on its ability to reduce complex disorders into stable, genetically linked phenotypes. P50 and P300 event-related potential (ERP) measures are endophenotype candidates for schizophrenia; however, their abnormalities are broadly observed across neuropsychiatric disorders. This study examined the diagnostic efficiency of P50 and P300 in schizophrenia as compared with healthy and bipolar disorder samples. Supplemental ERP measures and a multivariate classification approach were evaluated as methods to improve specificity. Methods: Diagnostic classification was first modeled in schizophrenia (SZ = 50) and healthy normal (HN = 50) samples using hierarchical logistic regression with predictors blocked by 4 levels of analysis: (1) P50 suppression, P300 amplitude, and P300 latency; (2) N100 amplitude; (3) evoked spectral power; and (4) P50 and P300 hemispheric asymmetry. The optimal model was cross-validated in a holdout sample (SZ = 34, HN = 31) and tested against a bipolar (BP = 50) sample. Results: P50 and P300 endophenotypes classified SZ from HN with 71% accuracy (sensitivity = .70, specificity = .72) but did not differentiate SZ from BP above chance level. N100 and spectral power measures improved classification accuracy of SZ vs HN to 79% (sensitivity = .78, specificity = .80) and SZ vs BP to 72% (sensitivity = .74, specificity = .70). Cross validation analyses supported the stability of these models. Conclusions: Although traditional P50 and P300 measures failed to differentiate schizophrenia from bipolar participants, N100 and evoked spectral power measures added unique variance to classification models and improved accuracy to nearly the same level achieved in comparison of schizophrenia to healthy individuals.Key words: event-related potential, P50, P300, N100, gamma frequency     

The osmoregulatory system and the renin-angiotensin-aldosterone system in pre-eclampsia and normotensive pregnancy

Plasma concentrations of arginine vasopressin (AVP), angiotensin II (A II), aldosterone (Aldo), serum osmolality (Sosm), urine volume (V), and free water clearance (CH2O) were determined in the third trimester of pregnancy, and 5 days and 3 months after delivery in pre-eclampsia (group I), in normotensive pregnancy (group II), and in non-pregnant control subjects (group III). The AVP was the same in the third trimester of pregnancy in groups I and II and did not deviate significantly from the level in group III. However, 5 days after delivery, AVP was lower and V and CH2O higher in group I than in group II. There was no correlation between AVP and Sosm in the third trimester in either group I or II, but 5 days after delivery a significant positive correlation was found between these parameters in both groups I and II as well as in group III. The A II and Aldo changed qualitatively in the same way in groups I and II, that is, considerable elevation in the third trimester and normalization after delivery. Also, A II and Aldo were lower in group I than in II. The AVP and A II were not correlated and there was no significant relationship between systolic or diastolic blood pressure on the one hand and AVP, A II or Aldo on the other in either group I or II. Thus the osmoregulatory system appears to be altered in both pre-eclampsia and normotensive pregnancy, but becomes normal again 5 days after delivery. In pre-eclampsia a suppression of AVP seems to be responsible for the elimination of excess water in pre-eclampsia 5 days after delivery. There was no evidence for a causal relationship between blood pressure and the osmoregulatory system or the renin-angiotensin-aldosterone system in any of the pregnant groups.     

Systemic Levels of CCL2, CCL3, CCL4 and CXCL8 Differ According to Age,Time Period and Season among Children Newly Diagnosed with type 1 Diabetes and their Healthy Siblings

The mechanisms by which antigen‐specific T cells migrate to the islets of Langerhans in type 1 diabetes (T1D) are largely unknown. Chemokines attract immune cells to sites of inflammation. The aim was to elucidate the role of inflammatory chemokines in T1D at time of diagnosis. From a population‐based registry of children diagnosed with T1D from 1997 to 2005, we studied five different inflammatory chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8). Four hundred and eighty‐two cases and 479 sibling frequencies matched on age and sample year distribution were included. Patients showed lower levels of CCL4 compared to siblings, but this result was not significant after correction for multiple testing. CCL2, CCL3, CCL4 and CXCL8 levels were highest in the most recent cohorts (P < 0.01) in both patients and siblings. A significant seasonal variation – for most of the chemokines – was demonstrated with the highest level during the summer period in both patients and siblings. In addition, there was a significant inverse relationship between CCL4 levels and age. When comparing patients and siblings, remarkably few differences were identified, but interestingly chemokine levels varied with age, season and period for the entire study population. Such variations should be taken into account when studying chemokines in paediatric populations.     

