Long-term effectiveness of Self-Help Plus in refugees and asylum seekers resettled in Western Europe: 12-month outcomes of a randomised controlled trial.

AIMS: As refugees and asylum seekers are at high risk of developing mental disorders, we assessed the effectiveness of Self-Help Plus (SH + ), a psychological intervention developed by the World Health Organization, in reducing the risk of developing any mental disorders at 12-month follow-up in refugees and asylum seekers resettled in Western Europe. METHODS: Refugees and asylum seekers with psychological distress (General Health Questionnaire-12 ⩾ 3) but without a mental disorder according to the Mini International Neuropsychiatric Interview (M.I.N.I.) were randomised to either SH + or enhanced treatment as usual (ETAU). The frequency of mental disorders at 12 months was measured with the M.I.N.I., while secondary outcomes included self-identified problems, psychological symptoms and other outcomes. RESULTS: Of 459 participants randomly assigned to SH + or ETAU, 246 accepted to be interviewed at 12 months. No difference in the frequency of any mental disorders was found (relative risk [RR] = 0.841; 95% confidence interval [CI] 0.389-1.819; p-value = 0.659). In the per protocol (PP) population, that is in participants attending at least three group-based sessions, SH + almost halved the frequency of mental disorders at 12 months compared to ETAU, however so few participants and events contributed to this analysis that it yielded a non-significant result (RR = 0.528; 95% CI 0.180-1.544; p-value = 0.230). SH + was associated with improvements at 12 months in psychological distress (p-value = 0.004), depressive symptoms (p-value = 0.011) and wellbeing (p-value = 0.001). CONCLUSIONS: The present study failed to show any long-term preventative effect of SH + in refugees and asylum seekers resettled in Western European countries. Analysis of the PP population and of secondary outcomes provided signals of a potential effect of SH + in the long-term, which would suggest the value of exploring the effects of booster sessions and strategies to increase SH + adherence.

Perception of healthcare workers on mobile app-based clinical guideline for the detection and treatment of mental health problems in primary care: a qualitative study in Nepal.

BACKGROUND: In recent years, a significant change has taken place in the health care delivery systems due to the availability of smartphones and mobile software applications. The use of mobile technology can help to reduce a number of barriers for mental health care such as providers' workload, lack of qualified personnel, geographical and attitudinal barriers to seek treatment. This study assessed the perception of Nepali primary healthcare workers about the feasibility, acceptability, and benefits of using a mobile app-based clinical guideline for mental health care. METHOD: A qualitative study was conducted in two districts Chitwan and Ramechhap of Nepal with purposively selected medical officers (n = 8) and prescribing primary healthcare workers (n = 35) who were trained in the World Health Organization mental health Gap Action Program Intervention Guide. Semi-structured interviews and focus group discussions were conducted in Nepali, audio recorded, transcribed and translated into English for data analysis. Data were analysed manually using a thematic analysis approach. RESULTS: The majority of the healthcare workers and medical officers reported a high level of interest, motivation and positive attitudes towards the mobile app-based clinical guidelines for detection and treatment of people with mental disorders in primary care. They respondents suggested that several features and functions should be included in the app: suggestive diagnosis and treatment options; clinical data recording system; sending messages to patients to promote follow-up visits; allow offline functions; minimal typing options and content to be available in Nepali language. The study participants reported that the app could help in bringing uniformity in diagnosis and management of mental disorders across all health facilities, enabling remote supervision, helping verification of health workers' diagnosis and treatment; and increasing patients' trust in the treatment. Lack of reliable internet connection in health facilities, possibility of distracting interaction between patient and provider, and confidentiality were the key factors potentially hindering the use of the app. CONCLUSION: The suggested functions and features as well as the potential risk factors highlighted by the health workers, will be considered when further developing the mobile app-based clinical guidelines, training modality and materials, and the supervision system.

Efficacy and acceptability of psychosocial interventions in asylum seekers and refugees: systematic review and meta-analysis.

