Digital Drugs: an anatomy of new medicines

Medicines are digitalized as aspects of their regulation and use are embodied in or draw from interlinked computerized systems and databases. This paper considers how this development changes the delivery of health care, the pharma industry, and regulatory and professional structures, as it reconfigures the material character of drugs themselves. It draws on the concept of assemblage in presenting a theory-based analysis that explores digital drugs’ ontological status including how they embody benefit and value. The paper addresses three interconnected domains – that of use of drugs (practice), of research (epistemology) and of regulation (structures)

A computer decision aid for medical prevention: a pilot qualitative study of the Personalized Estimate of Risks (EsPeR) system

BACKGROUND: Many preventable diseases such as ischemic heart diseases and breast cancer prevail at a large scale in the general population. Computerized decision support systems are one of the solutions for improving the quality of prevention strategies. METHODS: The system called EsPeR (Personalised Estimate of Risks) combines calculation of several risks with computerisation of guidelines (cardiovascular prevention, screening for breast cancer, colorectal cancer, uterine cervix cancer, and prostate cancer, diagnosis of depression and suicide risk). We present a qualitative evaluation of its ergonomics, as well as it's understanding and acceptance by a group of general practitioners. We organised four focus groups each including 6–11 general practitioners. Physicians worked on several structured clinical scenari os with the help of EsPeR, and three senior investigators leaded structured discussion sessions. RESULTS: The initial sessions identified several ergonomic flaws of the system that were easily corrected. Both clinical scenarios and discussion sessions identified several problems related to the insufficient comprehension (expression of risks, definition of familial history of disease), and difficulty for the physicians to accept some of the recommendations. CONCLUSION: Educational, socio-professional and organisational components (i.e. time constraints for training and use of the EsPeR system during consultation) as well as acceptance of evidence-based decision-making should be taken into account before launching computerised decision support systems, or their application in randomised trials

Roles of fire history and rewetting in peatland restoration and vegetation recovery on the Merang peat dome, South Sumatra, Indonesia

In the restoration of drained and degraded tropical peat swamp forest (PSF) it is not well understood whether fire suppression on its own is sufficient to facilitate regeneration, or if rewetting plays a key role. We attempt to answer this question in the Merang area, a 23,000-ha peatland located in South Sumatra province, Indonesia. As with more than 90 % of PSF in Southeast Asia, the area has been largely degraded by logging and drainage canals, along with multiple fires. It has been designated and managed as an ecosystem restoration area since 2016, by which time only a single 254 ha patch of original PSF habitat remained. However, scattered remnant PSF trees ( 4 fires), while Macaranga pruinosa, Melicope glabra and Melicope lunu-ankenda dominate in regenerating areas that have experienced 12 fires. While fire suppression is essential to prevent further loss of vegetation, effective rewetting is required before woody vegetation can recover

Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future.

The interest in RDN for hypertension has fluctuated recently, with a flurry of initial enthusiasm followed by sudden loss of interest by researchers and device manufacturers, with an almost as sudden resurgence in clinical trials activity and device innovation more recently. There is widespread consensus that this therapeutic strategy can be effective, at least for some of the technologies available. Major uncertainties remain as to the clinical role of RDN, and whether any of the emerging technologies such as AV-anastomosis formation, carotid body ablation, carotid bulb expansion, or baroreflex stimulation will have a future as effective treatment options in patients with hypertension. In our first consensus report in 2015, the European Expert Group pointed to the major unmet need of standardization of measurements, trial design and procedural performance.6 With the large number of different technologies currently in the pipeline, this need has even increased. Only through high-quality, collaborative research and openness to new methods for recruitment, patient selection, and assessment of outcomes will it be possible to establish incontrovertibly whether device therapies for hypertension are effective and what are preferred patient populations. Once the proof of concept is established, further studies with a design relevant to clinical reality will be needed to establish the place of new devices in the treatment armoury. The clinical and research community has a large responsibility to prove or disprove the value of new therapies, in order to ensure that antihypertensive devices provide future patients with the greatest benefit and the smallest risk. copy; The Author 2017

Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience.

International audiencePURPOSE: Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs. METHODS: 96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists. RESULTS: This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0. CONCLUSION: The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment

Streptococcal necrotising fasciitis from diverse strains of Streptococcus pyogenes in tropical northern Australia: case series and comparison with the literature

