The use of recovery animals in nonclinical safety assessment studies with monoclonal antibodies: further 3Rs opportunities remain.

Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies. This enabled a review of practices on recovery animal use during mAb development and identification of opportunities to reduce research animal use. Recovery animals were included in 68% of FIH-enabling and 69% of later-development studies, often in multiple studies in the same program. Recovery groups were commonly in control plus one test article-dosed group or in all dose groups (45% of studies, each design). Based on the shared data review and conclusions, limiting inclusion of recovery to a single nonclinical toxicology study and species, study design optimisation and use of existing knowledge instead of additional recovery groups provide opportunities to further reduce animal use within mAb development programs.

Self-initiated lifestyle interventions lead to potential insight into an effective, alternative, non-surgical therapy for mitochondrial disease associated multiple symmetric lipomatosis.

BACKGROUND: A 56-year-old female, diagnosed as a carrier of the mitochondrial DNA mutation (MTTK c.8344A > G) associated with the MERRF (myoclonic epilepsy with ragged red fibers) syndrome, presented with a relatively uncommon but well-known phenotypic manifestation: severe multiple symmetric lipomatosis (MSL). After surgical resection of three kilograms of upper mid-back lipomatous tissue, the patient experienced a significant decline in her functional capacity and quality of life, which ultimately resulted in her placement on long-term disability. METHODS: Dissatisfied with the available treatment options centered on additional resection surgeries, given the high probability of lipoma regrowth, the patient independently researched and applied alternative therapies that centred on a carbohydrate-restricted diet and a supervised exercise program. RESULTS: The cumulative effect of her lifestyle interventions resulted in the reversal of her MSL and her previously low quality of life. She met all her personal goals by the one-year mark, including reduced size of the residual post-surgical lipomas, markedly enhanced exercise tolerance, and return to work. She continues to maintain her interventions and to experience positive outcomes at the two-year mark. INTERPRETATION: This case report documents the timing and nature of lifestyle interventions in relation to the reversal in growth pattern of her previously expanding and debilitating lipomas. The profound nature of the apparent benefit on lipoma growth demonstrates the intervention's potential as a new feasible non-surgical therapy for mitochondrial-disease-associated MSL, and justifies its systematic study. We also describe how this case has inspired the care team to re-examine its approach to involved patients.

Opportunities for use of one species for longer-term toxicology testing during drug development: A cross-industry evaluation.

An international expert working group representing 37 organisations (pharmaceutical/biotechnology companies, contract research organisations, academic institutions and regulatory bodies) collaborated in a data sharing exercise to evaluate the utility of two species within regulatory general toxicology studies. Anonymised data on 172 drug candidates (92 small molecules, 46 monoclonal antibodies, 15 recombinant proteins, 13 synthetic peptides and 6 antibody-drug conjugates) were submitted by 18 organisations. The use of one or two species across molecule types, the frequency for reduction to a single species within the package of general toxicology studies, and a comparison of target organ toxicities identified in each species in both short and longer-term studies were determined. Reduction to a single species for longer-term toxicity studies, as used for the development of biologicals (ICHS6(R1) guideline) was only applied for 8/133 drug candidates, but might have been possible for more, regardless of drug modality, as similar target organ toxicity profiles were identified in the short-term studies. However, definition and harmonisation around the criteria for similarity of toxicity profiles is needed to enable wider consideration of these principles. Analysis of a more robust dataset would be required to provide clear, evidence-based recommendations for expansion of these principles to small molecules or other modalities where two species toxicity testing is currently recommended.

The Bacteroidales produce an N-acylated derivative of glycine with both cholesterol-solubilising and hemolytic activity.

The contribution of the gut microbiota to the metabolism of cholesterol is not well understood. In this study, we identify 21 fosmid clones from a human gut microbiome metagenomic library that, when expressed in Escherichia coli, produce halos on LB agar supplemented with 0.01% (w/v) cholesterol (LBC agar). Analysis of 14 of these clones revealed that they all share a fragment of DNA with homology to the genome of Bacteroides vulgatus. The gene responsible for halo production on LBC agar, named choA, was identified as an N-acyltransferase known to produce an acylated glycine molecule called commendamide. In this study we show that commendamide is capable of producing a halo on LBC agar suggesting that this molecule is solubilizing the cholesterol micelles in LBC agar. We also show that commendamide is responsible for the previously described hemolytic activity associated with the choA orthologue in Bacteroides fragilis. A functional analysis of ChoA identified 2 amino acids that are important for commendamide biosynthesis and we present phylogenetic and functional data showing that orthologues of choA are found only in the order Bacteroidales. Therefore, the production of commendamide may be an adaptation to the environments colonized by the Bacteroidales, including the mammalian gut.