AimsIn the past few years, there has been an unprecedented increase in the number of forcibly displaced migrants worldwide, of which a substantial proportion is refugees and asylum seekers. Refugees and asylum seekers may experience high levels of psychological distress, and show high rates of mental health conditions. It is therefore timely and particularly relevant to assess whether current evidence supports the provision of psychosocial interventions for this population. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the efficacy and acceptability of psychosocial interventions compared with control conditions (treatment as usual/no treatment, waiting list, psychological placebo) aimed at reducing mental health problems in distressed refugees and asylum seekers. METHODS: We used Cochrane procedures for conducting a systematic review and meta-analysis of RCTs. We searched for published and unpublished RCTs assessing the efficacy and acceptability of psychosocial interventions in adults and children asylum seekers and refugees with psychological distress. Post-traumatic stress disorder (PTSD), depressive and anxiety symptoms at post-intervention were the primary outcomes. Secondary outcomes include: PTSD, depressive and anxiety symptoms at follow-up, functioning, quality of life and dropouts due to any reason. RESULTS: We included 26 studies with 1959 participants. Meta-analysis of RCTs revealed that psychosocial interventions have a clinically significant beneficial effect on PTSD (standardised mean difference [SMD] = -0.71; 95% confidence interval [CI] -1.01 to -0.41; I2 = 83%; 95% CI 78-88; 20 studies, 1370 participants; moderate quality evidence), depression (SMD = -1.02; 95% CI -1.52 to -0.51; I2 = 89%; 95% CI 82-93; 12 studies, 844 participants; moderate quality evidence) and anxiety outcomes (SMD = -1.05; 95% CI -1.55 to -0.56; I2 = 87%; 95% CI 79-92; 11 studies, 815 participants; moderate quality evidence). This beneficial effect was maintained at 1 month or longer follow-up, which is extremely important for populations exposed to ongoing post-migration stressors. For the other secondary outcomes, we identified a non-significant trend in favour of psychosocial interventions. Most evidence supported interventions based on cognitive behavioural therapies with a trauma-focused component. Limitations of this review include the limited number of studies collected, with a relatively low total number of participants, and the limited available data for positive outcomes like functioning and quality of life. CONCLUSIONS: Considering the epidemiological relevance of psychological distress and mental health conditions in refugees and asylum seekers, and in view of the existing data on the effectiveness of psychosocial interventions, these interventions should be routinely made available as part of the health care of distressed refugees and asylum seekers. Evidence-based guidelines and implementation packages should be developed accordingly.

Translation, adaptation, and pilot of a guided self-help intervention to reduce psychological distress in South Sudanese refugees in Uganda.

BACKGROUND: In this period of unprecedented levels of displacement, scalable interventions are needed to address mental health concerns of forced migrants in low-resource settings. This paper describes the adaptation and piloting of a guided, multi-media, self-help intervention, Self-Help Plus (SH+), which was developed to reduce psychological distress in large groups of people affected by adversity. METHODS: Using a phased approach that included community consultations, cognitive interviewing, facilitator training, pilot implementation, and a qualitative process evaluation, we adapted SH+ for use among South Sudanese refugees in a refugee settlement in northern Uganda. RESULTS: The SH+ materials, including audio-recorded sessions and an accompanying illustrated manual, were translated into Juba Arabic. Cognitive interviewing primarily resulted in adaptations to language with some minor adaptations to content. Facilitator training and supervision led to further suggested changes to delivery methods. An uncontrolled pilot study (n = 65) identified changes in the expected direction on measures of psychological distress, functional impairment, depression, wellbeing, and psychological flexibility. The process evaluation resulted in further adaptations to intervention materials and the decision to focus future effectiveness evaluations of the intervention in its current form on South Sudanese female refugees. CONCLUSIONS: We found that this potentially scalable, guided self-help intervention could be adapted for and feasibly implemented among female South Sudanese refugees in northern Uganda. These findings lay the groundwork for a future rigorous evaluation of SH+ in this context.

