A mutated factor X activatable by thrombin corrects bleedings in vivo in a rabbit model of antibody-induced hemophilia A.

Rendering coagulation factor X sensitive to thrombin was proposed as a strategy that can bypass the need for factor VIII. In this paper, this non-replacement strategy was evaluated in vitro and in vivo in its ability to correct factor VIII but also factor IX, X and XI deficiencies. A novel modified factor X, named Actiten, was generated and produced in the HEK293F cell line. The molecule possesses the required post-translational modifications, partially keeps its ability to be activated by RVV-X, factor VIIa/tissue factor, factor VIIIa/factor IXa and acquires the ability to be activated by thrombin. The potency of the molecule was evaluated in respective deficient plasmas or hemophilia A plasmas, for some with inhibitors. Actiten corrects dose dependently all the assayed deficient plasmas. It is able to normalize the thrombin generation at 20 µg/mL showing however an increased lagtime. It was then assayed in a rabbit antibody-induced model of hemophilia A where, in contrast to recombinant factor X wild-type, it normalized the bleeding time and the loss of hemoglobin. No sign of thrombogenicity was observed and the generation of activated factor X was controlled by the anticoagulation pathway in all performed coagulation assays. This data indicates that Actiten may be considered as a possible non replacement factor to treat hemophilia's with the advantage of being a zymogen correcting bleedings only when needed.

Fc Sialylation Prolongs Serum Half-Life of Therapeutic Antibodies.

The long serum t 1/2 of IgGs is ensured by their interaction with the neonatal Fc receptor (FcRn), which salvages IgG from intracellular degradation. Fc glycosylation is thought not to influence FcRn binding and IgG longevity in vivo. In this article, we demonstrate that hypersialylation of asparagine 297 (N297) enhances IgG serum persistence. This polarized glycosylation is achieved using a novel Fc mutation, a glutamate residue deletion at position 294 (Del) that endows IgGs with an up to 9-fold increase in serum lifespan. The strongest impact was observed when the Del was combined with Fc mutations improving FcRn binding (Del-FcRn+). Enzymatic desialylation of a Del-FcRn+ mutant or its production in a cell line unable to hypersialylate reduced the in vivo serum t 1/2 of the desialylated mutants to that of native FcRn+ mutants. Consequently, our study proves that sialylation of the N297 sugar moiety has a direct impact on human IgG serum persistence.

Improved in vitro and in vivo activity against CD303-expressing targets of the chimeric 122A2 antibody selected for specific glycosylation pattern.

Plasmacytoid dendritic cells (pDCs) play a central role for both innate and adaptive antiviral responses, as they direct immune responses through their unique ability to produce substantial concentrations of type I interferon (IFNs) upon viral encounter while also activating multiple immune cells, including macrophages, DCs, B, natural killer and T cells. Recent evidence clearly indicates that pDCs also play a crucial role in some cancers and several auto-immune diseases. Although treatments are currently available to patients with such pathologies, many are not fully efficient. We are proposing here, as a new targeted-based therapy, a novel chimeric monoclonal antibody (mAb) that mediates a strong cellular cytotoxicity directed against a specific human pDC marker, CD303. This antibody, ch122A2 mAb, is characterized by low fucose content in its human IgG1 constant (Fc) region, which induces strong in vitro and in vivo activity against human pDCs. We demonstrated that this effect relates in part to its specific Fc region glycosylation pattern, which increased affinity for CD16/FcγRIIIa. Importantly, ch122A2 mAb induces the down-modulation of CpG-induced IFN-α secretion by pDCs. Additionally, ch122A2 mAb shows in vitro high pDC depletion mediated by antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis. Remarkably, in vivo ch122A2 mAb efficacy is also demonstrated in humanized mice, resulting in significant pDC depletion in bloodstream and secondary lymphoid organs such as spleen. Together, our data indicates that ch122A2 mAb could represent a promising cytotoxic mAb candidate for pathologies in which decreasing type I IFNs or pDCs depleting may improve patient prognosis.

Public Expenditures for Mental Health Services in Canadian Provinces: Dépenses publiques pour les services de santé mentale dans les provinces canadiennes.