Inhibition of neointimal hyperplasia by a specific thrombin inhibitor

Objective—Restenosis secondary to neointimal hyperplasia remains the major limiting factor after vascular interventions. Thrombin generated in high concentrations at the site of vascular injury plays a central role in thrombosis and hemostasis. Thrombin has also been implicated as a mitogen for smooth muscle cell proliferation that contributes to restenosis. This study was designed to determine the effects of a specific thrombin inhibitor on neointimal hyperplasia after balloon injury in a rat carotid artery model.

Design—A total of 47 male Sprague–Dawley rats were divided into five groups. All groups underwent balloon injury of the left carotid artery. A specific thrombin inhibitor, inogatran, was given in four different regimens: low and high dose injections, short‐term infusion for 3?h, and long‐term infusion for 1 week. After 2 weeks the animals were killed and the carotid neointima/media area ratio and the luminal narrowing were calculated.

Results—All treatments significantly reduced the neointimal hyperplasia. Inogatran given as a long‐term infusion for 1 week had the lowest neointima/media ratio compared with the other groups. The percentage of lumen narrowing was also significantly lower in all treatment groups compared with the control group.

Conclusion—A specific direct thrombin inhibitor, inogatran, reduces neointimal hyperplasia after arterial injury in rats. A more prolonged administration of the thrombin inhibitor gave a further reduction of the neointimal hyperplasia. It seems that inhibition of thrombin activity is not only important early after injury, but also later. This could have clinical implications in the treatment of restenosis and needs to be further evaluated.     

DNA ploidy, tumour site, and prognosis in colorectal cancer. A flow cytometric study of paraffin-embedded tissue

DNA ploidy patterns were studied by flow cytometry in nuclear suspensions from 149 paraffin-embedded colorectal adenocarcinomas. The DNA ploidy of rectal tumours was not significantly different from that of colonic tumours. Patients with DNA diploid tumours had a significant survival advantage compared with patients with non-diploid tumours, but DNA ploidy did not confer any significant additional prognostic information when tumour site, Dukes's stage, the invasiveness of the tumour, and the number of lymph node metastases were adjusted for in a proportional hazards regression analysis (Cox). It is concluded that DNA ploidy does not contribute significantly to the explanation of why patients with rectal cancer have a poorer prognosis than those with colonic cancer.     

Influence of branched-chain amino acid infusion on arterial concentrations and brain exchange of amino acids in patients with hepatic cirrhosis

Summary.

• 1 The influence of branched-chain amino acid (BCAA) infusion on arterial concentrations and brain exchange of amino acids was studied in seven patients with hepatic cirrhosis and in six healthy control subjects. Arterial levels and arterial-jugular venous (A-JV) concentration differences for amino acids, glucose, ketone bodies and lactate were measured in the basal state and during a constant rate, 150 min intravenous infusion of a BCAA solution (250 fmiol/min, 70% L-leucine, 20% L-valine and 10% L-isoleucine).
• 2 In the basal state the arterial whole blood concentrations of tyrosine, phenylalanine and methionine were 40–130 % higher in the cirrhotic patients compared to the controls, while the levels of the BCAA were 20–35 % lower. The patients' concentration of aspartic acid was 70% below the corresponding control value.
• 3 During BCAA infusion the arterial leucine concentration rose 4–5 fold while valine increased 60–95% and isoleucine rose 45–50%. The arterial levels of several amino acids decreased progressively in a similar manner in patients and controls. At the end of the 150 min infusion period methionine had decreased 35% (P<001), tyrosine 25% (P<0–001) and phenylalanine 35% (P<0–001) in the patient group.
• 4 Positive A-JV differences in amino acid concentration–indicating net brain uptake–were seen for leucine, isoleucine, valine, serine, tyrosine and lysine in both groups in the basal state. The patients had a greater A-JV difference than the controls for tyrosine (P<0–05) while the uptake of the other amino acids, including the BCAA, was similar in the two groups. The fractional uptake of leucine and valine was significantly increased in the patients.
• 5 During BCAA infusion the A-JV difference for leucine increased 2–3 fold in both patients and controls and the net uptake to the brain of tyrosine and phenylalanine was abolished in the patient group.
• 6 It is concluded that (a) patients with hepatic cirrhosis show a decreased whole blood concentration of aspartate indicating a reduced intracellular concentration of this amino acid, (b) brain uptake of tyrosine and fractional uptake of leucine and valine is augmented in patients with hepatic cirrhosis, demonstrating abnormal brain amino acid uptake in this disorder, and (c) BCAA infusion effectively lowers the arterial concentrations for tyrosine, phenylalanine and methionine in cirrhotic patients as well as in healthy controls and blocks the abnormal brain uptake of tyrosine. These findings provide a biochemical background to the suggested beneficial effect of BCAA infusion in patients with hepatic cirrhosis and portal systemic encephalopathy.