Self Help Plus: study protocol for a cluster-randomised controlled trial of guided self-help with South Sudanese refugee women in Uganda.

BACKGROUND: Exposure to armed conflict and forced displacement constitute significant risks for mental health. Existing evidence-based psychological interventions have limitations for scaling-up in low-resource humanitarian settings. The WHO has developed a guided self-help intervention, Self Help Plus (SH+), which is brief, implemented by non-specialists, and designed to be delivered to people with and without specific mental disorders. This paper outlines the study protocol for an evaluation of the SH+ intervention in northern Uganda, with South Sudanese refugee women. METHODS: A two-arm, single-blind cluster-randomised controlled trial will be conducted in 14 villages in Rhino Camp refugee settlement, with at least 588 women experiencing psychological distress. Villages will be randomly assigned to receive either SH+ with enhanced usual care (EUC), or EUC alone. SH+ is a five-session guided self-help intervention delivered in workshops with audio-recorded materials and accompanying pictorial guide. The primary outcome is reduction in overall psychological distress over time, with 3 months post-treatment as the primary end-point. Secondary outcomes are self-defined psychosocial concerns, depression and post-traumatic stress disorder symptoms, hazardous alcohol use, feelings of anger, interethnic relations, psychological flexibility, functional impairment and subjective wellbeing. Psychological flexibility is a hypothesised mediator, and past trauma history and intervention attendance will be explored as potential moderators. DISCUSSION: This trial will provide important information on the effectiveness of a scalable, guided self-help intervention for improving psychological health and wellbeing among people affected by adversity. TRIAL REGISTRATION: ISRCTN50148022; registered 13/03/2017.

The potential of low-intensity and online interventions for depression in low- and middle-income countries.

The World Health Organization (WHO) reports that low- and middle-income countries (LMICs) are confronted with a serious 'mental health gap', indicating an enormous disparity between the number of individuals in need of mental health care and the availability of professionals to provide such care (WHO in 2010). Traditional forms of mental health services (i.e. face-to-face, individualised assessments and interventions) are therefore not feasible. We propose three strategies for addressing this mental health gap: delivery of evidence-based, low-intensity interventions by non-specialists, the use of transdiagnostic treatment protocols, and strategic deployment of technology to facilitate access and uptake. We urge researchers from all over the world to conduct feasibility studies and randomised controlled studies on the effect of low-intensity interventions and technology supported (e.g. online) interventions in LMICs, preferably using an active control condition as comparison, to ensure we disseminate effective treatments in LMICs.

Fundus-first transumbilical single-incision laparoscopic cholecystectomy with a cholangiogram: a feasibility study.

BACKGROUND: An increasing number of techniques are emerging in the literature describing single-incision laparoscopic cholecystectomy (SILC). The advent of a new surgical approach is a reminder of the increase in bile duct injuries in the past when laparoscopic cholecystectomy was first introduced. With this in mind, the authors describe a safe and reproducible approach to SILC. METHODS: Between August 2008 and August 2009, 20 patients with symptomatic gallbladder disease underwent SILC using a totally transumbilical fundus-first approach with an intraoperative cholangiogram. Data including pain scores were collected prospectively. RESULTS: In this initial series, the median operative time was 103 min (range, 55-177 min), including the time for two patients undergoing additional procedures at the time of surgery. Intraoperative cholangiograms were completed for 18 of 19 patients. Additional ports were required in four patients for safe completion of the procedure. The mean pain score 12 h postoperatively was 2.5 on a visual analogue scale with a range of 0-10. There was no morbidity or mortality. CONCLUSION: According to the findings, SILC with an intraoperative cholangiogram can be performed safely using a fundus-first approach. However, for SILC to become the operation of choice for the treatment of gallbladder disease, evidence is required to demonstrate its advantage over laparoscopic cholecystectomy.

A randomised controlled trial of cognitive behaviour therapy for psychosis in a routine clinical service.