Inflammatory Cell Findings in the Female Rabbit Heart and Stress-associated Exacerbation with Handling and Procedures Used in Nonclinical Studies.

Despite the use of rabbits in biomedical research, including regulatory toxicology and cardiovascular studies, little data exist on heart findings in this species. This study was designed to document myocardial findings in female rabbits and the impact of study-related procedures typical for vaccine toxicology studies. One hundred and forty 6- to 8-month-old female New Zealand White rabbits were divided equally into 2 groups, high and low study procedure groups (group 1 and group 2, respectively). All animals received intramuscular (IM) injections of sterile saline every 2 weeks for 5 times and were necropsied 2 days after the final IM injection. Clinical chemistry, hematology, and urinalysis were evaluated. Blood for stress biomarkers (norepinephrine, epinephrine, cortisol, and corticosterone), C-reactive protein, cardiac troponin I, and creatine kinase were collected at time 0 (just before dose administration) and then at 4, 24, and 48 hr after dose administration in group 1 only. Hearts were assessed histologically. Focal to multifocal minimal inflammatory cell infiltrates were common (∼80%), particularly in the left ventricle and interventricular septum, and were similar to the types of infiltrates identified in other laboratory animal species. Additionally, study-related procedures elevated serum stress biomarkers and exacerbated the frequency and severity of myocardial inflammatory cell infiltrates.

Live virus vaccines based on a vesicular stomatitis virus (VSV) backbone: Standardized template with key considerations for a risk/benefit assessment.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viral and other microbial pathogens in their genome (so-called "chimeric virus vaccines"). Many such viral vector vaccines are now at various stages of clinical evaluation. Here, we introduce an attenuated form of recombinant vesicular stomatitis virus (rVSV) as a potential chimeric virus vaccine for HIV-1, with implications for use as a vaccine vector for other pathogens. The rVSV/HIV-1 vaccine vector was attenuated by combining two major genome modifications. These modifications acted synergistically to greatly enhance vector attenuation and the resulting rVSV vector demonstrated safety in sensitive mouse and non-human primate neurovirulence models. This vector expressing HIV-1 gag protein has completed evaluation in two Phase I clinical trials. In one trial the rVSV/HIV-1 vector was administered in a homologous two-dose regimen, and in a second trial with pDNA in a heterologous prime boost regimen. No serious adverse events were reported nor was vector detected in blood, urine or saliva post vaccination in either trial. Gag specific immune responses were induced in both trials with highest frequency T cell responses detected in the prime boost regimen. The rVSV/HIV-1 vector also demonstrated safety in an ongoing Phase I trial in HIV-1 positive participants. Additionally, clinical trial material has been produced with the rVSV vector expressing HIV-1 env, and Phase I clinical evaluation will initiate in the beginning of 2016. In this paper, we use a standardized template describing key characteristics of the novel rVSV vaccine vectors, in comparison to wild type VSV. The template facilitates scientific discourse among key stakeholders by increasing transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines.

The Use of Minipigs for Preclinical Safety Assessment by the Pharmaceutical Industry: Results of an IQ DruSafe Minipig Survey.

The use of minipigs in preclinical safety testing of pharmaceuticals is considered an alternative to the more traditional dog and nonhuman primate (NHP) nonrodent species. Substantial evidence exists to suggest that the anatomy, physiology, and biochemistry of minipigs are similar enough to humans to consider them as valid nonrodent models for pharmaceutical safety testing. Since the utilization of minipigs was last assessed over 5 years ago, the Preclinical Safety Leadership Group (DruSafe) of the International Consortium for Innovation and Quality in Pharmaceutical Development conducted this survey to provide an updated assessment of the utility, perceived value, and impediments to the use of minipigs in preclinical safety testing. Of the 32 participating members of DruSafe, 15 responded to the survey representing both large and small companies. Respondents indicated that the minipig has been utilized mostly for short-term safety assessment studies with dermal, oral, and parenteral routes of administration. Minipigs are widely accepted as appropriate models for cardiovascular assessments and have been used to a limited extent for reproductive toxicology testing. Overall responses indicated that safety testing for large molecules using this species is relatively low due to a lack of background data, reagents or biomarkers, concerns regarding immune system characterization and poor suitability for developmental toxicity assessments. Most companies utilized contract research organizations for definitive safety toxicity assessment studies. Conclusions of this survey indicate that minipig is an acceptable nonrodent species largely limited to studies using small molecules, primarily dermal products, and results are comparable to those reported 5 years ago.