OBJECTIVE: The purpose of this study is to measure provincial spending for mental health services in fiscal year (FY) 2013 and to compare these cost estimates to those of FY 2003. METHODS: This study estimated the costs of publicly funded provincial mental health services in FY 2013 and compared them to the estimates for FY 2003 from a previously published report. Our data were obtained from publicly accessible databases. The cross-year cost comparisons for provincial mental health services were restricted to general and psychiatric hospital inpatients, clinical payments to physicians and psychologists, and prescribed psychotropic medications. Total public expenditures were inflation adjusted and expressed per capita and as a percentage of the total provincial health spending. RESULTS: Total public spending for mental health and addiction programs/services was estimated to be $6.75 billion for FY 2013. The largest component of the expenditures was hospital inpatient services ($4.02 billion, 59.6%), followed by clinical payments to physicians or psychologists ($1.69 billion, 25%), and then publicly funded prescribed psychotherapeutic medications ($1.04 billion, 15.4%). Nationally, the portion of total public spending on health that was spent on mental health decreased from FY 2003 to FY 2013 from 5.4% to 4.9%. CONCLUSION: Our results reveal that mental health spending, as a proportion of public health care expenditures, decreased in the decade from FY 2003 to FY 2013. Due to large differences in how the provinces report community mental health services, we still lack a comprehensive picture of the mental health system.

Assessing the Costs and Benefits of Insuring Psychological Services as Part of Medicare for Depression in Canada.

OBJECTIVE: The study estimated costs and effects associated with increasing access to publicly funded psychological services for depression in a public health care system. METHODS: Discrete event simulation modeled clinical events (relapse, recovery, hospitalizations, suicide attempts, and suicide), health service use, and cost outcomes over 40 years in a population with incident depression. Parameters included epidemiologic and economic data from the literature and data from a secondary analysis of the 2012 Canadian Community Health Survey on mental health. Societal costs were measured with the human capital approach. Analyses estimated the incremental cost-effectiveness ratio associated with improved access to psychological services among individuals not receiving adequate mental health care and reporting an unmet need for such care compared with present use of health services for mental health reasons. RESULTS: Over 40 years, increased access to mental health services in a simulated population of adults with incident depression would lead to significantly lower lifetime prevalence of hospitalizations (27.9% versus 30.2% base case) and suicide attempts (14.1% versus 14.6%); fewer suicides (184 versus 250); a per-person gain of .17 quality-adjusted life years; and average societal cost savings of $2,590 CAD per person (range $1,266-$6,320). Publicly funding psychological services would translate to additional costs of $123,212,872 CAD ($67,709,860-$190,922,732) over 40 years. Savings to society would reach, on average, $246,997,940 CAD ($120,733,356-$602,713,120). CONCLUSIONS: In Canada, every $1 invested in covering psychological services would yield $2.00 ($1.78 to $3.15) in savings to society. Covering psychological services as part of Medicare for individuals with an unmet need for mental health care would pay for itself.

Reasons and Determinants for Perceiving Unmet Needs for Mental Health in Primary Care in Quebec.

OBJECTIVE: To evaluate the mental health care needs perceived as unmet by adults in Quebec who had experienced depressive and (or) anxious symptomatology (DAS) in the previous 2 years and who used primary care services, and to identify the reasons associated with different types of unmet needs for care (UNCs) and the determinants of reporting UNCs. METHOD: Longitudinal data from the Dialogue Project were used. The sample consisted of 1288 adults who presented a common mental disorder and who consulted a general practitioner. The Hospital Anxiety and Depression Scale was used to measure DAS, and the Perceived Need for Care Questionnaire facilitated the assessment of the different types of UNCs and their motives. RESULTS: About 40% of the participants perceived UNCs. Psychotherapy, help to improve ability to work, as well as general information on mental health and services were the most mentioned UNCs. The main reasons associated with reporting UNCs for psychotherapy and psychosocial interventions are "couldn't afford to pay" and "didn't know how or where to get help," respectively. The factors associated with mentioning UNCs (compared with met needs) are to present a high DAS or a DAS that increased during the past 12 months, to perceive oneself as poor or to not have private health insurance. CONCLUSIONS: To reduce the UNCs and, further, to reduce DAS, it is necessary to improve the availability and affordability of psychotherapy and psychosocial intervention services, and to inform users on the types of services available and how to access them.

[Publicly funded programs of psychotherapy in Australia and England]. / Les programmes de prise en charge financière des psychothérapies en Australie et en Angleterre.