OBJECTIVE: To evaluate cognitive behaviour therapy for psychosis (CBTp) delivered by non-expert therapists, using CBT relevant measures. METHOD: Participants (N = 74) were randomised into immediate therapy or waiting list control groups. The therapy group was offered 6 months of therapy and followed up 3 months later. The waiting list group received therapy after waiting 9 months (becoming the delayed therapy group). RESULTS: Depression improved in the combined therapy group at both the end of therapy and follow-up. Other significant effects were found in only one of the two therapy groups (positive symptoms; cognitive flexibility; uncontrollability of thoughts) or one of the two time points (end of therapy: general symptoms, anxiety, suicidal ideation, social functioning, resistance to voices; follow-up: power beliefs about voices, negative symptoms). There was no difference in costs between the groups. CONCLUSION: The only robust improvement was in depression. Nevertheless, there were further encouraging but modest improvements in both emotional and cognitive variables, in addition to psychotic symptoms.

Culture of human T cells in stirred bioreactors for cellular immunotherapy applications: shear, proliferation, and the IL-2 receptor.

Ex vivo expansion of T cells is a key step of many cellular immunotherapy protocols, which require large numbers of immune cells to eradicate malignant or virally infected cells. The use of stirred culture systems for T cell expansion offers many potential advantages over the static culture systems commonly used today, including homogeneity of culture conditions, ease of sampling, and implementation of control systems. Primary human T cells as well as the transformed TALL103/2 T cell line were cultured in 100-mL spinner flasks as well as 2-L bioreactors to investigate the effects of shear forces produced by agitation and sparging-based aeration on the expansion of T cells. Primary T cells could be successfully grown at agitation rates of up to 120 rpm in the spinner flasks and to 180 rpm in the bioreactors with no immediate detrimental effects on proliferation. Exposure to agitation and sparging did, however, cause a significantly increased rate of downregulation of the interleukin-2 receptor (IL-2R), resulting in lower overall expansion potential from a single stimulation as compared to static controls, with faster IL-2R downregulation occurring at higher agitation rates. For the primary T cells, no significant effects of agitation were found on expression levels of other key surface receptors (CD3, CD28, or CD62L) examined. No significant effects of agitation were observed on primary T cell metabolism or levels of cellular apoptosis in the cultures. The TALL103/2 T cell line was found to be extremely sensitive to agitation, showing severely reduced growth at speeds above 30 rpm in 100-mL spinner flasks. This unexpected increased fragility in the transformed T cell line as compared to primary T cells points out the importance of carefully selecting a model cell line which will accurately represent the characteristics of the cell system of interest.

Extracellular pH affects the proliferation of cultured human T cells and their expression of the interleukin-2 receptor.

Ex vivo expansion of T cells is an important aspect of many cellular immunotherapy protocols, and the effects of the culture environment on the cells must be understood to produce large numbers of functional cells. Extracellular pH is a fundamental parameter that has many different effects on cultured cells. In this study, peripheral blood mononuclear cells were stimulated with phytohemagglutinin and cultured at pH values of 7.0, 7.2, or 7.4. The effects of pH on the cells were studied during the 2 to 3 weeks of proliferation resulting from phytohemagglutinin stimulation, in order to examine the culture kinetics over realistic time scales for ex vivo expansion. The proliferation capacity of the T cells increased more than three-fold for the pH 7.0 and 7.2 cultures compared with the pH 7.4 cultures. The culture pH also affected the kinetics of the interleukin-2 receptor down-regulation process. The faster receptor down-regulation in both the pH 7.2 and 7.4 cultures resulted in a more than twofold greater fraction of interleukin-2 receptor(+) cells in the pH 7.0 cultures. Although the fraction of apoptotic cells (using the Annexin V flow-cytometric method) remained less than 10%, we observed 27% more apoptosis in the pH 7.4 cultures than in the 7.2 cultures and 49% more apoptosis in the pH 7.4 cultures than in the 7.0 cultures. These effects on interleukin-2 receptor expression and cellular apoptosis may partially explain the observed effects of pH on T-cell proliferation.

Low oxygen tension enhances the stimulation and proliferation of human T lymphocytes in the presence of IL-2.

