Conditional approval of cancer drugs in Canada: accountability and impact on public funding.

Background: We examined how conditional market approval of cancer pharmaceuticals by Health Canada (hc) affects public funding recommendations by the pan-Canadian Oncology Review (pcodr). We were also interested to see how often hc conditions are enforced. Methods: Health Canada and pcodr databases for 2010-2017 were analyzed for patterns in hc conditional authorization and post-authorization reviews of cancer drugs and for correlation with pcodr reimbursement recommendations. Results: Between 2010 and 2017, pcodr reviewed 105 unique drug-indication pairings; 21% (n = 22) had conditional hc authorization. In all cases, conditional authorization was given on the basis of preliminary data in a surrogate endpoint and was contingent on further data showing benefit in more robust outcome measures (for example, overall survival). Of those 22 drugs, 36% did not have updated data, 36% had updated data that met hc conditions, and 27% had data that met some, but not all, conditions. During the period considered, hc never revoked conditional authorization for failure to meet conditions. None of the 22 drugs was given an unconditional positive recommendation for public reimbursement by pcodr. A conditional recommendation was given to 11 of the drugs (50%), and reimbursement was not recommended for 6 drugs (27%) because of insufficient evidence. Conclusions: One fifth of the cancer drugs reviewed for public reimbursement in Canada were conditionally authorized by hc based on preliminary data. Conditional authorization was associated with a recommendation against public funding by pcodr. No drugs had their conditional market authorization revoked for failure to meet conditions, suggesting that a more robust hc reappraisal framework is needed.

Small intestinal absorption in patients with chronic obstructive pulmonary disease complicated by cor pulmonale - A pilot study.

BACKGROUND: Cor pulmonale is a common complication to Chronic Obstructive Pulmonary Disease (COPD), and may result in increased pressure in the inferior caval vein and stasis of the liver. The chronic pulmonary hypertension may lead to stasis in the veins from the small intestine and thereby compromise absorption of nutrients. AIM: To investigate whether patients with pulmonary hypertension have reduced absorption capacity compared to COPD patients without cor pulmonale. METHODS: Absorption of d-xylose (25 g) and zinc (132 mg), administered as a single dose, was tested in 14 COPD patients, seven with and seven without cor pulmonale. The presence of cor pulmonale was determined by echocardiography. The concentration of d-xylose and zinc were measured in peripheral blood one, two and three hours after ingestion and used as markers of absorption. Furthermore, urine was collected for five hours to determine the amount of excreted d-xylose. RESULTS: No significant difference in absorption of d-xylose (p = 0.28) or zinc (p = 0.51) was found between the two groups. However, a trend towards a delay in d-xylose absorption, as assessed by time-to-peak concentration, was observed in patients with cor pulmonale (p = 0.08). There was no significant difference in the amount of excreted d-xylose in the urine between the groups (p = 0.52). No correlation was found between the tricuspid regurgitation gradient and the absorption of both test-markers (rs = 0.34 and rs = -0.25). Likewise, no correlations were found between the inferior caval pressure during the in- and expiration phases and the absorption of d-xylose (rs = -0.09 rs = 0.23) or zinc (rs = -0.39, rs = -0.39). CONCLUSION: We found no indications that small intestinal absorption is affected in a clinically relevant degree in patients with cor pulmonale.

Behavioral performance follows the time course of neural facilitation and suppression during cued shifts of feature-selective attention.

A central question in the field of attention is whether visual processing is a strictly limited resource, which must be allocated by selective attention. If this were the case, attentional enhancement of one stimulus should invariably lead to suppression of unattended distracter stimuli. Here we examine voluntary cued shifts of feature-selective attention to either one of two superimposed red or blue random dot kinematograms (RDKs) to test whether such a reciprocal relationship between enhancement of an attended and suppression of an unattended stimulus can be observed. The steady-state visual evoked potential (SSVEP), an oscillatory brain response elicited by the flickering RDKs, was measured in human EEG. Supporting limited resources, we observed both an enhancement of the attended and a suppression of the unattended RDK, but this observed reciprocity did not occur concurrently: enhancement of the attended RDK started at 220 ms after cue onset and preceded suppression of the unattended RDK by about 130 ms. Furthermore, we found that behavior was significantly correlated with the SSVEP time course of a measure of selectivity (attended minus unattended) but not with a measure of total activity (attended plus unattended). The significant deviations from a temporally synchronized reciprocity between enhancement and suppression suggest that the enhancement of the attended stimulus may cause the suppression of the unattended stimulus in the present experiment.

