Nine-gene pharmacogenomics profile service: The Mayo Clinic experience.

PURPOSE: The Pharmacogenomics (PGx) Profile Service was a proof-of-concept project to implement PGx in patient care at Mayo Clinic. METHODS: Eighty-two healthy individuals aged 18 and older underwent genotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, HLA-B*58:01, and VKORC1. A PGx pharmacist was involved in ordering, meeting with patients, interpreting, reviewing, and documenting results. RESULTS: Ninety three percent were CYP1A2 rapid metabolizers, 92% CYP3A4 normal metabolizers, and 88% CYP3A5 poor metabolizers; phenotype frequencies for CYP2C19 and CYP2D6 varied. Seventy-three percent had normal functioning SLCO1B1 transporter, 4% carried the HLA-B*58:01 risk variant, and 35% carried VKORC1 and CYP2C9 variants that increased warfarin sensitivity. CONCLUSION: Pre-emptive PGx testing offered medication improvement opportunity in 56% of participants for commonly used medications. A collaborative approach involving a PGx pharmacist integrated within a clinical practice with regards to utility of PGx results allowed for implementation of the PGx Profile Service. KEY POINTS: The Mayo Clinic PGx (PGx) Profile Service was a proof-of-concept project to utilize PGx testing as another clinical tool to enhance medication selection and decrease serious adverse reactions or medication failures. Over one-half of participants in the pilot using the PGx Profile Service were predicted to benefit from pre-emptive PGx testing to guide pharmacotherapy. PGx pharmacists played a crucial role in the PGx Profile Service by educating participants, identifying medication-gene interactions, and providing evidence-based (CPIC and DPWG) PGx recommendations for past, current, and future medication us.

Person-centred experiential therapy versus cognitive behavioural therapy delivered in the English Improving Access to Psychological Therapies service for the treatment of moderate or severe depression (PRaCTICED): a pragmatic, randomised, non-inferiority trial.