BACKGROUND: Since the mid-1980's there has been a worldwide resurgence of severe disease from group A streptococcus (GAS), with clonal clusters implicated in Europe and the United States. However GAS associated sepsis and rheumatic fever have always remained at high levels in many less developed countries. In this context we aimed to study GAS necrotising fasciitis (NF) in a region where there are high background rates of GAS carriage and disease. METHODS: We describe the epidemiology, clinical and laboratory features of 14 consecutive cases of GAS NF treated over a seven year period from tropical northern Australia. RESULTS: Incidence rates of GAS NF in the Aboriginal population were up to five times those previously published from other countries. Clinical features were similar to those described elsewhere, with 7/14 (50%) bacteremic and 9/14 (64%) having associated streptococcal toxic shock syndrome. 11/14 (79%) had underlying chronic illnesses, including all four fatalities (29% mortality overall). Important laboratory differences from other series were that leukocytosis was absent in 9/14 (64%) but all had substantial lymphopenia. Sequence typing of the 14 NF-associated GAS isolates showed no clonality, with only one emm type 1 and two emm type 3 strains. CONCLUSIONS: While NF clusters can occur from a single emergent GAS clone, this was not evident in our tropical region, where high rates of NF parallel high overall rates of GAS infection from a wide diversity of strains. The specific virulence factors of GAS strains which do cause NF and the basis of the inadequate host response in those patients who develop NF on infection with these GAS require further elucidation

Inactivation of DltA Modulates Virulence Factor Expression in Streptococcus pyogenes

D-alanylated lipoteichoic acid is a virtually ubiquitous component of gram-positive cell walls. Mutations in the dltABCD operon of numerous species exhibit pleiotropic effects, including reduced virulence, which has been attributed to increased binding of cationic antimicrobial peptides to the more negatively charged cell surface. In this study, we have further investigated the effects that mutating dltA has on virulence factor expression in Streptococcus pyogenes.Isogenic Delta dltA mutants had previously been created in two distinct M1T1 isolates of S. pyogenes. Immunoblots, flow cytometry, and immunofluorescence were used to quantitate M protein levels in these strains, as well as to assess their ability to bind complement. Bacteria were tested for their ability to interact with human PMN and to grow in whole human blood. Message levels for emm, sic, and various regulatory elements were assessed by quantitative RT-PCR. Cell walls of Delta dltA mutants contained much less M protein than cell walls of parent strains and this correlated with reduced levels of emm transcripts, increased deposition of complement, increased association of bacteria with polymorphonuclear leukocytes, and reduced bacterial growth in whole human blood. Transcription of at least one other gene of the mga regulon, sic, which encodes a protein that inactivates antimicrobial peptides, was also dramatically reduced in Delta dltA mutants. Concomitantly, ccpA and rofA were unaffected, while rgg and arcA were up-regulated.This study has identified a novel mechanism for the reduced virulence of dltA mutants of Streptococcus pyogenes in which gene regulatory networks somehow sense and respond to the loss of DltA and lack of D-alanine esterification of lipoteichoic acid. The mechanism remains to be determined, but the data indicate that the status of D-alanine-lipoteichoic acid can significantly influence the expression of at least some streptococcal virulence factors and provide further impetus to targeting the dlt operon of gram-positive pathogens in the search for novel antimicrobial compounds

Does the routine use of global coronary heart disease risk scores translate into clinical benefits or harms? A systematic review of the literature

<p>Abstract</p> <p>Background</p> <p>Guidelines now recommend routine assessment of global coronary heart disease (CHD) risk scores. We performed a systematic review to assess whether global CHD risk scores result in clinical benefits or harms.</p> <p>Methods</p> <p>We searched MEDLINE (1966 through June 13, 2007) for articles relevant to our review. Using predefined inclusion and exclusion criteria, we included studies of any design that provided physicians with global risk scores or allowed them to calculate scores themselves, and then measured clinical benefits and/or harms. Two reviewers reviewed potentially relevant studies for inclusion and resolved disagreement by consensus. Data from each article was then abstracted into an evidence table by one reviewer and the quality of evidence was assessed independently by two reviewers.</p> <p>Results</p> <p>11 studies met criteria for inclusion in our review. Six studies addressed clinical benefits and 5 addressed clinical harms. Six studies were rated as "fair" quality and the others were deemed "methodologically limited". Two fair quality studies showed that physician knowledge of global CHD risk is associated with increased prescription of cardiovascular drugs in high risk (but not all) patients. Two additional fair quality studies showed no effect on their primary outcomes, but one was underpowered and the other focused on prescribing of lifestyle changes, rather than drugs whose prescribing might be expected to be targeted by risk level. One of these aforementioned studies showed improved blood pressure in high-risk patients, but no improvement in the proportion of patients at high risk, perhaps due to the high proportion of participants with baseline risks significantly exceeding the risk threshold. Two fair quality studies found no evidence of harm from patient knowledge of global risk scores when they were accompanied by counseling, and optional or scheduled follow-up. Other studies were too methodologically limited to draw conclusions.</p> <p>Conclusion</p> <p>Our review provides preliminary evidence that physicians' knowledge of global CHD risk scores may translate into modestly increased prescribing of cardiovascular drugs and modest short-term reductions in CHD risk factors without clinical harm. Whether these results are replicable, and translate across other practice settings or into improved long-term CHD outcomes remains to be seen.</p