Prescription data improve the medication history in primary care.

BACKGROUND: Incomplete medication lists increase the risk of medication errors and adverse drug effects. In Denmark, dispensing data and pharmacy records are available directly online to treating physicians. We aimed (1) to describe if use of pharmacy records improved the medication history among patients consulting their general practitioner and (2) to characterise inconsistencies between the medication history reported by the patient and the general practitioner's recordings. METHODS: Patients attending a general practitioner clinic were interviewed about their current medication use. Subsequently, the patients were contacted by phone and asked to verify the medication list previously obtained. Half of the patients were randomly selected for further questioning guided by their dispensing data: during the telephone interview, these patients were asked to clarify whether drugs registered in their pharmacy records were still in use. Pharmacy records show all drugs acquired on prescription from any national pharmacy in the preceding 2 years. The medication list was corrected accordingly. In all patients, the medication lists obtained on the in-clinic and telephone interviews were compared to the general practitioner's registrations. RESULTS: The 150 patients included in the study had a median age of 56 years (range 18-93 years), and 90 (60%) were women. Patients reported use of 849 drugs (median 5, range 0-16) at the in-clinic interview. Another 41 drugs (median 0, range 0-4) were added during the telephone interview. In the subgroup of 75 patients interviewed guided by pharmacy records, additionally 53 drugs (10%) were added to the 474 drugs already mentioned. The 27 patients adding more drugs guided by pharmacy records were significantly older and used more drugs (both p<0.05) than the 48 patients not adding drugs. When the medication lists were compared with the general practitioner's lists, specifically use of over-the-counter products and prescription-only medications from Anatomical Therapeutic Chemical Classification System group J, A, D, N and R were not registered by the general practitioner. DISCUSSION: Dispensing data provide further improvement to a medication history based on thorough in-clinic and telephone interviews. Use of pharmacy records as a supplement when recording a medication history seems beneficial, especially among older patients treated with polypharmacy.

Evidence that acute hyperinsulinaemia increases the cytokine content in essential organs after an endotoxin challenge in a porcine model.

BACKGROUND: Insulin has anti-inflammatory effects, as evaluated by its ability to reduce the plasma concentrations of cytokines. However, the inflammatory processing at the organ level is far less well established. The cytokine content in several organs after endotoxin (lipopolysaccharide, LPS) exposure and the effect of hyperinsulinaemia was examined. METHODS: Pigs (35-40 kg) were randomized into four groups, anaesthetized and mechanically ventilated for 570 min: group 1 (anaesthesia only; n = 10), group 2 (hyperinsulinaemic euglycaemic clamp, HEC; n = 9), group 3 (LPS; n = 10) and group 4 (LPS + HEC; n = 9). LPS was infused intravenously for 180 min (total dosage, 10 microg/kg). At the end of the study, i.e. 330 min after the termination of LPS or equivalent, cytokine mRNA and cytokine protein contents in the lungs, heart, liver, adipose tissue and spleen were measured. RESULTS: Hyperinsulinaemia led to increased interleukin-10 (IL-10) protein content in the heart and liver (by 40% and 28%, respectively) in comparison with normoinsulinaemic animals (P < 0.01 and P = 0.02, respectively), and increased tumour necrosis factor-alpha (TNF-alpha) protein content in the heart (P = 0.02). Animals exposed to LPS exhibited reduced TNF-alpha, IL-6 and IL-8 protein content in the heart (P = 0.02, P < 0.001 and P = 0.01, respectively). In the kidneys and adipose tissue, a particularly large cytokine protein content was observed. CONCLUSION: The findings strongly substantiate the role of insulin as an immune-modifying hormone at organ level during baseline and after an endotoxin challenge. Moreover, the kidneys and adipose tissue appear to be pivotal organs in terms of cytokine content shortly after endotoxin exposure, but the complexity remains to be clarified.

Ethical and practical problems in blood sampling for research purposes during pre-hospital emergencies.