Garlic revisited: antimicrobial activity of allicin-containing garlic extracts against Burkholderia cepacia complex.

The antimicrobial activities of garlic and other plant alliums are primarily based on allicin, a thiosulphinate present in crushed garlic bulbs. We set out to determine if pure allicin and aqueous garlic extracts (AGE) exhibit antimicrobial properties against the Burkholderia cepacia complex (Bcc), the major bacterial phytopathogen for alliums and an intrinsically multiresistant and life-threatening human pathogen. We prepared an AGE from commercial garlic bulbs and used HPLC to quantify the amount of allicin therein using an aqueous allicin standard (AAS). Initially we determined the minimum inhibitory concentrations (MICs) of the AGE against 38 Bcc isolates; these MICs ranged from 0.5 to 3% (v/v). The antimicrobial activity of pure allicin (AAS) was confirmed by MIC and minimum bactericidal concentration (MBC) assays against a smaller panel of five Bcc isolates; these included three representative strains of the most clinically important species, B. cenocepacia. Time kill assays, in the presence of ten times MIC, showed that the bactericidal activity of AGE and AAS against B. cenocepacia C6433 correlated with the concentration of allicin. We also used protein mass spectrometry analysis to begin to investigate the possible molecular mechanisms of allicin with a recombinant form of a thiol-dependent peroxiredoxin (BCP, Prx) from B. cenocepacia. This revealed that AAS and AGE modifies an essential BCP catalytic cysteine residue and suggests a role for allicin as a general electrophilic reagent that targets protein thiols. To our knowledge, we report the first evidence that allicin and allicin-containing garlic extracts possess inhibitory and bactericidal activities against the Bcc. Present therapeutic options against these life-threatening pathogens are limited; thus, allicin-containing compounds merit investigation as adjuncts to existing antibiotics.

Psychosocial treatment approaches to difficult-to-treat depression.

Coexisting psychiatric and medical conditions, environmental and contextual factors, inadequate diagnosis and treatment, medication non-adherence, and issues such as low self-esteem, hopelessness and cognitive reactivity, can play a role in difficult-to-treat depression. A reduction in symptoms due to pharmacological treatment does not equate with full recovery, and some level of rehabilitation is often required. The evidence base for psychosocial therapies in difficult-to-treat depression is small, with the research heavily weighted toward biological treatments. Nevertheless, combining psychological treatments with pharmacotherapy is likely to improve rates of recovery in difficult-to-treat depression. Psychological therapies can be useful in modifying health beliefs, treating comorbid anxiety and other disorders, dealing with contextual factors, and activating patients to facilitate their recovery. Effective treatment requires a multidisciplinary team involving a general practitioner and psychologist, and sometimes a psychiatrist. Effective communication and active engagement of patients and families is essential.

Discovery, optimisation and in vivo evaluation of novel GPR119 agonists.

GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.

A randomised trial of a psychosocial intervention for cancer patients integrated into routine care: the PROMPT study (promoting optimal outcomes in mood through tailored psychosocial therapies).

