Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer’s perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients. Considerable variability exists in how individual patients respond to pharmacological treatments. Differences in patients’ individual make-up arising from genetic, biological, behavioral and environmental factors are seen as causes of this variability -15. PatiSome physician groups already specify different treatments and doses taking into account factors such as patients’ ages, gender, family history and current co-morbidities ,27, and The recognition of the complexity of the various biological systems involved in different diseases ,34 helpsCYP2D6[As the knowledge of biological systems grows, drug pipelines should become more productive as well as improve subsequent patient care ,36,49,50CYP2D6-57. DosiCYP2D6-21,58, pCYP2D6,21,58. ICYP2D6.A different example is natalizumab, which was approved in 2004. In patients with relapsing remitting multiple sclerosis, natalizumab significantly reduced the number of relapses and the development of new inflammatory lesions ,61. HoweThese examples illustrate the opportunities and challenges that are concomitant with greater knowledge about disease progression and treatments.Adverse drug reactions (ADRs) add to the costs of healthcare by increasing hospital admissions -70. AverImproved knowledge of pharmacogenomics could potentially reduce ADRs ,18 throuIn Europe, the current financial crisis makes resource issues especially important. Pharmaceutical expenditure has been growing at a faster rate than other components of ambulatory care -83, equaConsequently, it is attractive to tailor treatments and resources to patients according to their genetic, medical and behavioral factors to achieve the greatest health gain, minimizing waste and maximizing the number of patients needed to harm ,16,18,22We are already seeing capacity building in genomics medicine and molecular diagnostics growing across countries, including Sri Lanka and Asia-Pacific countries -95. ThisPersonalized medicine and personalized healthcare are not new concepts ,47,96,97We recognize that the development of personalized approaches is complex. This is illustrated by recent research in breast cancer, suggesting that this cancer consists of many different types of tumors . GreaterHowever, as in many growing fields, the promises associated with pharmacogenomics have not always translated into appreciable improvements in patient care ,22,47. TConsequently, the objective of this review paper is to integrate current knowledge about the value of biomarkers and prognostic tests to improve patient care, as well as potential concerns, from a payer’s perspective. This is because published articles have generally not been written with this in mind. As a result, we hope this paper will provide guidance to all key stakeholder groups on potential ways to enhance future utilization and funding of new personalized approaches. This will be achieved by reviewing the current situation regarding personalized medicine, principally based on peer-reviewed papers, building on comments in the background; appraising key funding, organizational and healthcare issues that need to be addressed; and suggesting potential ways forward for all key stakeholder groups to enhance funding and utilization of new diagnostic and prognostic tests as well as new targeted drug treatments through an iterative process involving the co-authors.We will consider the need to distinguish between genetic tests that demonstrate a particular patient has susceptibility to a given disease and developments that help determine a patient’s responsiveness to a given drug and/or the potential for adverse reactions ,10,117.We are aware of the considerable controversies surrounding unregulated direct-to-consumer (DTC) genetic testing  and we wThe findings are consolidated under various headings, including general considerations, pharmacogenomics, biomarkers, challenges and concerns, and key issues for healthcare funding bodies to address.Multiple definitions have been assigned to personalized medicine, including stratified medicine. Essentially all definitions include targeting of diagnostic or treatment approaches to improve the future care of patients ,27,45,50CYP2D6 polymorphisms, explaining why slow CYP2D6 metabolizers lack an analgesic effect with codeine and why ultra-rapid metabolizers may experience adverse effects on therapeutic doses [As we explore the molecular pathophysiology of different diseases, we find increasing examples of genetic differences as explanations for inter-individual variability in drug responses ,22,37,47ic doses ,22,38,39ic doses ,16,21,36ic doses ,121,122.ic doses ,117,122.ic doses ,123. Thiic doses ,124.Pharmacogenomics includes the identification of host genetic factors that influence drug absorption, metabolism and action at the receptor level, which could subsequently reduce patient numbers needed to treat and minimize toxicity ,126. TheIL28B and drug response [IL28B is increasingly undertaken in hepatitis C clinics [AMPD1, ATIC, ITPA and MTHFD1 genes, to help predict response to methotrexate, leading to greater tailoring of treatment [For example, independent genome-wide studies involving patients with chronic hepatitis C infection, who were treated with pegylated interferon alpha and ribavirin, showed an association between a variant in the host genotype of response -129. In  clinics . Poly could affect its activity [CYP2C19 polymorphisms on subsequent cardiovascular events [CYP2C9 and VKORC1 is important both for the initial dose finding stage with warfarin as well as during maintenance therapy [There are also continuing controversies surrounding genetic testing prior to initiation with either clopidogrel or warfarin. Studies suggest there is an increased risk of adverse cardiovascular outcomes if effective and safe drug concentrations of these drugs are not reached ,125,179.activity . As a reactivity . This har events ,186. Ther events . They sur events ,109,187.r events . Recent  therapy .BRCA testing and Oncotype DX in terms of their associated costs and cost-effectiveness in practice. This is illustrated by variable funding among private and public insurance plans in the US for BRCA testing for patients at high risk of developing breast cancer, exacerbated by charges of US$3,340 per patient for full sequence testing [BRCA1/2 testing should be offered to patients if the likelihood of detecting a mutation is greater than 20%, although many testing centers offer the test if the likelihood is between 10% and 20% [BRCA1/2 testing to optimize subsequent treatment options that the genetic information makes possible [There is also continuing debate about the funding of  testing ,189. Nev and 20% ,191. Widpossible ,192. HowThe Oncotype DX breast cancer assay is a 21-gene assay conducted on a patient’s tumor specimen to estimate the risk of recurrence post surgery specifically in patients with hormone-positive, lymph node-negative breast cancer. It can also provide further information on the benefits patients will derive from postoperative chemotherapy. The impact of the Oncotype DX score was evaluated prospectively and led to treatment changes in 30% of cases . Both thThere is also an Oncotype DX colon cancer assay, which is a 12-gene assay to predict recurrence after resection of stage II and III colon cancer. This assay has been validated in a number of studies -199. WheThe costs of pharmacogenomics testing are envisaged to fall appreciably with their increasing use ,201. ThiThese case histories illustrate why it is crucial for researchers and commercial organizations to obtain data from trials demonstrating any association between biomarkers and disease outcomes to enhance future endorsement and funding of diagnostic tests. The same holds for new targeted treatments. Alongside this, a cohesive vision of what personalized medicine will constitute must be developed. The instigation of groups such as the Personalized Medicine Consortium and European Medical Research Council and the combining of research group activities should help with this ,16,46,47Pharmacogenomic research should be strengthened by bodies such as the International HapMap Consortium, the 1000 Genomes project , the MutIt is recognized that full targeting of diagnostic and treatment approaches will require appreciable understanding of the genetic background for different diseases and patient populations, rather than just the expression patterns of single gene associations. This has been demonstrated by the variable predictive yield of genome-wide association studies to date ,47,171. Future developments may include improved translation of single and combined biomarker test information. They may also include developments in technology platforms, mathematical models and systems biology ,17,36,46It is also recognized that clinical trials to evaluate new tests and/or targeted treatments may be complex and costly, and may also pose serious organizational and ethical problems if there are multiple subgroups with different treatment strategies ,99. ThisIt will be increasingly important for the European Medicines Agency and the FDA to collaborate on the development and establishment of harmonized guidelines for genotyping and biomarker testing, and their incorporation into future targeted treatments, to guide companies . This coAs this field evolves, the clinical utility in shaping patients’ treatment should become realistic . HoweverKey issues include clearer co-ordination between the various bodies responsible for funding of care and those evaluating new treatment approaches . ImproveThere also needs to be effective strategies that address current concerns among health authority and health insurance personnel regarding personalized medicine. This is because there are currently few examples of pharmacogenetic tests being integrated into routine care despite the initial optimism. In addition, the advice on whether to fund specific tests has changed on a number of occasions as more research data becomes available. Accommodating these costs will not be easy, especially with growing resource pressures ,35. HoweAs a result, there are a number of medical, ethical, legal, social, economic and organizational issues that need to be considered as the field of personalized medicine grows :Medical issues• Improvements in clinical effectiveness through tailoring treatments including their impact on length and quality of life as well as