Determinants of label non-adherence to non-vitamin K oral anticoagulants in patients with newly diagnosed atrial fibrillation.

Aims: To evaluate the extent and determinants of off-label non-vitamin K oral anticoagulant (NOAC) dosing in newly diagnosed Dutch AF patients. Methods and results: In the DUTCH-AF registry, patients with newly diagnosed AF (<6 months) are prospectively enrolled. Label adherence to NOAC dosing was assessed using the European Medicines Agency labelling. Factors associated with off-label dosing were explored by multivariable logistic regression analyses. From July 2018 to November 2020, 4500 patients were registered. The mean age was 69.6 ± 10.5 years, and 41.5% were female. Of the 3252 patients in which NOAC label adherence could be assessed, underdosing and overdosing were observed in 4.2% and 2.4%, respectively. In 2916 (89.7%) patients with a full-dose NOAC recommendation, 4.6% were underdosed, with a similar distribution between NOACs. Independent determinants (with 95% confidence interval) were higher age [odds ratio (OR): 1.01 per year, 1.01-1.02], lower renal function (OR: 0.96 per ml/min/1.73 m2, 0.92-0.98), lower weight (OR: 0.98 per kg, 0.97-1.00), active malignancy (OR: 2.46, 1.19-5.09), anaemia (OR: 1.73, 1.08-2.76), and concomitant use of antiplatelets (OR: 4.93, 2.57-9.46). In the 336 (10.3%) patients with a reduced dose NOAC recommendation, 22.9% were overdosed, most often with rivaroxaban. Independent determinants were lower age (OR: 0.92 per year, 0.88-0.96) and lower renal function (OR: 0.98 per ml/min/1.73 m2, 0.96-1.00). Conclusion: In newly diagnosed Dutch AF patients, off-label dosing of NOACs was seen in only 6.6% of patients, most often underdosing. In this study, determinants of off-label dosing were age, renal function, weight, anaemia, active malignancy, and concomitant use of antiplatelets.

Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Genetic determinants of multiple myeloma risk within the Wnt/beta-catenin signaling pathway.

BACKGROUND: Aberrant Wnt/beta-catenin pathway activation is implicated in Multiple Myeloma (MM) development, but little is known if genetic variants within this pathway contribute to MM susceptibility. METHODS: We performed a discovery candidate pathway analysis in 269 non-Hispanic white MM cases and 272 controls focusing on 171 variants selected from 26 core genes within the Wnt/beta-catenin pathway. Significant candidate variants (P < 0.05) were selected for validation in internal and external non-Hispanic white populations totaling 818 cases and 1209 controls. We also examined significant variants in non-Hispanic black and Hispanic case/control study populations to identify potential differences by race/ethnicity. Possible biological functions of candidate variants were predicted in silico. RESULTS: Seven variants were significantly associated with MM risk in non-Hispanic whites in the discovery population, of which LRP6:rs7966410 (OR: 0.57; 95 % CI: 0.38-0.88; P = 9.90 × 10-3) and LRP6:rs7956971 (OR: 0.64; 95 % CI: 0.44-0.95; P = 0.027) remained significant in the internal and external populations. CSNK1D:rs9901910 replicated among all three racial/ethnic groups, with 2-6 fold increased risk of MM (OR: 2.40; 95 % CI: 1.67-3.45; P = 2.43 × 10-6 - non-Hispanic white; OR: 6.42; 95 % CI: 2.47-16.7; P = 3.14 × 10-4 - non-Hispanic black; OR: 4.31; 95 % CI: 1.83-10.1; P = 8.10 × 10-4 - Hispanic). BTRC:rs7916830 was associated with a significant 37 % and 24 % reduced risk of MM in the non-Hispanic white (95 % CI: 0.49-0.82; P = 5.60 × 10-4) and non-Hispanic Black (95 % CI: 0.60-0.97; P = 0.028) population, respectively. In silico tools predicted that these loci altered function through via gene regulation. CONCLUSION: We identified several variants within the Wnt/beta-catenin pathway associated with MM susceptibility. Findings of this study highlight the potential genetic role of Wnt/beta-catenin signaling in MM etiology among a diverse patient population.

