Evaluation of a Web-Based, 'Purchase Event' Intensive Monitoring Method for Pharmacovigilance of Natural Health Products: Lessons and Insights from Development Work in New Zealand.

INTRODUCTION: Intensive monitoring methods are used in pharmacovigilance for prescription medicines but have not yet been implemented for natural health products (NHPs). OBJECTIVES: Our objective was to assess feasibility issues with a new 'purchase event' intensive monitoring method for pharmacovigilance of NHPs, including pharmacy and NHP purchaser recruitment rates, collection of NHP purchaser key patient identifier information for data linkage and quality and completeness of data. METHODS: For the Ginkgo study, 213 community pharmacies in the Auckland (Aotearoa New Zealand) District Health Board area were invited to participate. Staff in participating pharmacies (n = 3 [1.4%]) recorded ginkgo product sales and gave purchasers a study invitation card (October 2015-January 2016). Ginkgo purchaser participants were emailed links to web-based baseline and follow-up questionnaires about adverse events occurring during/after taking ginkgo. Participating pharmacists and consumers were invited to provide qualitative feedback about the study. For the NHP-Lite study, all NHPs were included for monitoring. Community pharmacies in the Green Cross Health network were invited to participate. Participating pharmacy staff gave all NHP purchasers a study invitation card over a 2-week period (May 2016). NHP purchaser participants were emailed links to web-based baseline, follow-up and feedback questionnaires. RESULTS: Few community pharmacists (Ginkgo study, n = 3; NHP-Lite study, n = 18) and NHP purchasers (Ginkgo study, n = 0; NHP-Lite study, n = 4) participated. Pharmacists (Ginkgo study, 3/3; NHP-Lite study, 11/18) described several reasons for participating and suggested ways to increase consumer recruitment, including simplifying study procedures. CONCLUSIONS: These web-based, purchase event, intensive monitoring studies, with cohorts built through NHP purchases in pharmacies, identified substantial issues with recruiting pharmacists/pharmacies and NHP purchasers that, at present, render such studies unfeasible. Future studies need to consider other methods of recruiting NHP purchasers and develop a simple method for recording NHP purchases.

Strengths, Limitations, and Recommendations for Instrumental Color Measurement in Forensic Soil Characterization.

Color determination of soil evidence is often done by visual comparison to soil color charts. A handheld spectrophotometer was tested with representative materials for its suitability for forensic soil characterization. Instrumental colorimetry provides accurate colorimetry with ~10-fold better precision than a soil color chart. The minimum sample size for accurate color determination was between 0.02 and 0.04 mg of fine soil for the specific instrument tested. Reporting colors in the L*a*b* space permits quantification of ΔE00 , a measure of perceptible color difference, could enable objective quantification of small color differences and thresholds for forensic soil comparisons. A ΔE00 greater than ~ 3.5 to 6 likely indicates disparate soil sources in a forensic comparison, in the absence of confounding factors like sample alteration. Despite the superior precision of instrumental colorimetry, this approach is inappropriate for samples which are mottled at an inseparable scale, attached to a substrate, or too small for instrumental measurement.

Hypnotherapy for smoking cessation.