number of patients needed to treat• Improvements in drug safety profiles/reductions in adverse drug reactions increasing the number of patients needed to harm rates• Relevance of surrogate results (diagnostic technologies)• Opportunities for preventive measures and interventions• Proportion of patents affected/re-classified• Need for post-marketing follow-up (post-introduction assessment) and not just pharmacovigilance• Improved knowledge of pharmacogenomics among physiciansLegal issues• Reassessing existing drugs and other technologies• Redefining existing regulatory policies• Need for including biomarkers that support indications and clinical decision making• Maintenance of citizens’ autonomy• Legal liability associated with targeted tests• Protection of any patient information generated• Whether professional ethical guidelines become statutes or mandatory guidelines• Harmonization of laws in different contexts• Patients’ autonomy• Advertising - particularly direct-to-consumer advertising• Harmonization of free movement of services to avoid or reduce citizens’ misconceptions and potentially unlawful practicesEconomic issues• Reduction in costs to healthcare systems with greater personalized approaches• Who pays for diagnosis - healthcare systems, manufacturers or patients? This especially with current fragmentation of care and budgets• Budget impact of new technologies and other considerations for reimbursement and funding including cost and Quality Adjusted Life Year considerations• Whether the inclusion of biomarkers will lead to more clearly defined subpopulations and indications for reimbursement (in addition to regulatory considerations)• Potential changes in reimbursement considerations and policies with smaller populations and targeted treatments• Redefining the conditions for orphan status for new targeted treatments• Financial incentives for citizens; active role of the citizen in his/her own health and wealth• Co-development of drugs and genome-based diagnostics that more tightly define indications or subpopulations - requirements for approval and/or incentives for reimbursement at premium pricesEthical issues• Change in the concept of health and disease (prediction)• Ownership of the information (not only genomic)• Sufficient understanding to justify population-based genome sequencing• Accessibility of diagnostic tests and targeted treatments within and across countries with companies seeking ‘orphan status’ for new targeted treatments• Patients’ understanding and patients’ role in future decision making• Human dignity - potential for stigmatization and discrimination• Human integrity - how this affects moral convictions, preferences and commitmentsSocial issues• Empowerment and increasing autonomy of patients and their relatives• Stigmatization of certain subpopulations according to their genomic, clinical and environmental data• Current technology makes internationalization of data possible• Policies to promote the implementation of personalized health services:○ people and subgroups involved○ support required○ costs involved○ people’s reaction for or against such services • Legal barriers concerning different reimbursement and pricing policies that have an impact on the implementation of personalized healthcare services and products. This can cause inequity or unequal access to new technologies if not addressedOrganizational issues• Emphasis on wellness and disease prevention• Change in health services paradigm with primary care and public health playing a greater role with greater stratification of patients resulting in potential changes in work- and patient-flow processes• Greater patient empowerment and shared decision-making:○ Scheduled time dedicated to patients○ Healthcare professional training on genomics including health literacy among providers○ Management of genomic information and its consequences○ Acquisition of shared decision-making skills• Potential centralization of diagnostic services• Potential decentralization of decision-making processes• Monitoring of physician adherence to any tightly defined subpopulations; potential ways to enhance adherence where concerns• Funds made available for data protection and complex computing systemsOverall, the medical, ethical, legal, social and economic challenges for personalized medicine are not unlike the scientific uncertainty, assessment, cost-effectiveness and access issues affecting traditional medicines. However, diverse ethical and social principles and their interpretation often lead to disparate views on the safety, equity and desirability of personalized therapy. For example, publicly directed genetic testing including newborn screening is being challenged to demonstrate, on the one hand, that informed consent, confidentiality and information accuracy are adequate and, on the other hand, that public and private good do result from identifying genetic abnormalities .In addition, there must be discussion whether identification of a genetic predisposition, regardless of manifestation, could lead to denial of healthcare, insurance, employment or educational opportunities . In termA key ethical concern going forward is equitable access to personalized therapies, which may affect drug development decisions. There may be, for example, fewer incentives for companies to develop drugs for ‘less profitable’ genotype groups . If suchThere are a number of potential ways forward for all the six main stakeholder groups to enhance the utilization and funding for new diagnostic or prognostic tests and treatment approaches that address the key issues highlighted above. These can be broken down into general issues as well as key issues pre-, peri- and post-launch ,210.Potential issues for key stakeholder groupsThe first stakeholder group consists of governments, health authorities and health insurance agencies ,107,109,General• To instigate Pan-European central, online, open-access repositories of biomarker and potential genomic tests of personalized therapy including their clinical utility and therapeutic implications. The data should be made readily and openly available to all key stakeholder groups.• To establish respected groups in each country that can assess the value of new genetic tests prior to and during reimbursement or funding discussions. This builds on current activities in France, the National Institute for Health and Care Excellence, UK, the UK Genetic Testing Network and the Medicines and Healthcare Products Regulatory Agency in the UK, and the EGAPP working group in the US. This also builds on developments among HTA bodies (below).• To introduce stricter definitions of orphan drug status to reduce the number of targeted drugs seeking this definition and their anticipated high acquisition costs, that is, 5 out of 100,000 rather than the current 5 out of 10,000 (below).• To explore collaborative opportunities with groups such as the European Union Personalised RNA Interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics consortium, and other European bodies, to deliver education to providers, practitioners and patients. This would address some of the complexities and misunderstanding that exists among key stakeholder groups regarding personalized medicine.• To establish and support networks of professional medical institutions including Drug and Therapeutic Committees to promote critical drug evaluation peri-launch and scientifically founded recommendations. This also includes groups to assess the sensitivity and specificity of new diagnostic and prognostic tests and the implications across populations building on, for instance, the classification criteria developed by the EGAPP working group.• To evaluate new ways of organizing care with personalized medicine placing particular emphasis on wellness and disease prevention replacing hospital-centerd care provision. This includes increased time between patients and physicians in primary care to fully explain the findings from any test to sufficiently empower patients in their decision making.• To fully consider the legal consequences of personalized care including citizens’ autonomy, legal liability and the protection of any information generated.• To refine new models of care broken down by pre-, per- and post-launch activities that enhance the utilization of new diagnostic technologies and new targeted treatments that can improve the care of patients.Pre-launch• To extend current Horizon Scanning, early assessment and alert systems as well as budget impact analyses to include new diagnostic and prognostic biomarkers and genetic tests. The objective is to ensure that independent information regarding the clinical utility of new tests, including issues surrounding their sensitivity and specificity as well as their overall predictive value, including data on the extent of false positives and false negatives, is available when new diagnostic approaches and new drugs are being considered for reimbursement. This may mean working initially with limited evidence while new data is generated. Such services can build on the activities of International Networks and EuroScan as well as Horizon Scanning activities in for instance Germany, Italy, Sweden and the UK. This should include an assessment of the likely budget impact of new diagnostic and prognostic approaches as well as new targeted treatments, including any costs avoided. It should also be ascertained beforehand whether tissue samples can be analyzed locally, for example, tissue samples have to be sent from Scotland to the US before initiating treatment with maraviroc, adding to the cost of treatment.• As part of this, to initiate early dialogue with groups such as the European Network for HTA, country HTA bodies and the European Medicines Agency, as well as groups developing mathematical models and system biology approaches to interpret the findings from pharmacogenomics studies and their implications for subsequent patient care.• Through such dialogue, facilitate discussions on whether new care pathways and facilities are needed prior to launch, as well as how new diagnostic and prognostic tests will be funded, especially if there is still fragmentation in funding care.• Where pertinent and feasible, seek partnerships between health authorities, academic institutions and commercial organizations to accelerate developments that can improve care at reduced costs - especially through greater use of generic therapies.Peri-launch• If necessary, to adjust the process of HTA and other assessment bodies to robustly handle the diagnostic component of new targeted treatments.