Quebec's HealthCommissioner on the performance of the health system clearly highlighted gaps in the collaboration between primary care physicians and mental health specialists, decreased accessibility and inequity in access to effective mental health services such as psychotherapy.Objectives The aim of this article was to describe the implementation of two publicly funded programs of psychotherapy in Australia and England with similar gatekeeper systems to the one in Quebec.Findings Following the Access to Allied Psychological Services (ATAPS) program introduced in Australia in 2003, one of the most important initiatives from the Council of Australian Governments' National Action Plan on Mental Health 2006-2011 was the Better Access Initiative which commenced in 2006. The plan included AUD1.2 billion in funding for integrating and improving the mental health care system. The purpose of Better Access was to improve the treatment and management of mental illnesses and increasing community access to mental health professionals and providing more affordable mental health care. GPs were encouraged to work more closely with mental health professionals. Under this program, these professionals are able to provide mental health services on a fee-for-service basis subsidized through Medicare. Access to psychological therapies is provided through private providers, rather than through fund holding arrangements. As of 2009 in Australia, 2 million people (1 in 11) had received over 11.2 million subsidized mental health services. A recent study showed clinical improvements in patients with depression associated with Better Access, concluding that the program is meeting previously unmet mental health needs.In the case of England, the IAPT - Improving Access to psychological Therapies-program enabled primary care trusts (PCTs) to implement evidence-based psychological therapies as recommended by National Institute for Health and Clinical Excellence for people suffering from depression and anxiety. In October 2007, the Secretary of State for Health announced additional funds totalling £173 million between 2008 and 2011 that would be used to deliver a major training program that would build a skilled workforce of qualified psychological therapists in 4 therapy areas for adults and children: cognitive behaviour therapy; psychodynamic psychoanalytic therapy; systemic and family therapy; humanistic therapy. The main goals of the program were to have: (i) 3,600 newly trained therapists with an appropriate skill mix and supervision arrangements; (ii) 900,000 more people treated; (iii) 50% of people who leave treatment are recovered; (iv) 25,000 fewer people on sick pay and benefits.Conclusion To date, the results in both countries have shown clinical improvements in symptoms associated with depression and anxiety for people entering the programs and at a population level, decreasing the unmet mental health needs of the population by allowing self-referrals to the program, and therefore rendering access to services to populations otherwise not reached.

[Costs and benefits of a funding program for psychotherapies for French people suffering from depressive or anxious disorders]. / Coûts et bénéfices d'un programme de financement des psychothérapies auprès des Français souffrant de troubles dépressifs ou anxieux.

Objectives Depressive or anxious disorders are a major source of social and economic burden. Many international good practice guidelines recommend structured psychotherapy for treating depressive or anxious disorders. The positive impact of psychotherapy on health, quality of life, productivity, and on the direct and indirect costs has been widely demonstrated. Nevertheless, the psychotherapies provided in private practice with a non-medical psychotherapist are not reimbursed to patients by French health cover systems.This article aims (1) to assess the cost and benefit of providing a funding program for psychotherapies for the community for French adults suffering from severe or recurrent depressive or anxious disorders, and (2) to estimate the number of psychotherapists that this program would be needed.Methods Data are based on the Enquête Indicateurs de santé mentale dans quatre régions françaises: a cross-sectional survey of a representative sample of 20,777 adults in the general population conducted in 2005. The questionnaires were administered by a telephone interview with the Composite International Diagnostic Interview - short form. A financial evaluation of covering the cost of psychotherapies was performed using the methodology of the British program Improving Access for Psychological Therapies adapted to the French context. The annual cost generated by depressive disorders was estimated at EUR4,702, cost generated by anxiety disorders at EUR1,500. The remission rate attributable to psychotherapies was assessed to be 30% ±10%. The number of sessions to be covered was defined according to clinical guidelines of the National Institute for Health and Clinical Excellence. The cost of a session was estimated at EUR41, the reimbursement rate by the compulsory health insurance system at 60%.Results The yearly cost for the cover of psychotherapeutic care - for 12.1 sessions on average was M EUR 514 (M EUR 308 for the compulsory systems) to treat 1,033M individuals in France, or 2.3% of the population. In terms of the cost-benefit ratio, EUR1 invested in psychotherapeutic treatment could, save from EUR1.14 (0.76-1.52) to EUR1.95 (1.30-2.60) for anxious or depressive disorders respectively.France has the 14,300 professionals qualified to provide the psychotherapies required to treat this population.Conclusion A funding program for psychotherapies proves to be a cost-efficient investment for the community from the short term, for both direct (health costs) and indirect (productivity, quality of life) costs, that is further that the positive impact and costs of psychotherapy on somatic disorders were not taken into account.With a view to providing appropriate care for patients, inter-professional collaboration among GPs and mental health professionals, and between clinical psychiatrists and psychologists, appears essential. These recommendations should be defined in national good practice guidelines.