BACKGROUND: Optimization of the culture environment for the ex vivo expansion of T cells is crucial for obtaining the large doses of cells needed for cellular immunotherapy. O2 tension is a key parameter that impacts the proliferation and quality of the expanded T cells. METHODS: Peripheral blood mononuclear cells were stimulated with either PHA or an anti-CD3 monoclonal antibody under 5% (low) or 20% (high) O2 atmospheres. After stimulation, cells were cultured in the presence of IL-2 under either low or high O2 conditions. RESULTS: T cells stimulated and grown under 5% O2 exhibited higher proliferation rates and a mean (n = 11) of 5.8-fold greater total expansion over T cells grown under 20% O2. Stimulation under 5% O2 produced a lasting proliferative effect even after a switch to 20% O2. Examination of apoptosis by the flow cytometry-based TUNEL assay showed a mean (n = 9) of 2.9-fold greater percentage of apoptotic cells under 20% O(2). Flow-cytometric analysis of the IL-2 receptor (CD25) showed that the normal downregulation kinetics - following stimulation-induced CD25 upregulation - were slowed under 5% O(2), such that the 5% O2 cultures had a greater number of CD25+ cells, and those CD25+ cells expressed an average (n = 6) of 41% higher levels of CD25 receptor per cell. No significant O2 tension effects were observed on other surface antigens (CD3, CD28, and CD62L) examined. The key metabolic parameters, specific glucose uptake rate, q(glu), and specific lactate production rate, q(lac), were both increased by a mean (n = 5) of 47% under 5% O2. DISCUSSION: Beyond the physiological significance, improved T-cell proliferation under 5% O2 would allow for decreased culture times in expanding T cells for cellular immunotherapies. Evidence of increased IL-2R expression and reduced apoptosis levels under 5% O2 may help explain this phenomenon.

A matrixed approach to long-term stability testing of pharmaceutical products.

A matrixed approach to long-term stability testing of pharmaceutical products is presented. The basic matrix design, suitable for testing three lots at one storage condition, may be extended to multiple product presentations or storage conditions. The design has full testing at the endpoints (0 and 36 months) and partial testing at the interim time points (3, 6, 9, 12, 18, and 24 months). The test points were selected with the assistance of a statistical search algorithm. The proposed matrix design provides a 37.5% reduction in analytical testing, while still permitting a reliable interim expiry estimate based on 12-month stability data. The expiration dating periods estimated using the matrixed approach are typically more conservative than estimates derived from a full-testing approach. A comparison of expiration dating period estimates for a metered-dose inhaler and capsule drug product using the matrixed and full-testing approaches is presented.

Mineralization of biphenyl and PCBs by the white rot fungus Phanerochaete chrysosporium.

The white rot fungus Phanerochaete chrysosporium is unique in its ability to totally degrade a wide variety of recalcitrant pollutants. We have investigated the degradation of biphenyl and two model chlorinated biphenyls, 2,2',4,4'-tetrachlorobiphenyl and 2-chlorobiphenyl by suspended cultures of P. chrysosporium grown under conditions that maximize the synthesis of lignin-oxidizing enzymes. Radiolabeled biphenyl and 2'-chlorobiphenyl added to cultures at concentrations in the range 260 nM to 8.8 microM were degraded extensively to CO(2) within 30 days. In addition, from 40% to 60% of the recovered radioactivity was found in water-soluble compounds. A correlation between the rate of degradation and the synthesis of ligninases or Mn-dependent peroxidases could not be observed, indicating that yet unknown enzymatic system may be responsible for the initial oxidation of PCBs. The more heavily chlorinated PCB congener, 2,2',4,4'-tetrachlorobiphenyl was converted to CO(2) less readily; approximately 9% and 0.9% mineralization was observed in cultures incubated with 40 nM and 5.3 microM, respectively. Overall, our results indicate that P. chrysosporium is a promising organism for the treatment of wastes contaminated with lightly and moderately chlorinated PCBs.