• To consider developing new quality indicators around new targeted therapies together with key stakeholder groups. This builds on existing processes. This should include their assessment in practice acknowledging that any indicators developed must have validity in terms of content, face, concurrence, construct and prediction.• To seek to include new indicators in any new guidance and guidelines associated with new targeted treatments, as well as potentially to consider their inclusion in any ongoing financial incentive schemes for physicians.• To be critical of any proposed risk-sharing arrangements including targeted therapies and biomarkers and to be mindful of the potential administration costs. However, also aware that such arrangements post-launch could facilitate reimbursement and funding of new premium-priced drugs.• Continually checking likely launch dates for new treatments with the relevant pharmaceutical companies to improve financial planning, especially given the premium prices requested for new targeted treatments.Post-launch• To integrate regular reviews of any reimbursement, funding or guidance especially as more data becomes available.• To monitor physician adherence to any agreed guidance or reimbursement restrictions for new targeted treatments.• To instigate additional demand-side measures such as educational initiatives and financial incentives if needed where there are concerns with adherence rates to any agreed guidance or subpopulations.The second stakeholder group includes HTA units ,228-231.General • To develop and refine new methodological approaches that take into account potential changes in clinical trials and increasing use of models in systems biology-based personalized medicine approaches - especially around defining subpopulations.• Possibly to include progression of constructive technology assessments until more data become available. However, to be mindful of concerns with surrogate data.• Possibly to involve HTA units with discussions to modify the legal framework as well as regulatory and approval processes as more information regarding personalized medicines become available.Post-launch• To assist with post-launch follow-up of drugs particularly to reassess product safety in routine clinical care, as well as to provide guidance where concerns.The third stakeholder group includes research institutions, research groups and professional medical, pharmaceutical and educational societies. The major issues for this group include:• To focus and promote comprehensive critical research and education to understand and explore the benefits and risks with personalized diagnostic and treatment strategies.• To assist with policy analysis and involvement in education on issues relating to personalized medicine among specialists, researchers and in the public area.The fourth stakeholder group are physicians ,107,109,General• To provide independent advice into clinical trial design for new biomarkers that are disease based; alternatively aimed at differentiating patients or populations based on either differences in drug metabolism, drug transporter capacity or receptor variants.• To help design trials that improve our understanding of the sensitivity and specificity of new diagnostic tests, thereby reducing the uncertainty with their use. Such studies could include cohort studies with samples and data collected prospectively. Nested case–control studies are also potentially useful so long as blinding is maintained.• To assist with the design of technology platforms and mathematical models that help with future decision making for individual patients as the complexity of biological systems unfold. By doing so, to improve the translation of research results into clinical practice.• To push for ongoing independent reinterpretation of the implications of genetic tests and therapies in the light of new discoveries. This will be achieved through using trained clinical pharmacologists and physicians specializing in areas such as molecular oncology. This builds on the current controversies surrounding the pre-testing of patients prescribed clopidogrel or warfarin.• To help translate the language of genomics into lay language to assist patients with their decision making, including the benefit:risk ratio of treatments. This will necessarily include improved knowledge of genomics among physicians from current low rates.Pre-launch• To work with health authorities and health insurance companies pre-launch to critically review new targeted treatments, especially where there are concerns about their potential value in practice.• As part of this, to provide guidance to health authorities and health insurance companies about potential new quality indicators.• To provide input into discussions on the potential value of new pharmacogenetic tests that optimize the use of new drugs post-launch especially where there are considerable uncertainties regarding their clinical value.Peri- and post-launch• To assist with the design of any patient registries or expansion in Electronic Health Records prior to launch, and follow this up after launch building on the experiences with, for instance, natalizumab.• To help authorities critically assess proposed risk sharing arrangements, especially regarding the potential administrative burden.• To assist hospital and ambulatory care Drugs and Therapeutic Committees with critically evaluating new targeted treatments, as well as to promote interface arrangements to improve the co-ordination of care between primary and secondary care physicians.• To help with the development of educational materials for physicians and patients peri- and post-launch based on agreed guidance.The fifth stakeholder group are patients and patient groups ,211,212.General• To support the development of patient registries and electronic record systems that help identify patients with specific genotypes to improve their care in the future.• Where pertinent, to work with all key stakeholder groups regarding potential goals for the sensitivity and specificity of new molecular and diagnostic genetic tests alone or in combination to reduce uncertainty with their use, especially if there is reluctance to fund ‘coverage with evidence’ schemes.• To help authorities and physicians involved in the development of personalized medicine translate the results of research findings into lay language to assist patients with future decision making.• To seek to be an integral part of national discussions concerning the ethics and implications of genetic testing for other family members.• To help authorities incorporate personalized medicine into patient education schemes to enhance their understanding of this complex field for better informed discussions with physicians.• To work with authorities to make sure that patients’ dignities and integrities are preserved with greater knowledge of their genetic make-up, and that specific groups are not excluded from societies (building on earlier comments).Pre-launch• To provide input to health authority and health insurance companies pre-launch discussions regarding key issues for new diagnostic tests or new targeted treatments from a patient’s perspective.• To support the development of patient registries or other data collection activities around new targeted approaches; the results of which can also be used to inform future clinical trials and future decision making.Pre- and peri-launch• To help with the design and distribution of any patient information regarding new drugs, especially where there are potential safety issues.• To help with the development of new quality indicators for new targeted drugs from a patient’s perspective to improve their validity.• To provide input into the assessment of the potential value of new technologies especially where the findings, including potential biomarkers, are inconclusive.Post-launch• To help refine information for patients as more knowledge becomes available about new diagnostic approaches or new drugs, especially with respect to major adverse reactions and their implications.• To help disseminate factual information to patients, especially where there are exaggerated claims unduly raising expectations among patients or where key issues regarding the potential side-effects of treatments have not been fully explained or adequately disseminated.The last stakeholder group includes pharmaceutical and diagnostic companies,91,98,99General• To make explicit in the trial design for new genetic tests and biomarkers whether they are dealing with diagnostic or prognostic; alternatively, disease-based or patient- or population-based technologies. This acknowledges that different trial populations will be needed, as well as different performance characteristics for different tests. For example, new screening biomarkers need high specificity to avoid generating an excessive number of false positives whereas high sensitivity is needed for new prognostic biomarkers to avoid denying treatment to patients who could potentially benefit.• To make the objectives of any trial design specific to answer key questions. This includes potential subpopulations where the health gain of new targeted drugs is greatest. It also includes designing studies to specifically answer questions about the sensitivity and specificity of new diagnostic and prognostic tests including the extent of any false positives and false negatives.Pre-launch• To instigate realism into corporate discussions regarding potential requested prices for new diagnostic tests or targeted treatments, acknowledging that the cost of providing tests includes both the acquisition costs as well as facility costs as resource pressures grow. This becomes even more important if multiple genetic tests are needed to plan future care.• As part of this, to avoid the temptation to seek ‘orphan status’ for new targeted therapies as resource pressures grow. This may avoid rejection or delayed funding even with risk-sharing or patient access schemes to lower acquisition costs. This includes recognition that without targeting new products are increasingly unlikely to achieve premium prices as more standard drugs become available as generics and niche areas diminish.• To acknowledge that the definition of orphan drug status may need redefining to smaller patient populations, especially with the increasing costs of orphan drugs and growing resource pressures.