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

Mental health impact on the unmet need for family planning and fertility rate in rural Ethiopia: a population-based cohort study.

AIMS: Although much research has focused on socio-demographic determinants of uptake of contraception, few have studied the impact of poor mental health on women's reproductive behaviours. The aim of this study was to examine the impact of poor mental health on women's unmet need for contraception and fertility rate in a low-income country setting. METHODS: A population-based cohort of 1026 women recruited in their third trimester of pregnancy in the Butajira district in rural Ethiopia was assessed for symptoms of antenatal common mental disorders (CMDs; depression and anxiety) using Self-Reporting Questionnaire-20. Women were followed up regularly until 6.5 years postnatal (between 2005 and 2012). We calculated unmet need for contraception at 1 year (n = 999), 2.5 (n = 971) and 3.5 years (n = 951) post-delivery of index child and number of pregnancies during study period. We tested the association between CMD symptoms, unmet need for contraception and fertility rate. RESULTS: Less than one-third of women reported current use of contraception at each time point. Unmet need for birth spacing was higher at 1 year postnatal, with over half of women (53.8%) not using contraception wanting to wait 2 or more years before becoming pregnant. Higher CMD symptoms 1 year post-index pregnancy were associated with unmet need for contraception at 2.5 years postnatal in the unadjusted [odds ratio (OR) 1.09; 95% confidence interval (CI) 1.04-1.15] and fully adjusted model [OR 1.06; 95% CI 1.01-1.12]. During the 6.5 year cohort follow-up period, the mean number of pregnancies per woman was 2.4 (s.d. 0.98). There was no prospective association between maternal CMD and number of pregnancies in the follow-up period. CONCLUSIONS: CMD symptoms are associated with increased unmet need for family planning in this cohort of women with high fertility and low contraceptive use in rural Ethiopia. There is a lack of models of care promoting integration of mental and physical health in the family planning setting and further research is necessary to study the burden of preconception mental health conditions and how these can be best addressed.

Patterns of racial/ethnic disparities in baseline health-related quality of life and relationship with overall survival in patients with colorectal cancer.

PURPOSE: Racial disparities are evident in colorectal cancer (CRC) prognosis with black patients experiencing worse outcomes than Hispanics and whites, yet mediators of these disparities are not fully known. The aim of this study is to identify variables that contribute to racial/ethnic disparities in health-related quality of life (HR-QoL) and overall survival in CRC. METHODS: Using SF-12 questionnaires, we assessed HR-QoL in 1132 CRC patients by calculating their physical (PCS) and mental composite summary (MCS) scores. Associations between poor PCS/MCS and sociodemographic factors were estimated and survival differences were identified by race/ethnicity. RESULTS: Hispanic patients who never married were at greater risk of poor PCS (OR 2.69; 95% CI 1.11-6.49; P = 0.028) than were currently married patients. College education was associated with a decreased risk of poor PCS in Hispanic and white, but not black, patients. Gender was significantly associated with poor MCS among white patients only. CRC patients who reported a poor PCS or MCS had poor survival, with differences in median survival times (MSTs) by race. The effect of PCS was strongest in white CRC patients with a difference in overall MST of > 116 months between those with favorable versus poor physical HR-QoL. Black patients who reported poor Physical and Mental HR-QoL showed significant risk of a poor outcome. CONCLUSION: These findings suggest that racial/ethnic disparities in CRC survival may be related to differences in HR-QoL. Identified mediators of HR-QoL could supplement current CRC management strategies to improve patients' survival.

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.

Is depression associated with pathways to care and diagnosis delay in people with tuberculosis in Ethiopia?