[Initial training in psychotherapy for psychiatrists in France, a national qualitative study]. / La formation aux psychothérapies des internes en psychiatrie en France : résultats d'une analyse qualitative.

Objectives To explore the level of satisfaction among residents regarding their training in psychotherapies, the interest they have in these therapies, and their wishes in the area of training.Methods A survey including both a quantitative and qualitative methodology was undertaken among 869 residents out of 1,334 enrolled in the psychiatric residency program. In the 2009-2010 academic year. The survey included five themes of study: theoretical academic training, psychoanalysis, training in institutes outside the university, supervision, wishes in the area of training. This article presents results from the qualitative sociological survey using a semi-guided interview with 27 residents. Their conceptions and practice in the field of psychotherapy, and its place in psychiatric practice were questioned in-depth.Results The vast majority of residents were interested in psychotherapy, but simultaneously dissatisfied with the training they had received. Almost half opted for various sorts of extra-curricular training, costly in time and money. The psychotherapeutic orientations among these residents were varied, and a plurality of methods and theoretical approaches was advocated both for reasons of having a wider viewpoint and good practice in psychiatry, and because the residents considered this plurality to be an essential component in their training. They saw psychotherapy as a medical practice, and considered that it is the responsibility of the psychiatric discipline to provide training in psychotherapies.Conclusion The absence of any real training in psychotherapies for residents in psychiatry is damaging for care quality in psychiatry. The recent creation of a protected title of psychotherapist for psychiatrists without the need of additional training suggests an urgent need to develop a training course. A proposal by the authors should be discussed in light of reflections and proposals already underway in other countries.

Costs and benefits of improving access to psychotherapies for common mental disorders.

BACKGROUND: Structured psychotherapies are treatments used in common mental health disorders (CMHDs) that are recommended by international good practice guidelines. Their efficacy and positive impact on health--and thereby on the reduction of related costs for health insurance schemes and society--have been widely demonstrated. However in France, despite the considerable financial burden of CMHDs, psychotherapies with a non-medical psychotherapist are not reimbursed by the health insurance schemes. AIMS OF THE STUDY: To assess the cost of coverage for psychotherapies by the health insurance bodies for adults aged 18 to 75 with CMHDs--depressive or anxious disorders, severe or recurrent--and to estimate the cost-benefit ratio for these psychotherapies for the community. METHODS: The data was derived from l'Enquete Indicateurs de sante mentale dans quatre regions francaises 2005, which is a cross-sectional study on 20,777 adults in the general population. Telephone interviews were backed up by the CIDI-SF. The Sheehan Disability Scale was used to assess the severity of the disorders. The proportion of patients who would agree to and then attend psychotherapies was estimated using the methodology developed in the UK in the Improving Access to Psychological Therapies programme, adapted to the French setting. The number of sessions to be covered was defined according to recommendations by the National Institute for Health and Clinical Excellence. The cost was estimated to be 41 per session, the reimbursement rate was set at 60% for the compulsory health coverage system. The annual costs engendered by CMHDs were estimated to be 4,702 for depressive disorders and 1,500 for anxiety disorders. The remission rate attributable to psychotherapies was estimated to be 30% pm10%. RESULTS: For average series of 10 sessions (anxiety disorders) to 18 sessions (depressive disorders) the yearly cost of psychotherapies would be 514 million Euros, of which 308 million would be covered by the compulsory coverage system, to treat 1.033 million patients, or 2.3% of the population. For patients with depressive disorders, 1 spent by the community for the psychotherapy would enable the community a saving of 1.95 (1.30-2.60), and for anxiety disorders a saving of 1.14 (0.76-1.52). DISCUSSION: This programme for provision of coverage for psychotherapies would have a positive impact for the community as a whole, in terms of quality-of-life, health and absenteeism. Funding psychotherapies proves to be a cost-efficient investment in the short and the long term, and this is backed up further by the fact that the impact of psychotherapies on somatic disorders interacting with CMHDs was not taken into account here. IMPLICATIONS FOR HEALTH POLICIES, HEALTH CARE PROVISION AND USE: Decision-makers in the health insurance schemes will thus have reliable medico-economic data available to assist in decisions for a possible policy for reimbursement of psychotherapies. Financial coverage of psychotherapies would in particular enable access to treatment by people for whom the financial barrier would have prevented access to this treatment. Furthermore, reimbursing sessions with non-medical psychotherapists could also improve conditions of care-provision by mental health professionals. Finally, this model could be replicated in other countries where the health system is sufficiently comparable to that prevailing in France. IMPLICATIONS FOR FUTURE RESEARCH: An in-depth study is required to detail cost and benefit of providing insurance coverage for psychotherapies for the different protagonists involved in this funding, and its effects.