BACKGROUND: Hypnotherapy is widely promoted as a method for aiding smoking cessation. It is intended to act on underlying impulses to weaken the desire to smoke, or strengthen the will to stop. OBJECTIVES: To evaluate the effect and safety of hypnotherapy for smoking cessation. SEARCH METHODS: For this update we searched the Cochrane Tobacco Addiction Group Specialized Register, and trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform), using the terms "smoking cessation" and "hypnotherapy" or "hypnosis", with no restrictions on language or publication date. The most recent search was performed on 18 July 2018. SELECTION CRITERIA: We considered randomized controlled trials that recruited people who smoked and implemented a hypnotherapy intervention for smoking cessation compared with no treatment, or with any other therapeutic interventions. Trials were required to report smoking cessation rates at least six months after the beginning of treatment. Study eligibility was determined by at least two review authors, independently. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data on participant characteristics, the type and duration of hypnotherapy, the nature of the control group, smoking status, method of randomization, and completeness of follow-up. These authors also independently assessed the quality of the included studies. In undertaking this work, we used standard methodological procedures expected by Cochrane.The main outcome measure was abstinence from smoking after at least six months' follow-up. We used the most rigorous definition of abstinence in each trial, and biochemically validated abstinence rates where available. Those lost to follow-up were considered to still be smoking. We summarized effects as risk ratios (RRs) and 95% confidence intervals (CIs). Where possible, we performed meta-analysis using a fixed-effect model. We also noted any adverse events reported. MAIN RESULTS: We included three new trials in this update, which brings the total to 14 included studies that compared hypnotherapy with 22 different control interventions. The studies included a total of 1926 participants. Studies were diverse and a single meta-analysis was not possible. We judged only one study to be at low risk of bias overall; we judged 10 studies to be at high risk of bias and three at unclear risk. Studies did not provide reliable evidence of a greater benefit from hypnotherapy compared with other interventions or no treatment for smoking cessation. Most individual studies did not find statistically significant differences in quit rates after six months or longer, and studies that did detect differences typically had methodological limitations.Pooling small groups of relatively comparable studies did not provide reliable evidence for a specific effect of hypnotherapy relative to controls. There was low certainty evidence, limited by imprecision and risk of bias, that showed no statistically significant difference between hypnotherapy and attention-matched behavioural treatments (RR 1.21, 95% CI 0.91 to 1.61; I2 = 36%; 6 studies, 957 participants). Results were similarly imprecise, and also limited by risk of bias, when comparing hypnotherapy to intensive behavioural interventions (not matched for contact time) (RR 0.93, 95% CI 0.47 to 1.82; I2 = 0%; 2 studies, 211 participants; very low certainty evidence). Results from one small study (40 participants) detected a statistically significant benefit of hypnotherapy compared to no intervention (RR 19.00, 95% CI 1.18 to 305.88), but this evidence was judged to be of very low certainty due to high risk of bias and imprecision. No significant differences were detected in comparisons of hypnotherapy with brief behavioural interventions (RR 0.98, 95% CI 0.57 to 1.69; I² = 0%; 2 studies, 269 participants), rapid/focused smoking (RR 1.00, 95% CI 0.43 to 2.33; I2 = 65%; 2 studies, 54 participants), and pharmacotherapies (RR 1.68, 95% CI 0.88 to 3.20; I2 = 5%; 2 studies, 197 participants). When hypnotherapy was evaluated as an adjunct to other treatments, the pooled result from five studies showed a statistically significant benefit in favour of hypnotherapy (RR 2.10, 95% CI 1.31 to 3.35; I² = 62%; 224 participants); however, this result should be interpreted with caution due to the high risk of bias across studies (four had a high risk or bias, one had an unclear risk), and substantial statistical heterogeneity.Most studies did not provide information on whether data specifically relating to adverse events were collected, and whether or not any adverse events occurred. One study that did collect such data did not find a statistically significant difference in the adverse event 'index' between hypnotherapy and relaxation. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether hypnotherapy is more effective for smoking cessation than other forms of behavioural support or unassisted quitting. If a benefit is present, current evidence suggests the benefit is small at most. There is very little evidence on whether hypnotherapy causes adverse effects, but the existing data show no evidence that it does. Further large, high-quality randomized controlled trials, and more comprehensive assessments of safety, are needed on this topic.

Motivations, Expectations and Experiences in Being a Mental Health Helplines Volunteer.

Volunteers in non-government organisations are increasingly providing mental health support due to increasing demand and in the context of overstretched publicly-funded mental health services. This descriptive, cross-sectional study explored a knowledge gap in the literature of mental health telephone counselling by examining the motivation and retention determinants of helpline volunteers. In total, 25 participants were recruited across four focus groups and five individual interviews from a non-government organisation which provides a national phone counselling service to callers in New Zealand. Interviews were electronically recorded, transcribed and thematically analysed. Volunteers were found to have a high regard for their role and enjoyed many aspects including initial training, ongoing supports (formal/informal) and nature of the phone calls. However, organisational priorities/communication, disconnectedness, technological issues, lack of recognition and lack of a sense of belonging were reasons cited for intention to leave but previous mental health experiences, autonomy/flexibility, self-discovery/skills development and being there for someone else were key factors for volunteers to start and remain in their role. Understanding these crucial factors may help modulate volunteer satisfaction and retention in mental health organisations but may also potentially be relevant to other types of volunteer organisations.

The uses of mental health telephone counselling services for Chinese speaking people in New Zealand: demographics, presenting problems, outcome and evaluation of the calls.