BACKGROUND: The UK Government's implementation in 2008 of the Improving Access to Psychological Therapies (IAPT) initiative in England has hugely increased the availability of cognitive behavioural therapy (CBT) for the treatment of depression and anxiety in primary care. Counselling for depression-a form of person-centred experiential therapy (PCET)-has since been included as an IAPT-approved therapy, but there is no evidence of its efficacy from randomised controlled trials (RCTs), as required for recommendations by the National Institute for Health and Care Excellence. Therefore, we aimed to examine whether PCET is cost effective and non-inferior to CBT in the treatment of moderate and severe depression within the IAPT service. METHODS: This pragmatic, randomised, non-inferiority trial was done in the Sheffield IAPT service in England and recruited participants aged 18 years or older with moderate or severe depression on the Clinical Interview Schedule-Revised. We excluded participants presenting with an organic condition, a previous diagnosis of personality disorder, bipolar disorder, or schizophrenia, drug or alcohol dependency, an elevated clinical risk of suicide, or a long-term physical condition. Eligible participants were randomly assigned (1:1), independently of the research team, and stratified by site with permuted block sizes of two, four, or six, to receive either PCET or CBT by use of a remote, web-based system that revealed therapy after patient details were entered. Those assessing outcomes were masked to treatment allocation. Participants were seen by appropriately trained PCET counsellors and CBT therapists in accordance with the IAPT service delivery model. Depression severity and symptomatology measured by the Patient Health Questionnaire-9 (PHQ-9) at 6 months post-randomisation was the primary outcome, with the PHQ-9 score at 12 months post-randomisation being a key secondary outcome. These outcomes were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients with complete data, and the per-protocol population, which comprised all participants who did not switch from their randomised treatment and received between four and 20 sessions. Safety was analysed in all randomly assigned patients. The non-inferiority margin was set a priori at 2 PHQ-9 points. Patient safety was monitored throughout the course of therapy, adhering to service risk procedures for monitoring serious adverse events. This trial is registered at the ISRCTN Registry, ISRCTN06461651, and is complete. FINDINGS: From Nov 11, 2014, to Aug 3, 2018, 9898 patients were referred to step three treatments in the Sheffield IAPT service for common mental health problems, of whom 761 (7·7%) were referred to the trial. Of these, we recruited and randomly assigned 510 participants to receive either PCET (n=254) or CBT (n=256). In the PCET group, 138 (54%) participants were female and 116 (46%) were male, and 225 (89%) were White, 16 (6%) were non-White, and 13 (5%) had missing ethnicity data. In the CBT group, 155 (61%) participants were female and 101 (39%) were male, and 226 (88%) were White, 17 (7%) were non-White, and 13 (5%) had missing ethnicity data. The 6-month modified intention-to-treat analysis comprised 401 (79%) of the enrolled participants (201 in the PCET group; 200 in the CBT group) and the 12-month modified intention-to-treat analysis comprised 319 participants (167 in the PCET group; 152 in the CBT group). The 6-month per-protocol analysis comprised 298 participants (154 in the PCET group; 144 in the CBT group). At 6 months post-randomisation, PCET was non-inferior to CBT in the intention-to-treat population (mean PHQ-9 score 12·74 [SD 6·54] in the PCET group and 13·25 [6·35] in the CBT group; adjusted mean difference -0·35 [95% CI -1·53 to 0·84]) and in the per-protocol population (12·73 [SD 6·57] in the PCET group and 12·71 [6·33] in the CBT group; 0·27 [95% CI -1·08 to 1·62]). At 12 months post-randomisation, there was a significant adjusted between-group difference in mean PHQ-9 score in favour of CBT (1·73 [95% CI 0·26-3·19]), with a 95% CI exceeding the 2-point non-inferiority margin. There were two deaths, one death by suicide in the PCET group and one due to chronic obstructive pulmonary disease in the CBT group. Both were assessed by the responsible clinician to be unrelated to the trial. In terms of using emergency departments for depression-related events, four people (three in the PCET group; one in the CBT group) made more than a single use and six people (three in the PCET group; three in the CBT group) made a single use. One patient in the PCET group had inpatient treatment for a depression-related event. INTERPRETATION: This trial is the first to examine the two most frequently administered psychological therapies in the IAPT service. The finding of non-inferiority of PCET to CBT at 6 months supports the results from large, routine, non-randomised datasets from the IAPT programme. Given the high demand for psychological therapies and the need for patient choice, our findings suggest the need for continued investment in the training and delivery of PCET for improving short-term outcomes, but suggest that PCET might be inferior to CBT at 12 months. FUNDING: British Association for Counselling and Psychotherapy Research Foundation.

A pragmatic randomised controlled trial assessing the non-inferiority of counselling for depression versus cognitive-behaviour therapy for patients in primary care meeting a diagnosis of moderate or severe depression (PRaCTICED): Study protocol for a randomised controlled trial.