Use of general practitioners versus mental health professionals in six European countries: the decisive role of the organization of mental health-care systems.

OBJECTIVE: To investigate patterns of use of general practitioners (GPs) and/or mental health professionals (MHPs) for mental health reasons, across six European countries, and the extent to which these patterns of use are associated with differences in mental health-care delivering systems. METHODS: Data are based on the European Study of the Epidemiology of Mental Disorders (ESEMeD): a cross-sectional survey of a representative sample of 8,796 non-institutionalized adults from six European countries, conducted between 2001 and 2003 using computer-assisted interviews with the CIDI-3.0. Countries were classified into: MHP- for countries where access to medical professionals tends to predominate (Belgium, France, Italy), and MHP+ where access to non-medical MHPs predominates (Germany, Spain, The Netherlands). RESULTS: Among respondents consulting GPs and/or MHPs in the past year (n = 1,019), respondents from the MHP- group more often consulted GPs (68 vs. 55 % in MHP+ group), GPs and psychiatrists (23 vs. 14 %). People from the MHP+ group more often used MHPs only (45 vs. 32 %), GPs and non-medical MHPs (16 vs. 8 %). GPs from the MHP+ group were more inclined to refer patients to MHPs. Factors associated with use of GPs versus MHPs were: being over 49 years, not highly educated, lower income and suffering from mood or severe mental disorders. CONCLUSIONS: Differences in the use of GPs versus MHPs are markedly linked to individual as well as organizational factors. Interventions are needed, in countries fostering medical access, to reimburse sessions with non-medical MHPs and improve cooperation between professionals to obtain better practice in access to care.

Factors associated with use of psychiatrists and nonpsychiatrist providers by ESEMeD respondents in six European countries.

OBJECTIVE: This study analyzed use of services from psychiatrists and other mental health professionals (psychologists, psychotherapists, counselors, and social workers) in six European countries. METHODS: Data were from respondents (N=8,796) to the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional survey (2001-2003) of a representative sample of noninstitutionalized adults in Belgium, France, Germany, Italy, the Netherlands, and Spain that was conducted via computer-assisted interviews with the Composite International Diagnostic Interview, version 3.0. RESULTS: Twenty-three percent of respondents reported lifetime use of any professional for mental health problems, and 60% consulted a mental health provider. Among these, 56% used a psychiatrist and 68% used a nonpsychiatrist provider. Factors associated with use of psychiatrists only were being retired or unemployed, having 12 or fewer years of education, living in France or Spain, having a severe disorder, and using psychotropic medication. Factors associated with use of nonpsychiatrist providers only were living in the Netherlands or Germany, never being married, and having an anxiety disorder. CONCLUSIONS: The findings suggest that there is no simple model of associations between mental health care system and patterns of service use. System characteristics, such as practitioner-population ratios, levels of practitioner availability, and gatekeeping and reimbursement policies, affect patterns of use of mental health providers. Recent British and Australian plans could be used as models for better allocation of services in some ESEMeD countries.

Religious advisors' role in mental health care in the European Study of the Epidemiology of Mental Disorders survey.

OBJECTIVE: To study the role of religious advisors in mental health problems in six European countries and to compare it to data from the USA. METHODS: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD) study, a cross-sectional study, conducted in Belgium, France, Germany, Italy, the Netherlands and Spain. 21,425 individuals, 18 and older, were interviewed with the Composite International Diagnostic Interview 3.0. Findings were compared to the National Comorbidity Survey (NCS) and replication of the NCS (NCS-R) in the US. RESULTS: In ESEMeD, 0.6% of individuals (0.3% exclusively) sought help from religious advisors concerning mental health problems during the previous year, compared to 2.6% in NCS and 3.4% (for human services) in NCS-R in the US. Among those using any form of service, 6.9% consulted religious advisors (12.2% in Germany to 2.1% in Spain) compared to 18.8% in the US. Being younger (less than 25 years old), being older (more than 64) and religiosity are associated with the use of religious advisors, whereas being a student is associated with a lower probability. CONCLUSIONS: Seeking help from religious advisors for mental health problems varies dramatically among ESEMeD countries. Except for Germany, organised religion in the ESEMeD countries could not be considered as an alternative.