AIM: This study aimed to investigate the call profiles of a Chinese-speaking mental health counselling helpline service in New Zealand (Chinese Lifeline provided by Lifeline Aotearoa) and to evaluate the calls and explore the possible factors influencing the outcome of the calls. METHOD: A random sample of 151 answered calls was involved. Descriptive analysis with appropriate statistical tests was used to analyse the client profile and outcome data. RESULTS: The majority of the calls were made by female callers, aged between 21-60 both single and married. Top three presenting problems were: 1) mental health issues (82.1%); 2) family/partner relationship issues (47.0%) and 3) communication and related difficulties (45.0%). The majority of the calls (65%) ended after a clear decision in overcoming the issues made by the caller, with the help from the counsellor. Discussing mental health issues, grief and loss issues, and communication and related difficulties were shown to have influenced length of calls (p<0.05). Caller's age, frequency of calls, discussing relationship problems with family/partner, and physical problems were shown to have influenced the helpline counsellors' satisfaction of the helpfulness of the calls (p<0.05). CONCLUSION: The service receives calls from callers with a wide range of demographics and a large variety of presenting issues. This study identified several important factors which influenced counsellors' satisfaction of the calls and the length of the calls.

A clinical psychologist in GP-Land: an evaluation of brief psychological interventions in primary care.

AIM: To evaluate the clinical outcomes and other impacts of brief therapy provided in a primary care setting by a clinical psychologist who was mainly employed in secondary mental health. METHOD: The outcomes of 23 primary care patients referred to a clinical psychologist were evaluated using the General Health Questionnaire (GHQ), the World Health Organisation Quality of Life (WHOQoL) scale, and the Beck Depression Inventory (BDI). A mixture of quantitative and qualitative data from patients and staff were analysed to identify other impacts of the intervention. RESULTS: Large improvements in BDI, GHQ, and WHOQOL scores were found, with strong changes consistent with the targets of the intervention. Patients reported primary-based clinical psychology input was more convenient and many engaged who had resisted referral to secondary mental health services. Other benefits to the service, including improved primary-secondary service integration, improved primary management of mental health difficulties, and improved liaison with mental health specialists, were reported by primary health staff. CONCLUSION: Brief psychological interventions by a visiting clinical psychologist in a general practice setting had substantial benefits for the patients and for the practice. This project indicates the value of integrated psychological input consistent with recent moves to better primary-secondary integration in mental health care.

The impact of New Zealand's 2008 prohibition of piperazine-based party pills on young people's substance use: results of a longitudinal, web-based study.

BACKGROUND: The last decade has seen the emergence of a new phenomenon in recreational substance use with the availability of herbal and synthetic, unregulated, psychoactive drugs in the market place; alongside this, international concern has developed in relation to their use and associated harms. New Zealand (NZ) was one of the first countries to experience this new phenomenon, with products containing chemicals of the piperazine group - mainly benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP). In 2008, the NZ Government prohibited these substances, but allowed a 6-month amnesty period for possession. Our study aimed to obtain a measure of change in BZP use over time. METHODS: This study used a longitudinal, web-based survey, with data collected at two time points from the same participants. The first survey was carried out 3 months after BZP prohibition, and included retrospective questions for the 6 months preceding the survey. The second survey was conducted 9 months after prohibition and also included retrospective questions for the 6 months preceding the survey. RESULTS: 273 sets of paired data were identified. The use of BZP party pills (p<0.0001) and legally available smokeable products (p=0.002) reduced over time. A majority of users of party pills obtained them from friends or from their own stockpiled supplies. The misuse of prescription drugs (p=0.02) increased over time, whereas statistically significant increases in stimulant or alcohol use were not noted. CONCLUSION: Following prohibition of piperazine-based party pills, we noted a significant reduction in the proportions of participants using them. The observed increase in the misuse of prescription medicines may relate to their perceived 'quality', or as being less 'illegal' than illicit drugs.

Hypnotherapy for smoking cessation.