BACKGROUND: Co-morbid depression is common in people with tuberculosis (TB). Symptoms of depression (low energy, impaired concentration, decreased motivation and hopelessness) may affect help-seeking; however, this impact has not been studied so far. The objectives of this study were to assess the impact of co-morbid depression on diagnostic delay, pathways to care, and to identify if it mediates other factors associated with diagnostic delay. METHODS: We analyzed cross-sectional data collected from 592 adults with newly diagnosed TB. We assessed probable depression using Patient Health Questionnaire, nine items (PHQ-9) at a cut-off 10. Data on diagnosis delay, pathways to TB care, socio-demographic variables, stigma, types of TB, substance use, co-morbid chronic illnesses, and perception about TB were assessed using a structured questionnaire. Generalized structural equation modelling was used to analyze the data. RESULTS: A total of 313 (52.9%) participants had probable depression. Pathway to TB care was direct for 512 (86.5%) of the participants and indirect for 80 (13.5%) of them. The median diagnosis delay was 12.0 weeks. Depression did not have a statistically significant association with pathways to TB care (ß = -0.45; 95% CI-1.85 to 0.96) or diagnostic delay [adjusted odds ratio (AOR) = 0.90; 0.77-1.06]. Indirect pathway to TB care was positively associated with diagnosis delay (AOR = 2.72; 95% CI 1.25-5.91). CONCLUSIONS: People with TB who had co-morbid probable depression visited the modern health care as directly as and as soon as those without co-morbid depression. How socio-demographic factors influence pathways to care and diagnosis delay require qualitative exploration.

Evaluating capacity-building for mental health system strengthening in low- and middle-income countries for service users and caregivers, service planners and researchers.

Efforts to support the scale-up of integrated mental health care in low- and middle-income countries (LMICs) need to focus on building human resource capacity in health system strengthening, as well as in the direct provision of mental health care. In a companion editorial, we describe a range of capacity-building activities that are being implemented by a multi-country research consortium (Emerald: Emerging mental health systems in low- and middle-income countries) for (1) service users and caregivers, (2) service planners and policy-makers and (3) researchers in six LMICs (Ethiopia, India, Nepal, Nigeria, South Africa and Uganda). In this paper, we focus on the methodology being used to evaluate the impact of capacity-building in these three target groups. We first review the evidence base for approaches to evaluation of capacity-building, highlighting the gaps in this area. We then describe the adaptation of best practice for the Emerald capacity-building evaluation. The resulting mixed method evaluation framework was tailored to each target group and to each country context. We identified a need to expand the evidence base on indicators of successful capacity-building across the different target groups. To address this, we developed an evaluation plan to measure the adequacy and usefulness of quantitative capacity-building indicators when compared with qualitative evaluation. We argue that evaluation needs to be an integral part of capacity-building activities and that expertise needs to be built in methods of evaluation. The Emerald evaluation provides a potential model for capacity-building evaluation across key stakeholder groups and promises to extend understanding of useful indicators of success.

Developing capacity-building activities for mental health system strengthening in low- and middle-income countries for service users and caregivers, service planners, and researchers.

There is increasing international recognition of the need to build capacity to strengthen mental health systems. This is a fundamental goal of the 'Emerging mental health systems in low- and middle-income countries' (Emerald) programme, which is being implemented in six low- and middle-income countries (LMICs) (Ethiopia, India, Nepal, Nigeria, South Africa, Uganda). This paper discusses Emerald's capacity-building approaches and outputs for three target groups in mental health system strengthening: (1) mental health service users and caregivers, (2) service planners and policy-makers, and (3) mental health researchers. When planning the capacity-building activities, the approach taken included a capabilities/skills matrix, needs assessments, a situational analysis, systematic reviews, qualitative interviews and stakeholder meetings, as well as the application of previous theory, evidence and experience. Each of the Emerald LMIC partners was found to have strengths in aspects of mental health system strengthening, which were complementary across the consortium. Furthermore, despite similarities across the countries, capacity-building interventions needed to be tailored to suit the specific needs of individual countries. The capacity-building outputs include three publicly and freely available short courses/workshops in mental health system strengthening for each of the target groups, 27 Masters-level modules (also open access), nine Emerald-linked PhD students, two MSc studentships, mentoring of post-doctoral/mid-level researchers, and ongoing collaboration and dialogue with the three groups. The approach taken by Emerald can provide a potential model for the development of capacity-building activities across the three target groups in LMICs.

Service user and caregiver involvement in mental health system strengthening in low- and middle-income countries: a cross-country qualitative study.

