Accelerating patient access to oncology medicines with multiple indications in Europe.

Background: In recent years, innovation in oncology has created new challenges for pricing and reimbursement systems. Oncology medicines with multiple indications face a number of access challenges: (1) the number of assessments and administrative burden; (2) aligning price to different values of the same product; (3) managing clinical uncertainty at time of launch; and (4) managing budget uncertainty. These challenges impact a range of stakeholders and can result in delayed patient access to life-saving treatments. Consequently, countries have taken steps to facilitate patient access. Methods: Drawing on the experience across Europe we have reviewed different mechanisms countries have adopted that address these challenges. These include approaches aimed directly at the issue, multi-year-multi-indication (MYMI) agreements (BE, NL), and other approaches to manage access: flexible access agreements for new indications with clinical uncertainty (UK); development of a new agreement for each new indication (IT); and immediate access for new indications and bundled assessments (DE). Results: MYMI agreements are valuable where existing rules mean that every indication faces the same upfront evaluation process that delays patient access. They are also useful in managing budget impact and uncertainty. Other approaches that adopt an indication-specific approach helps manage clinical uncertainty at the time of launch and realise different values for the same product. They can help align price to value, even though indication-based pricing does not exist. Bundled assessments reduce the administrative burden for stakeholders, and the benefits of immediate reimbursement is that patient access is not delayed. Conclusion: The challenges for medicines with multiple indications impact a range of stakeholders and can result in delayed patient access to life-saving treatments. MYMI agreements have created a more pragmatic approach to HTA for medicines with multiple indications to ensure both fast and broad patient access. Continued innovation in oncology will require further innovative approaches in pricing and reimbursement. It is important that policymakers, payers and manufacturers engage in early discussions and are willing to find new solutions to help accelerate patient access to innovative therapies.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. RESULTS: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. CONCLUSIONS: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.

The Global Genome Biodiversity Network (GGBN) Data Standard specification.

Genomic samples of non-model organisms are becoming increasingly important in a broad range of studies from developmental biology, biodiversity analyses, to conservation. Genomic sample definition, description, quality, voucher information and metadata all need to be digitized and disseminated across scientific communities. This information needs to be concise and consistent in today's ever-increasing bioinformatic era, for complementary data aggregators to easily map databases to one another. In order to facilitate exchange of information on genomic samples and their derived data, the Global Genome Biodiversity Network (GGBN) Data Standard is intended to provide a platform based on a documented agreement to promote the efficient sharing and usage of genomic sample material and associated specimen information in a consistent way. The new data standard presented here build upon existing standards commonly used within the community extending them with the capability to exchange data on tissue, environmental and DNA sample as well as sequences. The GGBN Data Standard will reveal and democratize the hidden contents of biodiversity biobanks, for the convenience of everyone in the wider biobanking community. Technical tools exist for data providers to easily map their databases to the standard.Database URL: http://terms.tdwg.org/wiki/GGBN_Data_Standard.

Against moral theories: reply to Benatar.

D Benatar argues that in the author's recent article Moral theories in teaching applied ethics, the author overlooked important roles that could be played by moral theories in such teaching. In this reply, the cases that Benatar suggests are considered and for each an alternative approach is suggested that will avoid the costs discussed in the original paper and will also be a more effective response to that particular issue.

Knowledge and attitudes to prescribed drugs in young and elderly patients.

Increasing patient knowledge of drug therapy is said to improve compliance and may reduce adverse drug reactions. We assessed patient knowledge of prescribed drugs in fifty patients attending a hypertension clinic [outpatients] and in elderly patients on admission to (n = 129) and on discharge from (n = 100) an acute geriatric assessment unit. We found that 88% of outpatients, 40% of elderly admissions, and 41% of elderly discharges knew the indications for their therapy; only 40% of outpatients, 8% of elderly admissions and 12% of elderly discharges could name their medications. Patients said that their information came principally from the prescribing doctor. In a further study we assessed doctor, nurse, young and elderly patients' ability to discriminate between commonly prescribed white tablets. Errors were made by the doctors on 25% occasions, nurses on 40% occasions and patients on 61% occasions. Young patients made errors 67% of the time and elderly patients 55% of the time. These studies indicate that both inpatients and outpatients, both young and elderly have poor knowledge of their medications. In addition, many commonly prescribed drugs are not easily distinguishable by patient, prescriber or drug administrator. We conclude that there is a need to improve knowledge both in patients and in prescribers. We suggest that prescribers should consider the colour and shape of medications prescribed concurrently as many "little white tablets" are difficult to tell apart.

Choreographing trauma resuscitation in the OR.

Survival rates are enhanced if severely injured trauma patients are admitted directly to the OR for resuscitation and surgical intervention. To increase the survivability and decrease the morbidity of trauma patients with penetrating trauma to the chest or abdomen, a hospital in La Jolla, Calif, developed a "direct to the OR" resuscitation program. This program substantially increased the survival rate of these trauma patients. Perioperative nurses respond to all major trauma situations and assist with surgical procedures completed in a trauma resuscitation room or in the OR.

[Does the ideal dental sterilizer exist]. / L'appareil idéal de stérilisation en médecine dentaire existe-t-il?

Heat sterilization is still the best known method to sterilize all dental instruments. No compromise is acceptable. The use of the so-called cold sterilizing solutions is only palliative. Glutaraldehyde and chlorine compounds seem to possess some sterilizing properties, but these solutions are recognized as being toxic, allergenic and probably carcinogenic. The use of two (2) or more sterilizers may be the ideal method to sterilize the metal, plastic and rubber materials... There are many practical sterilization systems on the market today. An intensive evaluation of these systems is necessary before one is used in a dental office and subsequently an annual reevaluation is suggested. The regular use of physical, chemical and especially biological indicators is the only sure way to control the many failures associated with sterilizers. The choice of equipment is directly related to the total aseptic protocol to be implemented. The objective of this article is to review and clarify certain ideas and controversies associated with this subject matter.

Surreptitious insulin administration in adolescents with insulin-dependent diabetes mellitus.

Six adolescents, 12 to 15 years old, with insulin-dependent diabetes mellitus were discovered to be secretively taking extra insulin, not with the intent of improving metabolic control. Large discrepancies between reported and observed insulin requirements were noted. Psychosocial problems antedated the discovery of surreptitious insulin administration in all. Psychological testing and psychiatric evaluation revealed a variety of psychiatric conditions; depression was common. In two patients surreptitious insulin administration was believed to represent suicidal behavior. In others, it appeared to represent symptom substitution when use of other health-threatening behaviors such as recurrent ketoacidosis was made increasingly difficult through appropriate intervention. Surreptitious insulin administration may be one symptom of serious underlying psychiatric dysfunction in adolescents with insulin-dependent diabetes.

Doxepin therapy for duodenal ulcer: a controlled trial in patients who failed to respond to cimetidine.

Ten patients with endoscopically proven active duodenal ulcers completed a double-blind placebo-controlled trial of doxepin hydrochloride. All ten had previously failed to respond to conventional cimetidine therapy. Doxepin was given at bedtime in a single 50-mg dose for the first week and, if needed, in a single 75-mg or 100-mg dose for the remainder of the six-week trial. After two weeks of therapy the decrease in average ulcer size was 54% in the doxepin group versus 38% in the placebo group (P less than 0.01); at the end of six weeks the decrease in mean ulcer size was 69% in the doxepin group versus 97% in the placebo group, a difference that was not significant. No serious side effects were attributed to doxepin, but two patients complained of mild dryness of the mouth. Suggestions for using this tricyclic antidepressant and possible mechanisms of action are discussed.