BACKGROUND: Hypnotherapy is widely promoted as a method for aiding smoking cessation. It is proposed to act on underlying impulses to weaken the desire to smoke or strengthen the will to stop. OBJECTIVES: To evaluate the efficacy of hypnotherapy for smoking cessation. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group Specialized Register and the databases MEDLINE, EMBASE, AMED, SCI, SSCI using the terms smoking cessation and hypnotherapy or hypnosis. Date of most recent searches July 2010. There were no language restrictions. SELECTION CRITERIA: We considered randomized controlled trials of hypnotherapy which reported smoking cessation rates at least six months after the beginning of treatment. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data on participant characteristics, the type and duration of the hypnotherapy, the nature of the control group, smoking status, method of randomization, and completeness of follow up. They also independently assessed the quality of the included studies.The main outcome measure was abstinence from smoking after at least six months follow up. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. Those lost to follow up were considered to be smoking. We summarised effects as risk ratios (RR). Where possible, we performed meta-analysis using a fixed-effect model. We also noted any adverse events reported. MAIN RESULTS: Eleven studies compared hypnotherapy with 18 different control interventions. There was significant heterogeneity between the results of the individual studies, with conflicting results for the effectiveness of hypnotherapy compared to no treatment, or to advice, or psychological treatment. We did not attempt to calculate pooled risk ratios for the overall effect of hypnotherapy. There was no evidence of a greater effect of hypnotherapy when compared to rapid smoking or psychological treatment. Direct comparisons of hypnotherapy with cessation treatments considered to be effective had confidence intervals that were too wide to infer equivalence. AUTHORS' CONCLUSIONS: We have not shown that hypnotherapy has a greater effect on six-month quit rates than other interventions or no treatment. There is not enough evidence to show whether hypnotherapy could be as effective as counselling treatment. The effects of hypnotherapy on smoking cessation claimed by uncontrolled studies were not confirmed by analysis of randomized controlled trials.

Aphasic or amnesic status epilepticus detected on PET but not EEG.

PURPOSE: To describe five patients with ictal aphasia and one patient with ictal amnesia, who had focal positron emission tomography (PET) hypermetabolism but no clear ictal activity on electroencephalography (EEG). METHODS: (18)F-Fluorodeoxyglucose (FDG)-PET scans with concomitant EEG were obtained in five patients with suspected ictal aphasia or ictal amnesia without ictal activity on EEG. We reviewed medical history, EEG, imaging data, and treatment outcome. RESULTS: Brain magnetic resonance imaging (MRI) showed no structural abnormalities in any of the patients. EEG showed left temporal irregular delta activity in three patients, with aphasia and nonspecific abnormalities in two other patients, all without clear ictal pattern. All patients demonstrated focal hypermetabolism on PET scan. The hypermetabolism was in the left frontotemporal region in patients with ictal aphasia and in the bilateral hippocampal region in the patient with amnesia. Three patients who received intravenous benzodiazepines during their episodes had transient clinical improvement. With antiepileptic drug (AED) treatment, symptoms gradually resolved in all patients. Concomitant resolution of PET hypermetabolism was documented in three patients who had follow up scans. One patient with ictal aphasia later developed recurrent episodes, each with recurrent PET hypermetabolism. This patient and one other patient required immune-modulating therapy in addition to AEDs. DISCUSSION: FDG-PET imaging should be considered as a diagnostic tool in patients with suspected ictal aphasia or amnesia, who fail to show clear evidence of ictal activity on EEG.

Induction of broad CD4+ and CD8+ T-cell responses and cross-neutralizing antibodies against hepatitis C virus by vaccination with Th1-adjuvanted polypeptides followed by defective alphaviral particles expressing envelope glycoproteins gpE1 and gpE2 and nonstructural proteins 3, 4, and 5.

Broad, multispecific CD4(+) and CD8(+) T-cell responses to the hepatitis C virus (HCV), as well as virus-cross-neutralizing antibodies, are associated with recovery from acute infection and may also be associated in chronic HCV patients with a favorable response to antiviral treatment. In order to recapitulate all of these responses in an ideal vaccine regimen, we have explored the use of recombinant HCV polypeptides combined with various Th1-type adjuvants and replication-defective alphaviral particles encoding HCV proteins in various prime/boost modalities in BALB/c mice. Defective chimeric alphaviral particles derived from the Sindbis and Venezuelan equine encephalitis viruses encoding either the HCV envelope glycoprotein gpE1/gpE2 heterodimer (E1E2) or nonstructural proteins 3, 4, and 5 (NS345) elicited strong CD8(+) T-cell responses but low CD4(+) T helper responses to these HCV gene products. In contrast, recombinant E1E2 glycoproteins adjuvanted with MF59 containing a CpG oligonucleotide elicited strong CD4(+) T helper responses but no CD8(+) T-cell responses. A recombinant NS345 polyprotein also stimulated strong CD4(+) T helper responses but no CD8(+) T-cell responses when adjuvanted with Iscomatrix containing CpG. Optimal elicitation of broad CD4(+) and CD8(+) T-cell responses to E1E2 and NS345 was obtained by first priming with Th1-adjuvanted proteins and then boosting with chimeric, defective alphaviruses expressing these HCV genes. In addition, this prime/boost regimen resulted in the induction of anti-E1E2 antibodies capable of cross-neutralizing heterologous HCV isolates in vitro. This vaccine formulation and regimen may therefore be optimal in humans for protection against this highly heterogeneous global pathogen.