BACKGROUND: NICE guidelines state cognitive behavioural therapy (CBT) is a front-line psychological treatment for people presenting with depression in primary care. Counselling for Depression (CfD), a form of Person-Centred Experiential therapy, is also offered within Improving Access to Psychological Therapies (IAPT) services for moderate depression but its effectiveness for severe depression has not been investigated. A full-scale randomised controlled trial to determine the efficacy and cost-effectiveness of CfD is required. METHODS: PRaCTICED is a two-arm, parallel group, non-inferiority randomised controlled trial comparing CfD against CBT. It is embedded within the local IAPT service using a stepped care service delivery model where CBT and CfD are routinely offered at step 3. Trial inclusion criteria comprise patients aged 18 years or over, wishing to work on their depression, judged to require a step 3 intervention, and meeting an ICD-10 diagnosis of moderate or severe depression. Patients are randomised using a centralised, web-based system to CfD or CBT with each treatment being delivered up to a maximum 20 sessions. Both interventions are manualised with treatment fidelity tested via supervision and random sampling of sessions using adherence/competency scales. The primary outcome measure is the Patient Health Questionnaire-9 collected at baseline, 6 and 12 months. Secondary outcome measures tap depression, generic psychological distress, anxiety, functioning and quality of life. Cost-effectiveness is determined by a patient service receipt questionnaire. Exit interviews are conducted with patients by research assessors blind to treatment allocation. The trial requires 500 patients (250 per arm) to test the non-inferiority hypothesis of -2 PHQ-9 points at the one-sided, 2.5% significance level with 90% power, assuming no underlying difference and a standard deviation of 6.9. The primary analysis will be undertaken on all patients randomised (intent to treat) alongside per-protocol and complier-average causal effect analyses as recommended by the extension to the CONSORT statement for non-inferiority trials. DISCUSSION: This large-scale trial utilises routinely collected outcome data as well as specific trial data to provide evidence of the comparative efficacy and cost-effectiveness of Counselling for Depression compared with Cognitive Behaviour Therapy as delivered within the UK government's Improving Access to Psychological Therapies initiative. TRIAL REGISTRATION: Controlled Trials ISRCTN Registry, ISRCTN06461651 . Registered on 14 September 2014.

Adipose tissue redistribution caused by an early consumption of a high sucrose diet in a rat model.

INTRODUCTION: Obesity is a major public health problem worldwide. The quantity and site of accumulation of adipose tissue is of great importance for the physiopathology of this disease. OBJECTIVES: The aim of this study was to assess the effect of a high carbohydrate diet on adipose tissue distribution. METHODS: Male Wistar rats, control (CONT) and high sucrose diet (HSD; 30% sucrose in their drinking water), were monitored during 24 weeks and total energy and macronutrient intake were estimated by measuring daily average consumption. A bioelectrical impedance procedure was performed at 22 weeks of treatment to assess body compartments and systolic arterial blood pressure was measured. Serum was obtained and retroperitoneal adipose tissue was collected and weighed. RESULTS: HSD ingested less pellets and beverage, consuming less lipids and proteins than CONT, but the same amount of carbohydrates. Retroperitoneal adipose tissue was more abundant in HSD. Both groups were normoglycemic; triglycerides, adiponectin and leptin levels were higher, while total cholesterol and HDL-cholesterol were lower in HSD; insulin, HOMA index and systolic blood pressure had a tendency of being higher in HSD. DISCUSSION: This model presents dyslipidemia and a strong tendency for insulin resistance and hypertension. Even though there was no difference in body compartments between groups, retroperitoneal adipose tissue was significantly increased in HSD. This suggests that a rearrangement of adipose tissue distribution towards the abdominal cavity takes place as a result of chronic high sucrose consumption, which contributes to a higher risk of suffering from metabolic and chronic degenerative diseases.

Introducción: la obesidad es uno de los mayores problemas de salud pública en todo el mundo. El momento en que se establecee, la distribución y cantidad de tejido adiposo son de gran importancia para comprender su fisiopatología. Objetivos: observar la distribución de tejido adiposo en una dieta alta en sacarosa desde una edad temprana en un modelo animal. Métodos: se utilizaron ratas Wistar recién destetadas, animales control (CONT; agua ad libitum) y animales con dieta alta en sacarosa (HSD; 30% de sacarosa en el agua) durante 24 semanas. Se calcularon las kilocalorías y macronutrientes ingeridos diariamente; se evaluaron por impedancia bioeléctrica los compartimientos corporales, se midió la presión sistólica, se obtuvo el tejido adiposo retroperitoneal y el suero para medir parámetros bioquímicos. Resultados: los animales HSD comieron y bebieron menos, obteniendo menos proteínas y lípidos, sin diferencia en los hidratos de carbono. El tejido adiposo fue más abundante en HSD. Ambos grupos CONT Y HSD fueron normoglucémicos; HSD tuvieron triglicéridos, adiponectina y leptina altos, y el colesterol y las HDL más bajos; la insulina, el HOMA y la presión sistólica tuvieron tendencia a ser mayores en HSD. Discusión: este modelo presenta dislipidemia y una tendencia a tener resistencia a la insulina e hipertensión. A pesar de no haber una diferencia en los compartimentos corporales entre grupos, el tejido adiposo tuvo una localización específica en la espalda y fue más abundante en HSD. En conclusión, la distribución de grasa en el abdomen es consecuencia de una ingestión crónica alta en sacarosa, lo que predispone a padecer enfermedades crónico-degenerativas.