BACKGROUND: Despite evidence that up to 35% of patients with cancer experience significant distress, access to effective psychosocial care is limited by lack of systematic approaches to assessment, a paucity of psychosocial services, and patient reluctance to accept treatment either because of perceived stigma or difficulties with access to specialist psycho-oncology services due to isolation or disease burden. This paper presents an overview of a randomised study to evaluate the effectiveness of a brief tailored psychosocial Intervention delivered by health professionals in cancer care who undergo focused training and participate in clinical supervision. METHODS/DESIGN: Health professionals from the disciplines of nursing, occupational therapy, speech pathology, dietetics, physiotherapy or radiation therapy will participate in training to deliver the psychosocial Intervention focusing on core concepts of supportive-expressive, cognitive and dignity-conserving care. Health professional training will consist of completion of a self-directed manual and participation in a skills development session. Participating health professionals will be supported through structured clinical supervision whilst delivering the Intervention. In the stepped wedge design each of the 5 participating clinical sites will be allocated in random order from Control condition to Training then delivery of the Intervention. A total of 600 patients will be recruited across all sites. Based on level of distress or risk factors eligible patients will receive up to 4 sessions, each of up to 30 minutes in length, delivered face-to-face or by telephone. Participants will be assessed at baseline and 10-week follow-up. Patient outcome measures include anxiety and depression, quality of life, unmet psychological and supportive care needs. Health professional measures include psychological morbidity, stress and burnout. Process evaluation will be conducted to assess perceptions of participation in the study and the factors that may promote translation of learning into practice. DISCUSSION: This study will provide important information about the effectiveness of a brief tailored psychological Intervention for patients with cancer and the potential to prevent development of significant distress in patients considered at risk. It will yield data about the feasibility of this model of care in routine clinical practice and identify enablers and barriers to its systematic implementation in cancer settings. TRIAL REGISTRATION: ACTRN12610000448044.

Plant host and sugar alcohol induced exopolysaccharide biosynthesis in the Burkholderia cepacia complex.

The species that presently constitute the Burkholderia cepacia complex (Bcc) have multiple roles; they include soil and water saprophytes, bioremediators, and plant, animal and human pathogens. Since the first description of pathogenicity in the Bcc was based on sour skin rot of onion bulbs, this study returned to this plant host to investigate the onion-associated phenotype of the Bcc. Many Bcc isolates, which were previously considered to be non-mucoid, produced copious amounts of exopolysaccharide (EPS) when onion tissue was provided as the sole nutrient. EPS production was not species-specific, was observed in isolates from both clinical and environmental sources, and did not correlate with the ability to cause maceration of onion tissue. Chemical analysis suggested that the onion components responsible for EPS induction were primarily the carbohydrates sucrose, fructose and fructans. Additional sugars were investigated, and all alcohol sugars tested were able to induce EPS production, in particular mannitol and glucitol. To investigate the molecular basis for EPS biosynthesis, we focused on the highly conserved bce gene cluster thought to be involved in cepacian biosynthesis. We demonstrated induction of the bce gene cluster by mannitol, and found a clear correlation between the inability of representatives of the Burkholderia cenocepacia ET12 lineage to produce EPS and the presence of an 11 bp deletion within the bceB gene, which encodes a glycosyltransferase. Insertional inactivation of bceB in Burkholderia ambifaria AMMD results in loss of EPS production on sugar alcohol media. These novel and surprising insights into EPS biosynthesis highlight the metabolic potential of the Bcc and show that a potential virulence factor may not be detected by routine laboratory culture. Our results also highlight a potential hazard in the use of inhaled mannitol as an osmolyte to improve mucociliary clearance in individuals with cystic fibrosis.

Quality of life and memory after vagus nerve stimulator implantation for epilepsy.

OBJECTIVE: This prospective, case control study evaluates quality of life (QOL), depressive affect, and memory outcomes of epilepsy patients implanted with a vagus nerve stimulator (VNS). METHODS: Three groups of patients with epilepsy underwent assessment on two occasions: 1) patients with a VNS were tested before and 12 months after implantation (n = 16); 2) patients who underwent cerebral resective surgery were tested pre- and post-operatively (n = 10); and 3) patients under medical management (n = 9). Group means were compared on the QOLIE-89, Geriatric Depression Scale, Wechsler Memory Scale - III, and the Memory Observation Questionnaire. Secondary analyses calculated the reliable change index, providing information on change beyond measurement error and chance. RESULTS: Mean ratings of QOL, depression, and memory complaints and objective memory scores remained stable or improved in all the groups. The QOL improved more after cerebral resective surgery than VNS or medication controls, but the VNS and medication control groups did not differ. In the VNS group, QOL was not related to seizure reduction. The percentage of cases showing real change in memory was equivalent across groups, except in one of eight indices (i.e., verbal recognition memory). CONCLUSIONS: This first case controlled design found that vagus nerve stimulation as an adjunctive therapy for seizure control did not change QOL, depressive affect, or objective memory scores over one-year more so than medical management alone. We point out the need for larger case control, non-industry funded investigations.

Correctors promote maturation of cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by binding to the protein.