• To seek scientific advice from relevant registration, HTA and funding bodies pre-launch on the potential need and relevance for developing markers and tests concurrently with developing new drugs, especially for small and medium-sized companies as part of their development process.• Similarly, seek scientific advice for new drugs that require associated genetic testing to maximize their value especially for clinical trials that could include small subgroups of patients.• To explore possible partnerships between diagnostic and pharmaceutical companies to provide a combined package at launch, for example, combined worldwide sales of trastuzumab and imatinib, both using established tests, were US$9.6 billion in 2010.• To initiate possible discussions concerning rebates or discounts peri-launch to enhance the value of new targeted treatments - recognizing the complexities of current funding arrangements.There are a number of issues arising from these considerations that need to be explored further. These include:•greater cohesion of what is meant by personalized medicine and associated training•the Human Microbiome Project•DTC advertising•evidence-based classification of genomic tests•funding of new targeted tests and therapies.To enhance acceptance of personalized medicine, there needs to be greater cohesion of what this constitutes. The advent of the European Science Foundation recruiting a group to analyze the complex field of personalized medicine may help, especially as their objective is to provide future policy advice ,36. This•ensuring a regulatory and funding environment that allows early patient access to novel and effective personalized medicine•increasing research and development funding to develop new personalized medicines•improving the education and training of healthcare professionals regarding personalized medicine and the various approaches•acknowledging that new approaches may be needed for reimbursement and HTA assessment, which are required for patient access to personalized medicine and recognition of their value•increasing awareness and understanding of personalized medicine among all stakeholder groups.The funding of any new diagnostic facilities, as well as the instigation of patient education, may also be a challenge as the range of therapeutic options increase and become more complicated to navigate. Moreover, additional training of healthcare professionals, including their full understanding of the concepts of personalized medicine and targeted approaches, will also need to be addressed . For insFollowing the completion of the Human Genome Project, there has been substantial growth in recent years in the Human Microbiome Project ,239. TheThis will be the subject of future research articles.One key issue that authorities will need to consider is the growth in private enterprises offering DTC genetic testing ,119. Thiecommerce, should help address some of these concerns [Unregulated, this could be a major source of anxiety given concerns with the limited clinical utility of some of the tests to date ,119,242.concerns . Whetherconcerns .As mentioned, algorithms have been developed in the US as part of the EGAPP initiative ,110. TheKey considerations in the recommendations ranging from ‘do not use in practice’ to ‘implement in practice’ include ,110:•level of evidence•level of certainty - from low to high•risk benefit profile - from unknown, unfavorable to favorable•extent of additional research needed•potential health impact•evidence recommendations and actions.As mentioned above, only one of the initial four genomic tests was recommended for implementation in practice using this approach .Additional funding of specific tests for diagnosis, prognosis and directing treatment options can be a major concern among health authorities and health insurance companies (payers) as resource pressures grow, negating the potential benefits from personalizing treatment approaches . This isThe UK is seeking to address some of these issues through establishing the UK Genetic Testing Network for single-gene disorders ,250. HowKRAS testing in selected patients with colorectal cancer before initiating cetuximab saved an estimated US$50 million per year compared to no testing [KRAS testing has also be estimated to save the US health system over US$600 million per year in the cost of cetuximab [KRAS resting [KRAS mutation testing prior to treatment with cetuximab saved costs [Funding of pharmacogenomic tests has been helped by investigators in Japan estimating that  testing ,254. Thi testing . KRAS teetuximab ,255. The resting . Other aed costs ,256.However, there are concerns among payers that targeting of new drugs to small populations will lead to them being considered as ‘orphan drugs’ , potentially resulting in premium prices above those of new drugs without orphan status -115. SucThere should be considerable benefits to all key stakeholders with new technologies that can improve the diagnosis, prognosis and treatment of patients, reducing the number of patients needed to treat and increasing the number of patients needed to harm. In addition, this will also reduce the cost and consequences of ADRs ,39,74,75CYP2D6 genotyping testing prior to initiation of tamoxifen [CYP2C19 genotyping testing prior to the initiation of treatment with clopidogrel [However, the complexity of biological systems means that gene mutations may not always express themselves as important phenotypic changes in disease patterns, making identification of potential biomarkers and new targeted treatments more difficult. This may explain why the promise of personalized medicine has not always translated into improvements in patient care in practice, and why only a limited number of targeted treatments are currently available and funded. This may also explain why advice about certain specific tests has been retracted as more data becomes available. This includes amoxifen ,25,28-31pidogrel -182.It is recognized that for new technologies to be funded, there needs to be improved co-ordination among groups responsible for the funding of care and those evaluating new technologies. This will facilitate funding of new technologies that improve diagnosis, prognosis or subsequent care, especially if funding for new personalized technologies cross sectors . This isThe envisaged reduction in the costs of pharmacogenetic tests ,201,252 A growing concern among payers is the requested price for new targeted treatments, especially if these increasingly resemble requested prices for orphan drugs, which is already happening ,257-259.Payers across Europe are already seeking ways to release resources to help fund new technologies. This is through increased use of low-cost generics versus patented drugs in a class or related class, which will grow as more standard therapies lose their patents ,267-273.Governments and health authorities also need to tackle the ethical issues associated with an increasing personalized approach. These include who will own the genomic data if population-based genomic sequencing increases, as well as issues of equity if high prices persist for diagnostic and prognostic tests and for new targeted treatments .In conclusion, we hope we have stimulated the debate about personalized medicine and the ways forward for all key stakeholder groups. As a result, we hope this will help translate the promise of personalized medicine into clinical practice to benefit patients in the future.ADRs: Adverse drug reactions; DTC: Direct-to-consumer; EGAPP: Evaluation of genomic applications in practice and prevention; EGFR: epidermal growth factor receptors; FDA: US Food and drug administration; HTA: Health technology assessment; IgE: Immunoglobulin E; PARP: Poly (adenosine diphosphate–ribose) polymerase; PML: Progressive multifocal leukoencephalopathy.No author has a financial competing interest to declare. The majority of authors are employed by health authorities, health insurance companies, Physician Associations or are advisers to them working in Universities or for other organisations. These include BG , EZ-B , I G-I , JJ , REM (KI and Stockholm County Council), EA , MB (NHS Scotland), IB (NHS Scotland), AB , SC , ED , JF , KG , AH , HH , KHv and CK (Norwegian Medicine Agency), SJ , MK , OL , S-AL , AM , LM , FN , GS , CS , US , DT , VV-P , LV , MvW , CZ .However, the content of the paper and the conclusions are those of each author and may not necessarily reflect those of the organization that employs them.BG, AFF, PKC, EZ-B, REM, LLG and RA - developed the first draft and co-ordinated activities and inputs regarding additional drafts. This included potential definitions  as well as authority perspectives from Sweden . IG-I - provided examples, critiqued subsequent drafts, co-ordinated the development around key medical, ethical, legal, social, economic and organizational issues, and contributed to the iterative process for the development of stakeholder recommendations generally as well as for Spain. He also critiqued subsequent drafts following reviewer comments. JJ - provided input especially from a timing perspective regarding input from key stakeholder groups, critiqued subsequent drafts including those following reviewer comments. EA - inputted into the development of the paper particularly from the perspective of authorities in Finland. This included the iterative process for key issues and the development of recommendations. CB - provided input into the first drafts based on his experience with personalized medicine, especially from a regulatory perspective. In addition, critiqued subsequent drafts including the iterative process for key issues and the development of recommendations. MB, IB and KP – inputted into the development of the paper particularly from the perspective of the authorities in Scotland. This included the iterative process for key issues and the development of recommendations. AB - inputted into the development of the paper particularly from the perspective of authorities in Austria (including EZ-B) as well as generally across Europe. This included the iterative process for key issues and the development of recommendations. AF, KHa, AH and AM - inputted into the development of the paper including the perspective of authorities in the UK , as well as critiqued subsequent drafts. This included the iterative process for key issues and the development of recommendations. SC also critiqued subsequent drafts following reviewer comments as well as from the perspective of authorities in the UK . ED and CZ - inputted into