Variable patterns of programmed death-1 expression on fully functional memory T cells after spontaneous resolution of hepatitis C virus infection.

The inhibitory receptor programmed death-1 (PD-1) is present on CD8(+) T cells in chronic hepatitis C virus (HCV), but expression patterns in spontaneously resolving infections are incompletely characterized. Here we report that PD-1 was usually absent on memory CD8(+) T cells from chimpanzees with resolved infections, but sustained low-level expression was sometimes observed in the absence of apparent virus replication. PD-1-positive memory T cells expanded and displayed antiviral activity upon reinfection with HCV, indicating conserved function. This animal model should facilitate studies of whether PD-1 differentially influences effector and memory T-cell function in resolved versus persistent human infections.

Hepatitis C virus envelope glycoprotein immunization of rodents elicits cross-reactive neutralizing antibodies.

Neutralizing antibody responses elicited during infection generally confer protection from infection. Hepatitis C virus (HCV) encodes two glycoproteins E1 and E2 that are essential for virus entry and are the major target for neutralizing antibodies. To assess whether both glycoproteins are required for the generation of a neutralizing antibody response, rodents were immunized with a series of glycoproteins comprising full length and truncated versions. Guinea pigs immunized with HCV-1 genotype 1a E1E2p7, E1E2 or E2 generated high titer anti-glycoprotein antibody responses that neutralized the infectivity of HCVpp and HCVcc expressing gps of the same genotype as the immunizing antigen. Less potent neutralization of viruses bearing the genotype 2 strain J6 gps was observed. In contrast, immunized mice demonstrated reduced anti-gp antibody responses, consistent with their minimal neutralizing activity. Immunization with E2 alone was sufficient to induce a high titer response that neutralized HCV pseudoparticles (HCVpp) bearing diverse glycoproteins and cell culture grown HCV (HCVcc). The neutralization titer was reduced 3-fold by the presence of lipoproteins in human sera. Cross-competition of the guinea pig anti-E1E2 immune sera with a panel of epitope mapped anti-E2 monoclonal antibodies for binding E2 identified a series of epitopes within the N-terminal domain that may be immunogenic in the immunized rodents. These data demonstrate that recombinant E2 and E1E2 can induce polyclonal antibody responses with cross-reactive neutralizing activity, supporting the future development of prophylactic and therapeutic vaccines.

Cationic microparticles are a potent delivery system for a HCV DNA vaccine.

We initially evaluated in mice the ability of naked DNA encoding intracellular forms of the E1E2 envelope proteins from HCV to induce antibody responses and compared the responses induced with the same plasmid adsorbed onto cationic poly (lactide co-glycolide) (PLG) microparticles. Although naked DNA was only able to induce detectable responses at the 100 microg dose level, making this approach impractical for evaluation in larger animals, PLG/DNA induced detectable responses at 10 microg. In addition, the PLG/DNA microparticles induced significantly enhanced responses to naked DNA when compared at the same dose level. Remarkably, PLG/DNA induced comparable responses to recombinant E1E2 protein adjuvanted with the emulsion MF59. Furthermore, PLG/DNA effectively primed for a booster response with protein immunization, while naked DNA did not. Therefore, PLG/DNA was selected for further evaluation in a non-human primate model. In a study in rhesus macaques, PLG/DNA induced seroconversion in 3/3 animals following three immunizations. Although the antibody responses appeared lower than those induced with recombinant protein adjuvanted with MF59, following a fourth dose, PLG/DNA and protein induced comparable responses. However, a single booster dose of recombinant protein administered to the animals previously immunized with PLG/DNA induced much higher responses. In addition, one of three animals immunized with PLG/DNA showed a cytotoxic T lymphocyte response in peripheral blood lymphocytes. In conclusion, cationic PLG microparticles with adsorbed HCV DNA generates potent immune responses.