The most common cause of cystic fibrosis (CF) is defective folding of a cystic fibrosis transmembrane conductance regulator (CFTR) mutant lacking Phe(508) (DeltaF508). The DeltaF508 protein appears to be trapped in a prefolded state with incomplete packing of the transmembrane (TM) segments, a defect that can be repaired by expression in the presence of correctors such as corr-4a, VRT-325, and VRT-532. To determine whether the mechanism of correctors involves direct interactions with CFTR, our approach was to test whether correctors blocked disulfide cross-linking between cysteines introduced into the two halves of a Cys-less CFTR. Although replacement of the 18 endogenous cysteines of CFTR with Ser or Ala yields a Cys-less mutant that does not mature at 37 degrees C, we found that maturation could be restored if Val(510) was changed to Ala, Cys, Ser, Thr, Gly, Ala, or Asp. The V510D mutation also promoted maturation of DeltaF508 CFTR. The Cys-less/V510A mutant was used for subsequent cross-linking analysis as it yielded relatively high levels of mature protein that was functional in iodide efflux assays. We tested for cross-linking between cysteines introduced into TM6 and TM7 of Cys-less CFTR/V510A because cross-linking between TM6 and TM7 of P-glycoprotein, the sister protein of CFTR, was inhibited with the corrector VRT-325. Cys-less CFTR/V510A mutant containing cysteines at I340C(TM6) and S877C(TM7) could be cross-linked with a homobifunctional cross-linker. Correctors and the CFTR channel blocker benzbromarone, but not P-glycoprotein substrates, inhibited cross-linking of mutant I340C(TM6)/S877C(TM7). These results suggest that corrector molecules such as corr-4a interact directly with CFTR.

A review of psychosocial aspects of motor neurone disease.

Motor neurone disease (MND) is an illness involving the progressive degeneration of upper and lower motor neurones. There is no known cause or cure. The physical aspects of MND frequently receive the majority of attention, with psychosocial aspects accorded secondary importance. We undertook a comprehensive search of the available literature published between 1966 and 2006 on the psychosocial aspects of MND, including quality of life (QoL), depression, social support, life sustaining treatment (LST), coping, spirituality and current practice. The literature identified that QoL correlated more strongly with measures of suffering, social support and hopelessness than with the physical state of the patient. Depression is relatively common (prevalence rates up to 50%), as are other forms of psychological distress in the MND population, and is not associated with illness severity and functional status. Depression strongly correlates with QoL. Social support is often limited for MND patients and this also influences QoL. Hope and hopelessness are important issues for MND patients with hopelessness contributing significantly to suffering and, for some, a desire for hastened death. Choices and decisions about life sustaining treatments pose a burden for patients and carers. Despite the physical and emotional suffering associated with MND, a significant number cope well and find positive meaning in life. Many patients opting for life sustaining treatment report a satisfactory QoL. In conclusion, psychosocial aspects of life are important for patients with MND. Depression and other expressions of distress require recognition and treatment. Issues of hope, spirituality and life and death also require attention in clinical practice. Although guidelines exist to direct physicians to attend to the physical care, there is a distinct lack of guidance to attend to the psychological state of the MND patient.

Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial.

BACKGROUND: Mixed reports exist about the impact of supportive-expressive group therapy (SEGT) on survival. METHODS: From 485 women with advanced breast cancer recruited between 1996-2002, 227 (47%) consented and were randomized within an average 10 months of cancer recurrence in a 2:1 ratio to intervention with 1 year or more of weekly SEGT plus three classes of relaxation therapy (147 women) or to control receiving three classes of relaxation therapy (80 women). The primary outcome was survival; psychosocial well-being was appraised secondarily. Analysis was by intention-to-treat. RESULTS: SEGT did not prolong survival (median survival 24.0 months in SEGT and 18.3 in controls; univariate hazard ratio for death 0.92 [95% CI, 0.69-1.26]; multivariate hazard ratio, 1.06 [95% CI, 0.74-1.51]). Significant predictors of survival were treatment with chemotherapy and hormone therapy (p<0.001), visceral metastases (p<0.001) and advanced disease at first diagnosis (p<0.05). SEGT ameliorated and prevented new DSM-IV depressive disorders (p = 0.002), reduced hopeless-helplessness (p = 0.004), trauma symptoms (p = 0.04) and improved social functioning (p = 0.03). CONCLUSIONS: SEGT did not prolong survival. It improved quality of life, including treatment of and protection against depression.

A qualitative examination of the experience of 'depression' in hospitalized medically ill patients.