the development of the paper particularly from the perspective of authorities in Spain  as well as generally from a clinical pharmacology perspective. This included the iterative process for key issues and the development of recommendations. JF - inputted into the development of the paper particularly from the perspective of authorities in Slovenia as well as critiquing subsequent drafts. This included the iterative process for key issues and the development of recommendations. KG - inputted into the development of the paper particularly from the perspective of authorities in Lithuania, as well as critiquing subsequent drafts. This included the iterative process for key issues and the development of recommendations. MG - inputted into the development of the paper particularly from the perspective of authorities in Portugal. This included the iterative process for key issues and the development of recommendations. HH, GS, US - inputted into the development of the paper particularly from the perspective of Sickness Funds, Physician Associations and their advisers in Germany. This included the iterative process for key issues and the development of recommendations. KHv, CK - inputted into the development of the paper particularly from the perspective of the national authorities in Norway and critiqued subsequent drafts. This included the iterative process for key issues and the development of recommendations. SJ – inputted into the paper following reviewer comments - particularly from the perspective of managed care organizations in the US. This included the iterative process for key issues and the development of recommendations. MK - inputted into the development of the paper particularly from the perspective of the authorities in Serbia and critiqued subsequent drafts. This included the iterative process for key issues and the development of recommendations. OL - inputted into the development of the paper particularly from the perspective of the authorities in Estonia. This included the iterative process for key issues and the development of recommendations. S-AL, FN - inputted into the development of the paper particularly from the perspective of authorities in Sweden  - building on comments from REM and LLG. This included the iterative process for key issues and the development of recommendations. KM, MW - inputted into the development of the paper particularly from the perspective of the various authorities in Poland including critiquing subsequent drafts. This included the iterative process for key issues and the development of recommendations. LM - inputted into the development of the paper particularly from the perspective of authorities in Ireland as well as generally using her health economic background. This included the iterative process for key issues and the development of recommendations. CS - inputted into the development of the paper particularly from the perspective of the various national authorities in France. This included the iterative process for key issues and the development of recommendations. SS - inputted into paper following reviewer comments based on his experience as well as generally from the perspective of authorities in Belgium. This included the iterative process for key issues and the development of recommendations. DT - inputted into the development of the paper particularly from the perspective of the national authorities in Slovakia. This included the iterative process for key issues and the development of recommendations. VV-P and LV - inputted into the development of the paper particularly from the perspective of the authorities in Croatia as well as critiqued subsequent drafts. This included the iterative process for key issues and the development of recommendations. MvW - inputted into the development of the paper based on his experience with quality indicators as well as generally from the perspective of authorities in the Netherlands. This included the iterative process for key issues and the development of recommendations. DW-R - inputted into the development of the paper particularly from the patients’ perspective based on her considerable experience in this area. This included he iterative process for key issues and the development of recommendations. All authors read and approved the manuscript.


In a study of 68 private drinking water wells in northeastern Pennsylvania and New York, methane contamination rose sharply with proximity to natural gas drilling and hydraulic fracturing (“fracking”) sites.The researchers measured concentrations of gases and certain isotopes of carbon in methane and other hydrocarbons to distinguish the ancient thermogenic gas stores sought in drilling operations from methane generated by microbial degradation of organic matter. The closer the well was to an active drilling site, the more likely it was the methane detected was thermogenic.Flammable levels of natural gas are common in water supplies, and explosions—even reports of flammable drinking water—have occurred near fracking sites, says Abrahm Lustgarten, a reporter for Propublica who has investigated gas drilling across the United States. But no peer-reviewed studies have investigated health effects of chronic ingestion of small amounts of methane, Jackson says.John Hanger, a former head of the Pennsylvania Department of Environmental Protection (DEP), blames poor gas well construction or design, not fracking, for methane contamination noted to date. He says repairs or plugging of gas wells eliminated contamination in 14 of 19 previously contaminated water wells tested in 2010 by the DEP. But Jackson maintains fracking cannot be ruled out as a cause, given the high pressures used in the practice.Just how likely are leaks? Based on a non-peer-reviewed survey of the five states that systematically report incidents at wells where fracking occurs and where complaints have spurred inspections, Ronald E. Bishop, a lecturer in chemistry and biochemistry at the State University of New York, Oneonta, estimates nearly 2% of such gas wells may end up contaminating groundwater with fracking fluids.Hanger says Pennsylvania has enacted strict standards for design, construction, and materials used in gas wells, which became effective in February 2011.


Responses to public health need require information on the distribution of mental and physical ill health by demographic and socioeconomic factors at the local community level.The South East London Community Health (SELCoH) study is a community psychiatric and physical morbidity survey. Trained interviewers conducted face-to-face computer assisted interviews with 1698 adults aged 16 years and over, from 1076 randomly selected private households in two south London boroughs. We compared the prevalence of common mental disorders, hazardous alcohol use, long standing illness and general physical health by demographic and socioeconomic indicators. Unadjusted and models adjusted for demographic and socioeconomic indicators are presented for all logistic regression models.Of those in the sample, 24.2% reported common mental disorder and 44.9% reported having a long standing illness, with 15.7% reporting hazardous alcohol consumption and 19.2% rating their health as fair or poor. The pattern of indicators identifying health inequalities for common mental disorder, poor general health and having a long term illness is similar; individuals who are socioeconomically disadvantaged have poorer health and physical health worsens as age increases for all groups. The prevalence of poor health outcomes by ethnic group suggests that there are important differences between groups, particularly for common mental disorder and poor general health. Higher socioeconomic status was protective for common mental disorder, fair or poor health and long standing illness, but those with higher socioeconomic status reported higher levels of hazardous alcohol use. The proportion of participants who met the criteria for common mental disorder with co-occurring functional limitations was similar or greater to those with poor physical health.Health service providers and policy makers should prioritise high risk, socially defined groups in combating inequalities in individual and co-occurring poor mental and physical problems. In population terms, poor mental health has a similar or greater burden on functional impairment than long term conditions and perceived health. Even before the birth of modern epidemiology, inner cities have been recognised to represent particular challenges to individual health and public health ,2. DenseWhilst the nature of health hazards associated with urban living have changed, health inequalities associated with living in inner cities remain an issue of considerable concern. The pattern is complex - in the UK, some inner city areas  have among the highest life expectancies; whilst others (particularly in Scotland and northern England) have the lowest . Within th-20th centuries, to economic migration from former British colonies and more recently Eastern Europe in the 20th and 21st century, and people now seeking asylum from conflict zones in the Middle East, North Africa and Central Asia. Migration patterns in London and other cities worldwide result in continuous demographic and socioeconomic transformations and potential shifts in health profiles of these groups. Thus, the generation of data at the local community level should be an ongoing, integrative process that allows for the identification of high risk groups as an initial step towards understanding how the experience of demographic and socioeconomic statuses become part of a complex matrix of exposures implicated in poor mental and physical health.In the UK, inner cities are also likely to be the first port of call for migrants and as with migrants to other cities, many with general health problems influenced by former circumstances, such as exposure to conflict and war, persecution or poverty ,6. At thA wide range of mental and physical health indicators are needed to begin to identify and understand health inequalities within local communities. Common mental disorder as a term has been used frequently to describe the impact of mental disorders in the community, recognising the fact that distinct diagnostic constructs such as anxiety and depression used in secondary care do not adequately represent the mixed symptomatology that is more often seen in epidemiological samples . For exaSubstance use, alcohol being among the most commonly used, has also been a