BACKGROUND: Research in the pre-hospital phase of emergencies involves certain ethical and practical challenges. Severely ill or injured patients are not able to give informed consent in the immediate stressful situation. The aim of this pilot study was to find an ethically acceptable method to carry out research in acutely ill or injured patients before any treatment was given in order to be able to study the acute and unmodified systemic inflammatory response to trauma. METHODS: Younger physicians were assigned to the mobile emergency care unit (MECU) on a volunteer basis. They drew blood samples 'at the scene' from patients exposed to accidental injury or from patients with acute medical emergencies. The ethical committee accepted that informed consent to blood analyses could be postponed until later or given by relatives. Pro- and anti-inflammatory cytokines, catecholamines and cortisol were measured. RESULTS: During 6 months, the study group accompanied the MECU on approximately 500 call-outs. Blood samples were drawn from 42 patients. Consent to the analysis of blood samples was obtained in 30 cases. In 20 cases, it was not possible to draw the blood sample before medication. CONCLUSION: This pilot study showed that it was possible to conduct blood sampling from acutely ill patients 'at the scene'. However, the present legislation on informed consent makes this type of research very time consuming. When patients die in hospital and no relatives can be found, consent cannot be obtained, and information from these severely affected patients is lost.

Inflammatory response during hyperglycemia and hyperinsulinemia in a porcine endotoxemic model: the contribution of essential organs.

BACKGROUND: During euglycemia acute hyperinsulinemia diminishes the cytokine response to endotoxin [Lipopolysaccharide (LPS)] exposure. In this study we elucidated whether acute hyperglycemia and hyperinsulinemia modify the cytokine content in several organs during LPS challenge in a porcine model. METHODS: Pigs (35-40 kg) were randomized to either normoglycemia (group 1, n = 8) or hyperglycemia and hyperinsulinemia (group 2, n = 8), anesthetized and mechanically ventilated. Both groups received a 180-min intravenous infusion of LPS (total 10 microg kg(-1)). Groups 1 and 2 were clamped at plasma glucose concentrations of 5 mM and 15 mM, respectively. Group 1 maintained a baseline insulin level while the hyperglycemic group exhibited increased insulin levels. RESULTS: Circulating cytokines, cytokine mRNA and cytokine protein content were examined in the heart, liver, kidneys, lungs, spleen, adipose and muscle tissue. After LPS exposure, in both groups vast and equal plasma cytokines were elicited by approximately 70-5000-fold. A 10-fold higher level of IL-10, IL-6 and TNF-alpha protein was found in kidney tissue compared to the other organs together with a 3-10-fold increase of TNF-alpha in adipose tissue. However, cytokine mRNAs as well as organ function were without statistical difference between the groups. CONCLUSION: Endotoxemia elicited a pronounced cytokine response in both plasma and at organ level. The kidneys and adipose tissue showed the highest cytokine protein content. Acute hyperglycemia apparently counteracts the well-established anti-inflammatory effects of insulin on the inflammatory response in a LPS challenged porcine model. Whether the observation can be extrapolated to more long-term stress-exposure remains to be clarified.

Plasma cytokines do not reflect expression of pro- and anti-inflammatory cytokine mRNA at organ level after cardiopulmonary bypass in neonatal pigs.

BACKGROUND: Plasma concentrations of inflammatory markers are increased in response to the trauma of cardiac surgery and cardiopulmonary bypass (CPB). It is, however, unknown whether the plasma cytokine levels and cytokine mRNA expression at organ level reflect each other. METHODS: Twenty-six piglets (17-19 days) were allocated to the sham-group (sternotomy only, n = 13) or to the CPB-group (sternotomy, 120 min CPB procedure with 60-min aortic cross-clamp, n = 13). The pigs were observed for 0.5 h or 4 h post-CPB. Plasma levels of IL-1beta, IL-6, IL-8 and IL-10 and mRNA expression of TNF-alpha, IL-1beta, IL-6, IL-8, IL-10 and iNOS in organs were registered with concomitant changes in oxygenation index (OI) and expiratory nitric oxide (NO). RESULTS: In pigs killed 0.5 h post-CPB there was a significant increase in IL-10 mRNA in the lungs and kidneys compared with the sham-group. IL-1beta mRNA was detectable in the kidneys and lungs of the CPB-pigs, while IL-6 mRNA was up regulated only in lungs. In pigs killed 4 h post-CPB a significantly higher IL-6 mRNA was found in heart tissue and a lower IL-10 mRNA was found in lungs of CPB pigs compared with the sham-group. There was a concomitant significant increase in OI and increased plasma IL-8 and IL-10 concentrations in the CPB-pigs compared with the sham-pigs. CONCLUSION: The cytokine mRNA expression pattern was very different for the pigs killed already 0.5 h after the CPB procedure compared with the pigs killed 4 h post-CPB. The plasma cytokine levels poorly reflected mRNA expression of the pro- and anti-inflammatory cytokines.