BACKGROUND: Research into depression in the medically ill has progressed without sufficient attention being given to the validity, in this group, of the taxonomic categories. We aimed to describe, using qualitative interviews, the experience of 'being depressed', separating experiences that are unique to depression from experiences that are common to being ill and in hospital. METHOD: Forty-nine patients hospitalized for medical illness underwent a 30-min interview in which they were asked to 'Describe how you have been unwell and, in particular, how that has made you feel.' From the transcripts, a 'folk' taxonomy was constructed using a phenomenological framework involving four steps: frame elicitation to identify the important themes, componential analysis to systematically cluster the attributes into domains, a comparison of the experiences of patients screening depressed and not-depressed, and a theoretical analysis comparing the resulting taxonomy with currently used theoretical constructs. RESULTS: Experiences common to all patients were being in hospital, being ill or in pain, adjusting to not being able to do things, and having time to think. In addition, all participants described being depressed, down or sad. Patients who were identified by screening as being depressed described unique experiences of depression, which included 'having to think about things' (a forceful intrusive thinking), 'not being able to sleep', 'having to rely on others', 'being a burden' to others (with associated shame and guilt), feelings of 'not getting better' and 'feeling like giving up'. Theoretical analysis suggested that this experience of depression fitted well with the concept of demoralization described by Jerome Frank. CONCLUSIONS: Demoralization, which involves feelings of being unable to cope, helplessness, hopelessness and diminished personal esteem, characterizes much of the depression seen in hospitalized medically ill patients.

Assessing the effectiveness of integrated interventions: terminology and approach.

Integrated care is a term that embraces several concepts, all of which imply that the target patients have complex or chronic illness. There is an assumption that such patients require integrated care and benefit from it. Attempts to test this hypothesis have produced evidence of only modest benefit, and much of the evidence is conflicting. Demonstration of effectiveness of integrated interventions in the clinical setting has been less convincing. Often, interventions are introduced uncritically and without adequate follow-up of their effectiveness. More rigorous research is required on definitions, theoretic constructs,outcome measures, the science of data synthesis, and translation to the clinical setting. Recent developments in theoretic constructs in these areas give promise of better answers to the question, "What works for whom in what context?". Qualitative methodology should form part of this research.

Rethinking the place of the psyche in health: toward the integration of health care systems.

OBJECTIVE: To review the value provided when health care systems independently manage medical and psychiatric care. METHOD: The authors draw on data from the world literature, their own experiences and reflections (one author as an international consultant in the coordination of physical and behavioural health care), and input from colleagues throughout the world who face similar challenges to improve outcomes for complex, high cost patients in their own health care systems. RESULTS: Most health care systems in the world approach the administration and delivery of mental health care separately from that of general medical care. This practice is no longer supported as effective, efficient or inexpensive. Rather accumulating data indicates that concurrent and coordinated medical and psychiatric care, which can only be accomplished by integrating physical and behavioural health through infrastructure change, should replace the present system of independently provided sequential care; that is, one which provides first medical and then psychiatric treatment, or vice versa, with little communication between clinicians in the two sectors. CONCLUSIONS: By making mental health treatment an integral part of general medical care through reorganization of the funding system, a higher percentage of those now untreated for their psychiatric disorders, both within and outside of the medical setting, can have their mental health needs addressed in coordination with their physical disorders. At the same time, the number of patients that can be treated within the same budget will be expanded.

No alternative? The regulation and professionalization of complementary and alternative medicine in the United Kingdom.

In conjunction with its growing popularity, complementary and alternative medicine (CAM) in the United Kingdom has witnessed increasing professionalization, partly prompted by the landmark Parliamentary Inquiry that reported in November 2000. Professionalization has become a significant strategy for practitioner associations and a key focus for the government, media, and patient groups. It is being driven by concern over the interests of patients and consumers, and in relation to the possible integration of certain forms of CAM into publicly funded healthcare. It is, moreover, being reconfigured in explicitly national terms. This paper draws on research into practitioner associations representing nine CAM modalities in the UK-aromatherapy, Chinese herbal medicine, chiropractic, crystal healing, feng shui, 'lay' homeopathy, medical homeopathy, osteopathy, and Radionics-, examining the recent wave of professionalization in relation to Foucault's concern with 'techniques of the self.' It highlights the contrasting experience of an association of Chinese herbalists seeking statutory self-regulation (SSR) and an association of chiropractors that was instrumental in securing SSR for chiropractic.