focus of building health profiles due to its association with morbidity, mortality and high social, medical, and economic costs . HoweverAlong with capturing longstanding illness and functional limitations, self-rated health is a valuable source of subjective health status and an important indicator of overall health, as well as a significant predictor of morbidity and mortality ,21. SelfThe majority of information about the distribution of mental and physical ill health by demographic and socioeconomic characteristics has come from national studies, such as the National Comorbidity Study in the US  and theIn response to this need, we conducted a community based epidemiological study, developed by and in partnership with the clinicians serving the local population, to provide relevant prevalence estimates of mental and physical health symptoms in an ethnically and socioeconomically diverse, geographically defined, inner city community. This paper addresses the following aims: (1) to estimate the prevalence common mental disorders, hazardous alcohol consumption, general physical health and the presence of a long standing illness; (2) to investigate (a) the distribution of health outcomes by socio-demographic and socioeconomic indicators and (b) associations between health outcomes; and (3) to examine the association between the health outcomes of interest and functioning in work or other daily activities. The outcomes were chosen to capture morbidity of general mental and physical ill health and when present, have been identified as determinants of functional limitations. Thus, we selected available measures that represent mood and anxiety disorders and substance misuse, self-rated health and chronic physical illness.The South East London Community Health (SELCoH) study is a community survey of psychiatric and physical morbidity of 1698 adults, aged 16 years and over from 1075 randomly selected households in the south London boroughs of Southwark and Lambeth. In the two boroughs, there is higher deprivation than the England average, but similar proportions of economically active and inactive residents in comparison to greater London -31. The From 2008-2010, households  were identified through random sampling, applying similar methods to the British National Psychiatric Morbidity surveys  - i.e. rHaving sent a letter describing the study two weeks in advance, interviewers visited each selected household at least four times at different times of day, and on weekdays and weekends, before closing the household from selection due to non-response. During each household visit interviewers attempted contact with a resident to describe the study, inform them that participation was voluntary, seek consent and conduct as many interviews or make as many appointments for interviews as possible.We designed a computer assisted interview schedule and carried out a pilot study to assess reliability, validity and feasibility of the study procedures and questionnaire. Closely supervised, trained interviewers conducted face-to-face interviews with these schedules. The survey questionnaire collected information on the following topics: (1) socio-demographics; (2) migration; (3) socioeconomic status (SES); (4) psychosocial factors ; (5) neighbourhood characteristics; (6) social adversity; (7) health behaviours; (8) physical and mental health symptoms; and (9) treatment and health service use. Translators were used in interviews with non-English speaking adults. Participants received 15 GBP for a completed interview. The study received approval from the King's College London research ethics committee, reference CREC/07/08-152.Common mental disorder was assessed with the Revised Clinical Interview Schedule (CIS-R)- a strucHazardous alcohol use was measured with the Alcohol Use Disorders Identification Test (AUDIT) , developFair or poor general health was indicated by self-rated current general health, a single item from the 12-item Short Form (SF-12) questionnaire . IndividParticipants were classified as having a long standing illness if they indicated that they had a long-standing illness, disability or infirmity that troubled the participant over a period of time.Distributions of the outcomes were described by gender, ethnicity, age, relationship status and borough of residence. Self-reported ethnicity indicated identification with one of the following groups: White British, Black Caribbean, Black African, Indian, Pakistani, Bangladeshi, or Other. South Asian  and Other ethnic groups were collapsed to improve distribution. A continuous age indicator was recoded into a categorical variable representing the following six groups for ease of interpretation: 16 to 24 years; 25 to 34 years; 35 to 44 years; 45 to 54 years; 55 to 64 years and 65 years and over. A participant's relationship status was classified into never married, married or cohabiting, divorced or separated, or widowed. Finally, borough indicated the location of the residence in one of the two sampled London boroughs (Southwark and Lambeth).Indicators of socioeconomic status included educational attainment, social class, employment status, household income and housing tenure. Educational attainment was indicated by reporting having no qualifications, qualifications up to GCSE or Ordinary level , qualifications up to Advanced level  and higher degree or above . Social class was measured by current occupation categorized according to the Registrar General's classification  into six2 tests with Rao & Scott second-order corrections with 95 percent confidence intervals for categorical health outcomes. Odds ratios (OR) with 95 percent confidence intervals were calculated for associations between demographic and socioeconomic indicators with the categorical outcomes. Unadjusted and models adjusted for gender, age (continuous), ethnicity, relationship status, employment status, household income and housing tenure were presented for all logistic regression models.Analyses were completed in STATA 11 . We usedOf 3600 selected addresses, 359 were declared unusable because they were not residential, not private households or vacant, 957 addresses were approached but no contact was made with household members, 31 addresses were duplicates, 16 households from the pilot study were not included in the main study and for 76 addresses, contact was made with a household member but there was no follow up contact. Thus, contact was established with 2070 private households, of which 1075 households had at least one member interviewed, representing a 51.9% household participation rate. Of 2359 people eligible within the participating households, 1698 (71.9%) participated .As described in Table The mean total score for the CIS-R was 7.6  and CMD was present in 24.2% of the sample, 17.9% of men and 27.3% of women. As described in Table Table Table Table In fully adjusted models in Table The co-occurrence of health outcomes Table  showed tIn comparisons to those who reported no limits to social functioning, all poor health indicators were associated with increased risk of reporting limitations to social functioning Table . With thUsing data from the SELCoH study, an epidemiological study of an inner city community population, we aimed to identify the demographic and socioeconomic distribution of common mental disorder (CMD), hazardous drinking, long standing illness and self-rated health. Our findings identified high risk groups across health outcomes and there were notable differences between hazardous alcohol use and the other health outcomes. The prevalence of poor health outcomes by ethnic group suggests that there are important differences between groups. In particular, patterns for hazardous alcohol use highlight a risk group characterised by being male, younger, never married, identifying their ethnicity as White and being in higher SES categories. Women and individuals who are socioeconomically disadvantaged were worse off for other outcomes. Overall, there is considerable co-occurrence of poor mental and physical problems and this is likely to contribute to the extent of functional limitations resulting from health problems, particularly in the presence of poor mental health.Several of the findings are consistent with previous studies at the community and national levels. As in many previous national studies -42, our In terms of the proportion of individuals with poor health outcomes in local community samples, this population fares worse in terms of self-rated health in comparison to samples from epidemiological community samples with similar design in urban areas, such as the Baltimore Epidemiological Catchment Area study in the US . InteresFor all health outcomes, the evidence suggests that there are similar patterns for individual- and household-level SES indicators ; however the traditional use of occupational social class is not as informative as educational level, income and occupational status. Our findings for increased fair or poor general health among groups that identified as Black Caribbean, in the other ethnic category, never married or in low SES groups require more attention. It is possible that other social exclusion factors are contributing to this health assessment that has been so strongly correlated to increased morbidity and mortality . There iThese findings suggest that routinely capturing these SES indicators during health visits could alert health practitioners to identifying groups that may be particularly at differential high risk for various poor health outcomes, though not necessarily in a predictable manner. For example, identifying someone with high SES group in this community should signal the need to inquire about alcohol intake. Given that these findings are not consistent with the finding showing no differences by SES in the 2000 National Psychiatric Morbidity survey in the UK , these dFinally, the relationship between the health outcomes and the relationship between the health outcomes and functioning portrayed the complexity of ill health for most people. Our findings suggest that the co-occurrence of mental and physical ill health is common in the local population, with particular implications for functioning. Nearly half of the participants with CMD reported having a long standing illness, such as high blood pressure and asthma, and the proportion of those with CMD with functional limitations were similar or greater to those with poor physical health. In addition, as in previous studies, we demonstrated that self-rated