Adipose tissue redistribution caused by an early consumption of a high sucrose diet in a rat model / Redistribución del tejido adiposo en un modelo de rata debido al alto consumo de sacarosa desde edad temprana

Introduction: obesity is a major public health problem worldwide. The quantity and site of accumulation of adipose tissue is of great importance for the physiopathology of this disease. Objectives: the aim of this study was to assess the effect of a high carbohydrate diet on adipose tissue distribution. Methods: male Wistar rats, control (CONT) and high sucrose diet (HSD; 30% sucrose in their drinking water), were monitored during 24 weeks and total energy and macronutrient intake were estimated by measuring daily average consumption. A bioelectrical impedance procedure was performed at 22 weeks of treatment to assess body compartments and systolic arterial blood pressure was measured. Serum was obtained and retroperitoneal adipose tissue was collected and weighed. Results: HSD ingested less pellets and beverage, consuming less lipids and proteins than CONT, but the same amount of carbohydrates. Retroperitoneal adipose tissue was more abundant in HSD. Both groups were normoglycemic; triglycerides, adiponectin and leptin levels were higher, while total cholesterol and HDLcholesterol were lower in HSD; insulin, HOMA index and systolic blood pressure had a tendency of being higher in HSD. Discussion: this model presents dyslipidemia and a strong tendency for insulin resistance and hypertension. Even though there was no difference in body compartments between groups, retroperitoneal adipose tissue was significantly increased in HSD. This suggests that a rearrangement of adipose tissue distribution towards the abdominal cavity takes place as a result of chronic high sucrose consumption, which contributes to a higher risk of suffering from metabolic and chronic degenerative diseases (AU)

Introducción: la obesidad es uno de los mayores problemas de salud pública en todo el mundo. El momento en que se establece, la distribución y cantidad de tejido adiposo son de gran importancia para comprender su fisiopatología. Objetivos: observar la distribución de tejido adiposo en una dieta alta en sacarosa desde una edad temprana en un modelo animal. Métodos: se utilizaron ratas Wistar recién destetadas, animales control (CONT; agua ad libitum) y animales con dieta alta en sacarosa (HSD; 30% de sacarosa en el agua) durante 24 semanas. Se calcularon las kilocalorías y macronutrientes ingeridos diariamente; se evaluaron por impedancia bioeléctrica los compartimientos corporales, se midió la presión sistólica, se obtuvo el tejido adiposo retroperitoneal y el suero para medir parámetros bioquímicos. Resultados: los animales HSD comieron y bebieron menos, obteniendo menos proteínas y lípidos, sin diferencia en los hidratos de carbono. El tejido adiposo fue más abundante en HSD. Ambos grupos CONT Y HSD fueron normoglucémicos; HSD tuvieron triglicéridos, adiponectina y leptina altos, y el colesterol y las HDL más bajos; la insulina, el HOMA y la presión sistólica tuvieron tendencia a ser mayores en HSD. Discusión: este modelo presenta dislipidemia y una tendencia a tener resistencia a la insulina e hipertensión. A pesar de no haber una diferencia en los compartimentos corporales entre grupos, el tejido adiposo tuvo una localización específica en la espalda y fue más abundante en HSD. En conclusión, la distribución de grasa en el abdomen es consecuencia de una ingestión crónica alta en sacarosa, lo que predispone a padecer enfermedades crónico-degenerativas (AU)