AIMS: The aims of this paper are to: (i) explore the experiences of involvement of mental health service users, their caregivers, mental health centre heads and policy makers in mental health system strengthening in three low- and middle-income countries (LMICs) (Ethiopia, Nepal and Nigeria); (ii) analyse the potential benefits and barriers of such involvement; and (iii) identify strategies required to achieve greater service user and caregiver participation. METHODS: A cross-country qualitative study was conducted, interviewing 83 stakeholders of mental health services. RESULTS: Our analysis showed that service user and caregiver involvement in the health system strengthening process was an alien concept for most participants. They reported very limited access to direct participation. Stigma and poverty were described as the main barriers for involvement. Several strategies were identified by participants to overcome existing hurdles to facilitate service user and caregiver involvement in the mental health system strengthening process, such as support to access treatment, mental health promotion and empowerment of service users. This study suggests that capacity building for service users, and strengthening of user groups would equip them to contribute meaningfully to policy development from informed perspectives. CONCLUSION: Involvement of service users and their caregivers in mental health decision-making is still in its infancy in LMICs. Effective strategies are required to overcome existing barriers, for example making funding more widely available for Ph.D. studies in participatory research with service users and caregivers to develop, implement and evaluate approaches to involvement that are locally and culturally acceptable in LMICs.

Adapting the Bayley Scales of infant and toddler development in Ethiopia: evaluation of reliability and validity.

BACKGROUND: There is a need for valid and reliable observational measures of early child development in low-income and middle-income country settings. METHODS: The aims of the study were to adapt the Bayley Scales of Infant Development (Bayley III) for a rural Ethiopian setting and evaluate reliability and validity. The study was carried out between January 2008 and January 2009 in the Butajira demographic surveillance site, south central Ethiopia. The Bayley III was adapted to be socioculturally appropriate for a rural Ethiopian context. Nurses and high school graduates were trained in administration of the measure for 10 days. Inter-rater reliability was evaluated (n = 60). Content, construct and convergent validity was then examined on a population-based cohort of children at the ages of 30 (n = 440) and 42 months (n = 456). Mokken scale analysis was used to determine the scalability of items in unidimensional, hierarchical sub-scales. The mean score was compared by age of child and by stunting status (less than -2 z scores below the standard height-for-age). RESULTS: The intra-class correlations between raters were above 0.90 for all sub-scales of the child development measure. Some scale items were not contextually relevant and showed poor scalability. However, the majority of items scaled onto the existing sub-scales of the international measure to form adequate-to-strong hierarchical scales with good internal consistency (Cronbach's α above 0.70 except for gross motor and expressive language sub-scales). Item-scale coefficients were good. The mean score of all sub-scales was significantly higher in the older group of children (33.02 higher total score; P < 0.001) and in the children who were stunted (total Bayley score 2.58 (95% confidence interval 0.07 to 5.10) points lower at 30 months and 3.87 (1.94 to 5.81) points lower at 42 months. CONCLUSIONS: An adapted version of an international, observational measure of child development was found to be reliable, valid and feasible in a rural Ethiopian setting.

Developing mental health research in sub-Saharan Africa: capacity building in the AFFIRM project.

BACKGROUND: There remains a large disparity in the quantity, quality and impact of mental health research carried out in sub-Saharan Africa, relative to both the burden and the amount of research carried out in other regions. We lack evidence on the capacity-building activities that are effective in achieving desired aims and appropriate methodologies for evaluating success. METHODS: AFFIRM was an NIMH-funded hub project including a capacity-building program with three components open to participants across six countries: (a) fellowships for an M.Phil. program; (b) funding for Ph.D. students conducting research nested within AFFIRM trials; (c) short courses in specialist research skills. We present findings on progression and outputs from the M.Phil. and Ph.D. programs, self-perceived impact of short courses, qualitative data on student experience, and reflections on experiences and lessons learnt from AFFIRM consortium members. RESULTS: AFFIRM delivered funded research training opportunities to 25 mental health professionals, 90 researchers and five Ph.D. students across 6 countries over a period of 5 years. A number of challenges were identified and suggestions for improving the capacity-building activities explored. CONCLUSIONS: Having protected time for research is a barrier to carrying out research activities for busy clinicians. Funders could support sustainability of capacity-building initiatives through funds for travel and study leave. Adoption of a train-the-trainers model for specialist skills training and strategies for improving the rigor of evaluation of capacity-building activities should be considered.

Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer.

Breast tumors in (FVB × BALB-NeuT) F1 mice have characteristic loss of chromosome 4 and sporadic loss or gain of other chromosomes. We employed the Illumina GoldenGate genotyping platform to quantitate loss of heterozygosity (LOH) across the genome of primary tumors, revealing strong biases favoring chromosome 4 alleles from the FVB parent. While allelic bias was not observed on other chromosomes, many tumors showed concerted LOH (C-LOH) of all alleles of one or the other parent on sporadic chromosomes, a pattern consistent with cytogenetic observations. Surprisingly, comparison of LOH in tumor samples relative to normal unaffected tissues from these animals revealed significant variegated (stochastic) deviations from heterozygosity (V-LOH) in every tumor genome. Sequence analysis showed expected changes in the allelic frequency of single nucleotide polymorphisms (SNPs) in cases of C-LOH. However, no evidence of LOH due to mutations, small deletions, or gene conversion at the affected SNPs or surrounding DNA was found at loci with V-LOH. Postulating an epigenetic mechanism contributing to V-LOH, we tested whether methylation of template DNA impacts allele detection efficiency using synthetic oligonucleotide templates in an assay mimicking the GoldenGate genotyping format. Methylated templates were systematically over-scored, suggesting that the observed patterns of V-LOH may represent extensive epigenetic DNA modifications across the tumor genomes. As most of the SNPs queried do not contain standard (CpG) methylation targets, we propose that widespread, non-canonical DNA modifications occur during Her2/neuT-driven tumorigenesis.

ASXL1 mutations are frequent and prognostically detrimental in CSF3R-mutated chronic neutrophilic leukemia.

Colony stimulating factor 3 receptor gene (CSF3R) mutations have recently been associated with chronic neutrophilic leukemia (CNL). Fourteen patients with CSF3R-mutated CNL (median age 67 years; 57% males) were screened for additional mutations; 8 (57%) and 5 (38%) harbored an ASXL1 and/or SETBP1 mutation (two patients expressed both), respectively. Two patients developed blastic transformation, both SETBP1-mutated and ASXL1-unmutated, whereas two other cases evolved into chronic myelomonocytic leukemia (CMML), both ASXL1-mutated and SETBP1-unmutated. Median survival was 23.2 months (10 deaths documented). On multivariable analysis mutated ASXL1 (P = 0.009; HR 19.6, 95% CI 2.1-184.1) and thrombocytopenia (P = 0.005; HR 28.8, 95% CI 2.8-298.2) were independently predictive of shortened survival. This study provides information on the natural history of CSF3R-mutated CNL and identifies mutant ASXL1 and thrombocytopenia as risk factors for survival. The study also suggests pathogenetic roles for SETBP1 and ASXL1 mutations in disease evolution into blast phase disease and CMML, respectively.

Generating evidence to narrow the treatment gap for mental disorders in sub-Saharan Africa: rationale, overview and methods of AFFIRM.

There is limited evidence on the acceptability, feasibility and cost-effectiveness of task-sharing interventions to narrow the treatment gap for mental disorders in sub-Saharan Africa. The purpose of this article is to describe the rationale, aims and methods of the Africa Focus on Intervention Research for Mental health (AFFIRM) collaborative research hub. AFFIRM is investigating strategies for narrowing the treatment gap for mental disorders in sub-Saharan Africa in four areas. First, it is assessing the feasibility, acceptability and cost-effectiveness of task-sharing interventions by conducting randomised controlled trials in Ethiopia and South Africa. The AFFIRM Task-sharing for the Care of Severe mental disorders (TaSCS) trial in Ethiopia aims to determine the acceptability, affordability, effectiveness and sustainability of mental health care for people with severe mental disorder delivered by trained and supervised non-specialist, primary health care workers compared with an existing psychiatric nurse-led service. The AFFIRM trial in South Africa aims to determine the cost-effectiveness of a task-sharing counselling intervention for maternal depression, delivered by non-specialist community health workers, and to examine factors influencing the implementation of the intervention and future scale up. Second, AFFIRM is building individual and institutional capacity for intervention research in sub-Saharan Africa by providing fellowship and mentorship programmes for candidates in Ethiopia, Ghana, Malawi, Uganda and Zimbabwe. Each year five Fellowships are awarded (one to each country) to attend the MPhil in Public Mental Health, a joint postgraduate programme at the University of Cape Town and Stellenbosch University. AFFIRM also offers short courses in intervention research, and supports PhD students attached to the trials in Ethiopia and South Africa. Third, AFFIRM is collaborating with other regional National Institute of Mental Health funded hubs in Latin America, sub-Saharan Africa and south Asia, by designing and executing shared research projects related to task-sharing and narrowing the treatment gap. Finally, it is establishing a network of collaboration between researchers, non-governmental organisations and government agencies that facilitates the translation of research knowledge into policy and practice. This article describes the developmental process of this multi-site approach, and provides a narrative of challenges and opportunities that have arisen during the early phases. Crucial to the long-term sustainability of this work is the nurturing and sustaining of partnerships between African mental health researchers, policy makers, practitioners and international collaborators.

Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis.

Janus kinase 2 (JAK2) mutations define polycythemia vera (PV). Calreticulin (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations are specific to JAK2-unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF). We examined the effect of these mutations on long-term disease outcome. One thousand five hundred eighty-one patients from the Mayo Clinic (n = 826) and Italy (n = 755) were studied. Fifty-eight percent of Mayo patients were followed until death; median survivals were 19.8 years in ET (n = 292), 13.5 PV (n = 267; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.2), and 5.9 PMF (n = 267; HR, 4.5; 95% CI, 3.5-5.7). The survival advantage of ET over PV was not affected by JAK2/CALR/MPL mutational status. Survival in ET was inferior to the age- and sex-matched US population (P < .001). In PMF (n = 428), but not in ET (n = 576), survival and blast transformation (BT) were significantly affected by mutational status; outcome was best in CALR-mutated and worst in triple-negative patients: median survival, 16 vs 2.3 years (HR, 5.1; 95% CI, 3.2-8.0) and BT, 6.5% vs 25% (HR, 7.6; 95% CI, 2.8-20.2), respectively. We conclude that life expectancy in morphologically defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status. In PMF, JAK2/CALR/MPL mutational status is prognostically informative.

Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients.

CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n = 402) and validation (n = 625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P = 0.005) and younger age with type-2 (P = 0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P = 0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P = 0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis.

Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children.

BACKGROUND: Epidemiological studies have suggested that gastro-intestinal infections including Helicobacter pylori, intestinal microflora (commensal bacteria) and geohelminths may influence the risk of asthma and allergy but data from early life are lacking. OBJECTIVE: We aimed to determine the independent effects of these infections on allergic disease symptoms and sensitization in an Ethiopian birth cohort. METHODS: In 2008/09, 878 children (87% of the 1006 original singletons in a population-based birth cohort) were followed up at age 3 and interview data obtained on allergic symptoms and potential confounders. Allergen skin tests to Dermatophagoides pteronyssinus and cockroach were performed, levels of Der p 1 and Bla g 1 in the child's bedding measured and stool samples analysed for geohelminths and, in a random subsample, enterococci, lactobacilli, bifidobacteria and H. pylori antigen. The independent effects of each exposure on wheeze, eczema, hayfever and sensitization were determined using multiple logistic regression. RESULTS: Children were commonly infected with H. pylori (41%; 253/616), enterococci (38.1%; 207/544), lactobacilli (31.1%; 169/544) and bifidobacteria (18.9%; 103/544) whereas geohelminths were only found in 8.5% (75/866). H. pylori infection was associated with a borderline significant reduced risk of eczema (adjusted OR 0.49, 95% CI 0.24-1.01, P=0.05) and D. pteronyssinus sensitization (adjusted OR 0.42, 95% CI 0.17-1.08, P=0.07). Geohelminths and intestinal microflora were not significantly associated with any of the outcomes measured. CONCLUSION AND CLINICAL RELEVANCE: Among young children in a developing country, we found evidence to support the hypothesis of a protective effect of H. pylori infection on the risk of allergic disease. Further investigation of the mechanism of this effect is therefore of potential therapeutic and preventive value.