health is an important indicator of the multiple dimensions of health . HoweverThis study administered a validated structured psychiatric interview (CIS-R) and additional health assessments on a diverse sample residing in an urban community setting with high levels of social deprivation. In considering mental health as an outcome, the focus of these analyses was on the generic category of 'common mental disorder'. Differentiation between component diagnostic groups was beyond the scope here but will be considered in future output. We acknowledge concerns about the validity of measures, such as the CIS-R being administered by trained lay interviewers . HoweverThe present survey was, in part, a response to the needs of the local health economy to develop a public health strategy in relation to the epidemiological information on the basic and relevant demographic and socioeconomic distribution of common mental disorders and general physical health in the local population. While identifying the prevalence and distribution of health inequalities by demographic and socioeconomic factors is particularly important at the local community level, it does not detect the proportion of people that are actually in need of treatment or how health services can meet the challenge of such a large proportion of people, particularly those with co-occurring mental and physical ill health. The greatest challenge to functioning in daily life and for local health services will continue to be the presentation of mental ill health in combination with poor physical health. Population approaches to better health-related functioning and quality of life should consider this at every stage of improving care.The authors declare that they have no competing interests.MH designed the study, sought and obtained funding, oversaw data collection and analysis, and commented on drafts of the paper. SLH oversaw the data collection, wrote all drafts of the manuscript and conducted the analysis. SF and MV coordinated the data collection and commented on drafts of the paper. BK, JC, BG, RM and research assistants on the SELCoH team collected the data, prepared some of the descriptive analyses and commented on drafts of the paper. SLH, RS, NTF, CM and AR all contributed to the study's design and RS, NTF, CM and AR commented on drafts of the paper.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/861/prepub


Several studies have reported osteomyelitis of the jaw (OMJ) as a side effect of bisphosphonates (BPs), and the risk of oral BPs has been recently clarified. However, other systemic risk factors of OMJ remain unclear. Importantly, the possibility of risk classification based on the clinical characteristics of patients has not been explored. Here, we clarified risk factors of OMJ and evaluate the predictive accuracy of risk indices in osteoporosis patients.We performed sub-analysis using a database developed for a retrospective cohort study in patients taking medications for osteoporosis at Kyoto University Hospital. Risk indices for OMJ were constructed using logistic regression analysis, and odds ratios (OR) for OMJ cases and 95% confidence intervals (CI) were estimated. Potential risk factors included in the statistical analysis were age; sex; diabetes; use of oral BPs, corticosteroids, cancer chemotherapy, antirheumatic drugs, and biologic agents; and their interactions. Risk indices were calculated by the sum of potential risk factors of an individual patient multiplied by the regression coefficients. The discriminatory power of the risk indices was assessed by receiver operating characteristic (ROC) analysis.In analysis of all patients, oral BPs , age  and sex-chemotherapy interaction  were significant risk factors of OMJ. Areas under the ROC curves of these risk indices provided moderate sensitivity or specificity regardless of group (0.683 to 0.718).Our data suggest that oral BP use, age, and sex-chemotherapy are predictors of OMJ in osteoporosis patients. The risk indices are moderately high, and allow the prediction of OMJ incidence. Oral bisphosphonates (BPs) are useful in the treatment of various bone metabolic diseases, such as postmenopausal osteoporosis or Paget disease , but theSeveral academic associations have published position papers and guidelines which suggest that practitioners should beware of the incidence of OMJ in BPs users, particularly patients with other potential systematic risk factors for OMJ, such as diabetes, corticosteroid use and cancer chemotherapy -14. MostHere, we investigated potential systemic risk factors for OMJ and evaluated the predictive accuracy of risk indices for OMJ using data from our hospital-based cohort study in patients with osteoporosis.We performed sub-analysis using a database previously constructed for a retrospective cohort study conducted at Kyoto University Hospital from February 2011 to July 2012 . SubjectWe then excluded patients who had the presence of primary or metastatic tumors, a history of trauma or radiation therapy in the maxillofacial region, or treatment with intravenous BPs.Hospital data were extracted from the electronic medical records (EMR) using an EMR retrieval system . This syAlthough several academic societies have stated that the hallmark of BP-related ONJ is exposed necrotic bone in the maxillofacial region that has persisted for more than 8 weeks ,13,20, wOMJ was independently reconfirmed by two trained oral and maxillofacial surgeons using proposed criteria based on findings obtained from panoramic X-ray, technetium bone scan, computed tomography, histological picture or surgery, either alone or in combination. Inter-observer agreement was moderate . Detailed information on patients and methods is reported in our previous work ,19.The following risk factors were included into the statistical analysis: age, sex, diabetes; use of oral BPs, corticosteroids, cancer chemotherapy, antirheumatic drugs, and biologic agents; and the interactions of potential risk factors. Diabetes was diagnosed if the patient had received a diagnosis of diabetes, and had either received any treatment with hypoglycemic medication (hypoglycemic agent and/or insulin) or had an HbA1c ≥6.5% . SteroidP values were two-sided at the significance level of 5%. All statistical analyses were performed using SAS Version 9.2 .Patient characteristics were summarized using descriptive statistics (range and percentages). The risk indices for OMJ were constructed using logistic regression analysis with OMJ as the dependent variable. Odds ratios (OR) for OMJ cases and 95% confidence intervals (CI) were estimated in all patients taking any osteoporosis medication and in the subset of oral BP users. Risk indices were calculated by the sum of the potential risk factors of an individual patient multiplied by the regression coefficients. The discriminatory power of the risk indices was assessed by receiver operating characteristic (ROC) analysis. All The protocol for this study was approved by the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine and the study was conducted according to the Declaration of Helsinki. We did not obtain written informed consent because this is a retrospective study. The Ethics Committee follows the ethical guidelines for epidemiological research of the Japanese Ministry of Health, Labour and Welfare, and accordingly does not require written informed consent for these studies.Patient characteristics are summarized in Our study had two major findings. First, we clarified three systemic risk factors for OMJ in patients with osteoporosis, namely age, oral BP use and sex-chemotherapy. In contrast, diabetes, or the use of corticosteroids, antirheumatic drugs, and biologic agents were not identified as significant risk factors of OMJ. Second, our ROC analysis of risk indices of systemic risk factors, to our knowledge the first time this has been investigated, found that ROC curve provided moderate sensitivity or specificity to allow the prediction of OMJ incidence in subsets of patients at high risk of OMJ.Previous studies did not clarify in detail the association between potential systemic risk factors and the incidence of OMJ in osteoporosis patients nor the accuracy of prediction based on such risk factors -10, althOur ROC analysis suggests that other risk factors contribute to the incidence of OMJ. As one such predictor, oral bacteria, are hypothesized to confer risk, given that osteomyelitis in BPs users develops only in the jawbones , albeit Nevertheless, our findings do provide relevant information to support decision-making by practitioners involved in the treatment of patients taking oral BPs. At the initiation of BP use, physicians or pharmacists may predict the risk of OMJ incidence according to the clinical characteristics of patients and consult oral specialists in advance. Dentists or oral and maxillofacial surgeons may also consider these risk factors in their care of patients using oral BPs, and the modification of practice patterns is likely useful in preventing OMJ incidence.Several limitations of the study warrant mention. First, selection bias is inherent to single-center studies, and the present study was additionally subject to inherent referral bias toward the selection of more severe cases, given that our hospital is a lead institution in Kyoto City. Patient characteristics at our hospital might therefore differ somewhat from those at other hospitals or clinics. Second, although our estimation models adjusted for potential risk factors, including age, sex, diabetes, use of oral BPs, corticosteroids, cancer chemotherapy, antirheumatic drugs, and biologic agents and their interactions, no adjustment was made for other possible risk factors related to OMJ, such as smoking or oral BP dose, etc.. HoweverIn conclusion, our data suggest that oral BP use is strong risk factor for OMJ, and that age and sex-chemotherapy are also systemic risk factors in osteoporosis patients. The risk indices are moderately high, and allow the prediction of OMJ incidence.Appendix S1Diagnoses and 10th International Classification of Diseases codes for osteoporosis.(DOCX)Click here for additional data file.Appendix S2Drug and generic names for osteoporosis medications approved in Japan between November 2000 and October 2010.(DOCX)Click here for additional data file.Appendix S3Diagnoses and 10th International Classification of Diseases codes for case definition for osteomyelitis or osteonecrosis of the Jaw .(DOCX)Click here for additional data file.