Shared experience in 13 local Danish EPR projects: the Danish EPR Observatory.

In 1996 a national strategy for the development of electronic patient records (EPR) for the Danish hospitals and primary care was launched. An element in the strategy was to support a number of regional EPR development projects. The EPR-Observatory has in the two recent years collected data from the regional projects, dealing with the expectations in four areas: 1) Impact on organisational issues, 2) Benefits of EPR, 3) Integration of EPR with other information systems and 4) security aspects of EPR. Among the observations an increasing teamwork and im-proved knowledge about the patient was found. What was expected, but not found, was resistance to EPR, as a result of changes in skills and power. The most obvious benefits are increased data accessibility and improved decision ma-king. The most considerable disadvantage is an enormous growth in discontent with the systems performance and the fact, that all the projects are delayed. Many different types of integration solutions are chosen, because of a lack of a common model for integration. Generally the projects find, that EPJ yields increased security, but logistical problems arise in having the systems running 24 hours 7 days a week. Economical benefits cannot be documented. This relates to the fact, that the regional projects are stand-alone projects. The ongoing growth in discontent with the EPR-systems and the fact, that all the projects are delayed must be subject to further exploration.

The Danish EPR Observatory. Assessing organisational impact from EPR implementation.

The EPR Observatory has studied 13 local Danish electronic patient record (EPR) projects through 2 years. The focus has been on expectations and experiences in relation to organisational changes. The main conclusions are that the healthcare professionals, working with the development, implementation and/or use of EPR, are in a very important and difficult process settling up with old traditions and cultures tied to the healthcare professions. Especially the healthcare professionals, working with EPR, shows interest and readiness to participate in new ways of collaboration and to work with highly structured data in structured frameworks. EPR is at this point of time only diffused in few relatively small and isolated healthcare organisations, and the preliminary assessment in the study only outlines the perspectives for what will happen on a wider scale when EPR systems get more diffused.

An architecture for bridging between research and practical use in health informatics.

Health informatics is a true interdisciplinary research discipline combining computer engineering, health science and fields dealing with organisation and communication issues. Much of the research published within the area has a common goal: to develop optimal information systems for better access to relevant data, information, and knowledge in the health care sector. As a respond to existing discontinuity between research and practical use, we present an architecture for an interdisciplinary virtual organisation promoting synergy across health informatics environments including research, industry, clinical, and educational settings. A set of key lessons learned from a practical implementation of the architecture are reported.

Evaluation of the diagnostic performance of the expert EMG assistant MUNIN.

The diagnostic performance of the medical expert system MUNIN for diagnosis of neuromuscular disorders was evaluated on a set of 30 test cases. The cases were provided by 7 experienced electromyographers who were subsequently invited to participate in the evaluation. To reasonably cover the range of disorders, the electromyographers were asked to provide cases from patients with different types of muscular dystrophy, with neuromuscular transmission disorders, with motor neurone disease, and with different types of polyneuropathies. In addition, patients with a range of local neuropathies were provided. Out of the 30 cases, 11 cases were evaluated by an "almost peer review" method and the remaining 19 cases were evaluated by a "silver standard" method. The number of cases evaluated by "almost peer review" was limited to 11 due to time constraints on the evaluation procedure. During the "almost peer review," each electromyographer was asked to diagnose patients, using a vocabulary that closely resembled MUNIN's vocabulary. Subsequently, we attempted to provide a consensus diagnosis for the patients based on discussion among the participating electromyographers. The electromyographers were also asked to assess how well MUNIN had performed in each case. The remaining 19 cases were evaluated by a "silver standard" procedure, where MUNIN's diagnosis was compared to the diagnosis of the expert who provided the case. The results indicated that MUNIN performed well, and the electromyographers considered "that MUNIN performed at the same level as an experienced neurophysiologist." In particular, it was noted that MUNIN handled cases with conflicting findings well, and that it was able to diagnose patients with multiple diseases.