Albert Liu and colleagues report early experiences with uptake and delivery of pre-exposure prophylaxis(PrEP)for HIV prevention in three different settings in San Francisco. PrEP can be an important component of a comprehensive HIV prevention program and can complement efforts to increase HIV testing, linkage to care, and early initiation of antiretroviral therapy.Please see later in the article for the Editors' Summary Pre-exposure prophylaxis (PrEP) has been demonstrated to be safe and efficacious in clinical trials and emtricitabine/tenofovir was approved by the United States Food and Drug Administration for use as PrEP in 2012.We report early experiences with PrEP uptake and delivery in three different settings in San Francisco: a PrEP demonstration project in a municipal sexually transmitted diseases (STD) clinic, and two PrEP delivery programs .Interest in PrEP is high in San Francisco, particularly among men who have sex with men attending the STD clinic, and it is feasible to incorporate PrEP into busy clinical settings. Key next steps for PrEP implementation include increasing PrEP knowledge; expanding PrEP access; combating PrEP stigma; and optimizing interventions to promote PrEP uptake and adherence while reinforcing risk reduction strategies.PrEP can be an important component of a comprehensive HIV prevention program and complement efforts to increase HIV testing, linkage to care, and early initiation of antiretroviral therapy.In July 2012, more than 30 years after the initial HIV case reports, the United States (US) Food and Drug Administration (FDA) approved the first drug for the prevention of sexually acquired HIV infection. On the basis of compelling safety and efficacy data from pre-exposure prophylaxis (PrEP) trials of men who have sex with men (MSM) conducted across four continents and serodifferent heterosexual couples and young men and women in sub-Saharan Africa Although the FDA approval marks an important milestone in HIV prevention, several factors, including negative results from two recently completed PrEP trials among women in Africa On the basis of promising efficacy data from PrEP trials, programs to evaluate PrEP delivery launched in San Francisco, a metropolitan area heavily impacted by HIV, with an HIV prevalence of 23% among MSM San Francisco City Clinic (SFCC), the city's municipal STD clinic, offers a range of sexual health services, including HIV and STD screening, diagnosis and treatment, HIV post-exposure prophylaxis (PEP), family planning, and emergency contraception. In 2011, the clinic conducted approximately 19,000 visits with 12,000 patients, of whom 38% were MSM and 1% transgender. HIV incidence among MSM at SFCC is high, with a 2.3% annual seroconversion rate From September 2012–2013, 571 individuals have been evaluated at SFCC for PrEP, and 261 participants have enrolled in The Demo Project, for an overall uptake of 49% among potentially eligible clients . The mosPrEP-related stigma (participants feeling stigmatized by others regarding their decision to use PrEP) has deterred some clients from accessing PrEP. Participants in the Demo Project are asked quarterly about social harms related to study participation. Fifteen of 20 social harms reported to date were related to PrEP stigma. Participants reported stigma from peers, who believe that PrEP will lead to increased risk-taking behavior and may divert resources away from HIV-positive people, and medical providers, who are unwilling to prescribe them PrEP or appear judgmental about their decision to use PrEP.Kaiser Permanente Health Plan provides comprehensive primary and specialty medical care to over 185,000 members in San Francisco. More than 2,500 HIV-positive adults receive care through Kaiser's HIV Care and Prevention Program. Health plan members have a broad spectrum of payor sources for access to Kaiser insurance, including employer-based programs, Medi-Cal, and Healthy San Francisco  Since the launch of the Kaiser's PrEP program in San Francisco in April 2012, more than half of the 123 men and women referred by both HIV-specialty providers (65%) and non-HIV-specialty providers (35%) have initiated PrEP . Most coBay Area Perinatal AIDS Center (BAPAC) is a program of the University of California San Francisco, providing comprehensive preconception management and prenatal care to HIV-positive women and HIV-negative women with HIV-positive male partners . BAPAC mSince 2010, 15 HIV-negative women with HIV-infected male partners have been screened as part of comprehensive HIV prevention counseling at BAPAC for PrEP eligibility. Seven of these women initiated PrEP during prenatal or preconception care, one of whom stopped PrEP after a few days due to nausea and low risk perception given her partner's long term viral suppression. Reasons for not initiating PrEP included lack of insurance coverage, and a combination of low risk perception, concerns about risks to themselves or their babies, and cessation of risk behavior.While only a few women have initiated PrEP at BAPAC thus far, data suggest HIV-serodifferent couples in the US want to incorporate PrEP as a safer conception option. Between 2006 and 2011, the National Perinatal HIV Hotline and Clinicians' Network took 152 calls regarding conception for serodifferent couples; the volume of calls has increased over time, from ten calls in 2006 to 43 in 2011 Lessons learned from three San Francisco PrEP programs can inform future PrEP rollout. First, accurate consumer knowledge about PrEP is a critical first step in PrEP implementation, and prior PrEP awareness was associated with increased uptake in the STD clinic setting. Second, across all three programs, patient risk perception and concern about side effects appear to play an important role in PrEP uptake, adherence, and persistence (continuing PrEP over time) and will need to be addressed to optimize PrEP targeting and implementation. Third, ensuring adequate clinic capacity and sustainable delivery of PrEP is critical to addressing ongoing high demand for PrEP. For time-limited PrEP programs , it is important to create linkage to ongoing PrEP access after program completion. While this may be a lesser concern for PrEP programs embedded within existing clinical systems , insurance coverage for PrEP is an important consideration in determining ongoing PrEP access across all programs. Finally, PrEP stigma can pose a barrier to uptake and retention and will need to be addressed among both providers and communities to maximize the impact of PrEP.On the basis of these lessons learned, we have identified priority next steps to address emerging delivery issues and to maximize PrEP's public health impact. While the examples provided focused on PrEP implementation in the US, several of these concepts and principles may be generalizable to PrEP delivery outside of the US.Increasing PrEP knowledge among potential PrEP users is a key step to facilitating PrEP implementation As interest in PrEP among high seroincidence populations continues to rise in San Francisco, additional PrEP delivery sites in the community are needed. Increasing access to PrEP requires ensuring patients have affordable access to FTC/TDF. Some commercial private insurers are providing coverage for PrEP, although co-pays vary by plan, and some insurers may require prior authorization Developing a cadre of skilled providers will also be essential to scaling up PrEP PrEP delivery systems will also need to accommodate the increased visit volume associated with scaling up comprehensive PrEP services. PrEP delivery is feasible, but requires staff, time, space, and expertise. A range of models for PrEP delivery have been proposed, including STD clinics Promoting accurate risk perception and information about potential FTC/TDF side effects and strategies to cope with them will be critical to successful PrEP implementation. Risk assessment tools are currently being developed and validated Participants in the Demo Project and other PrEP studies have reported feeling stigmatized by their decision to use PrEP by medical providers, friends, and sex partners. HIV-related stigma and discrimination have a profoundly negative impact on people living with and at risk for HIV As the PrEP and HIV prevention fields evolve, several key questions will need to be addressed to optimize PrEP delivery. These issues include determining the optimal target populations for PrEP, standardizing guidelines for initiating and discontinuing PrEP, and evaluating cost-effectiveness. Our early experience with PrEP in San Francisco has illustrated that interest in PrEP is high among populations at risk for HIV infection, and PrEP can be incorporated into busy clinical settings. We believe PrEP can be an important component of comprehensive HIV prevention programs that include efforts to improve HIV testing, linkage to care, and early initiation of antiretroviral therapy.Table S1Characteristics of PrEP delivery systems in San Francisco.(DOCX)Click here for additional data file.Text S1PrEP basics.(DOCX)Click here for additional data file.