Smartphone-assisted guided self-help cognitive behavioral therapy for young people with distressing voices (SmartVoices): study protocol for a randomized controlled trial.

BACKGROUND The long-standing view that auditory verbal hallucinations (AVH) or hearing voices is a sign of schizophrenia has been challenged by research demonstrating that they lie on a continuum ranging from normal to pathological experience related to distress and need for care. Hearing voices is more prevalent in adolescence than in later life, and hearing voices during adolescence indicates a risk for severe psychopathology, functional impairments, and suicide later in life. While there is increasing evidence for the efficacy of cognitive behavioral therapy for voices (CBTv) in adults with schizophrenia, research on psychological treatments for youth with distressing voices has been scarce. The aim of the current study is to examine the efficacy of CBTv, delivered using smartphone-based Ecological Momentary Assessment Intervention (EMI) in a transdiagnostic sample of youth. METHODS This is a superiority randomized controlled trial comparing 8 weeks of CBTv-based EMI in addition to treatment as usual (TAU) versus TAU only. TAU covers both no treatment and any form of psychiatric/psychological treatment. In the EMI condition, participants will be prompted twice a day to complete an EMA survey, and receive one intervention proposal per assessment. One-hundred fifty-four youth aged 14-25 years with distressing voices will be recruited from psychiatric clinics, local private practices, internet forums, and advertisements in print and social media. Before and after the intervention phase, participants will undergo a 9-day EMA. Single-blinded assessments will be conducted at baseline (T0) and at 3-month (T1) and 6-month (T2) follow-up. The primary outcome is the distress dimension of the Auditory Hallucinations subscale of the Psychotic Symptom Rating Scales at T1. Secondary outcomes include perceived hostile intention, power, and dominance of voices, passive, aggressive, and assertive relating to voices, and negative core beliefs about the self. DISCUSSION Adolescence provides a crucial window of opportunity for early intervention for hearing voices. However, youth are notoriously reluctant help-seekers. This study offers a low-intensity psychological intervention for youth with distressing voices beyond diagnostic boundaries that, using a mobile technology approach, may match the treatment preferences of the generation of "digital natives." TRIAL REGISTRATION German Clinical Trials Register DRKS00026243. Registered on 2 September 2021

Malaria surveillance in the Democratic Republic of the Congo: comparison of microscopy, PCR, and rapid diagnostic test

Malaria surveillance is critical for control efforts, but diagnostic methods frequently disagree. Here we compare microscopy, PCR, and a Rapid Diagnostic Test in 7,137 samples from children in the Democratic Republic of the Congo using Latent Class Analysis. PCR had the highest sensitivity (94.6%) and microscopy had the lowest (76.7%)

Government interventions and control policies to contain the first COVID-19 outbreak: An analysis of evidence

Background: The overarching aim of this study was to evaluate the effectiveness over time of government interventions and policy restrictions and the impact of determinants on spread and mortality during the first-wave of the COVID-19 pandemic, globally, regionally and by country-income level, up to 18 May 2020. Methods: We created a global database merging World Health Organization daily case reports (from 218 countries/territories) with other socio-demographic and population health measures from 21 January to 18 May 2020. A four-level government policy interventions score (low to very high) was created based on the Oxford Stringency Index. Results: Our results support the use of very high government interventions to suppress both COVID-19 spread and mortality effectively during wave one globally compared to other policy levels of control. Similar trends in virus propagation and mortality were observed in all country-income levels and specific regions. Conclusions: Rapid implementation of government interventions was needed to contain the first wave of the COVID-19 outbreak and to reduce COVID-19-related mortality.Peer ReviewedPostprint (author's final draft

A Cross-Sectional Survey of Plasmodium falciparum pfcrt Mutant Haplotypes in the Democratic Republic of Congo

In the Democratic Republic of the Congo (DRC), artesunate-amodiaquine is first-line therapy for falciparum malaria; little is known about the prevalence of molecular markers of parasite drug resistance. Across the DRC, we genotyped 166 parasites in Plasmodium falciparum chloroquine resistance transporter (pfcrt) using polymerase chain reaction (PCR) and sequencing. Of these parasites, 73 (44%) parasites were pure wild-type CVMNK, 55 (31%) parasites were chloroquine-resistant CVIET, 35 (21.1%) parasites were mixed CVMNK and CVIET, and 3 parasites were other genotypes. Ninety-two infections (55.4%) harbored the pfcrt K76T substitution that is highly correlated with chloroquine failure. The amodiaquine-resistant SVMNT haplotype was absent. Geographically, pfcrt haplotypes were not clearly clustered. Chloroquine accounted for 19.4% of antimalarial use, and amodiaquine accounted for 15.3% of antimalarial use; there were no associations between drug use and mutant haplotype prevalence. In the DRC, our molecular survey indicates that resistance to chloroquine is substantial but that resistance to amodiaquine is absent. These contrasting findings highlight the need for molecular surveillance of drug resistance to inform malaria control policies

Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors

Aging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells (PBMCs), we first undertook transcriptional profiling and found that PBMCs isolated from old individuals (≥ 65 years) exhibited a delayed and altered response to stimulation with TLR4, TLR7/8, and RIG-I agonists compared to cells obtained from adults (≤ 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro-inflammatory and antiviral cytokines and chemokines including TNFα, IL-6, IL-1β, IFNα, IFNγ, CCL2, and CCL7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMCs from old subjects also had a lower frequency of CD40+ monocytes, impaired up-regulation of PD-L1 on monocytes and T cells, and increased expression of PD-L2 and B7-H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR-stimulated PBMCs (minus CD3 T cells) from old subjects elicited significantly lower levels of adult T-cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction (MLR). Collectively, these age-associated changes in cytokine, chemokine and interferon production, as well as co-stimulatory protein expression could contribute to the blunted memory B- and T-cell immune responses to vaccines and infections

Affinity-restricted memory B cells dominate recall responses to heterologous flaviviruses

Memory B cells (MBCs) can respond to heterologous antigens either by molding new specificities through secondary germinal centers (GCs) or selecting pre-existing clones without further affinity maturation. To distinguish these mechanisms in flavivirus infections and immunizations, we studied recall responses to envelope protein domain III (DIII). Conditional deletion of activation induced cytidine deaminase (AID) between heterologous challenges of West Nile, Japanese encephalitis, Zika, and Dengue viruses did not affect recall responses. DIII-specific MBCs were contained mostly within the plasma cell-biased CD80(+) subset and few GCs arose following heterologous boosters, demonstrating that recall responses are confined by pre-existing clonal diversity. Measurement of monoclonal antibody binding affinity to DIII proteins, timed AID deletion, single cell RNA-sequencing, and lineage tracing experiments point to selection of relatively low affinity MBCs as a mechanism to promote diversity. Engineering immunogens to avoid this MBC diversity may facilitate flavivirus type-specific vaccines with minimized potential for infection enhancement

Plasmodium falciparum sulfadoxine resistance is geographically and genetically clustered within the DR Congo

Understanding the spatial clustering of Plasmodium falciparum populations can assist efforts to contain drug-resistant parasites and maintain the efficacy of future drugs. We sequenced single nucleotide polymorphisms (SNPs) in the dihydropteroate synthase gene (dhps) associated with sulfadoxine resistance and 5 microsatellite loci flanking dhps in order to investigate the genetic backgrounds, genetic relatedness, and geographic clustering of falciparum parasites in the Democratic Republic of the Congo (DRC). Resistant haplotypes were clustered into subpopulations: one in the northeast DRC, and the other in the balance of the DRC. Network and clonal lineage analyses of the flanking microsatellites indicate that geographically-distinct mutant dhps haplotypes derive from separate lineages. The DRC is therefore a watershed for haplotypes associated with sulfadoxine resistance. Given the importance of central Africa as a corridor for the spread of antimalarial resistance, the identification of the mechanisms of this transit can inform future policies to contain drug-resistant parasite strains

Genetic Evidence of Importation of Drug-Resistant Plasmodium falciparum to Guatemala from the Democratic Republic of the Congo

Molecular markers and population genetics were effective tracking tools.Imported malaria threatens control and elimination efforts in countries that have low rates of transmission. In 2010, an outbreak of Plasmodium falciparum malaria was reported among United Nations peacekeeping soldiers from Guatemala who had recently returned from the Democratic Republic of the Congo (DRC). Epidemiologic evidence suggested that the soldiers were infected in the DRC, but local transmission could not be ruled out in all cases. We used population genetic analyses of neutral microsatellites to determine the outbreak source. Genetic relatedness was compared among parasites found in samples from the soldiers and parasite populations collected in the DRC and Guatemala; parasites identified in the soldiers were more closely related to those from the DRC. A phylogenetic clustering analysis confirms this identification with >99.9% confidence. Thus, results support the hypothesis that the soldiers likely imported malaria from the DRC. This study demonstrates the utility of molecular genotyping in outbreak investigations

The geography of malaria genetics in the Democratic Republic of Congo: A complex and fragmented landscape

Understanding how malaria parasites move between populations is important, particularly given the potential for malaria to be reintroduced into areas where it was previously eliminated. We examine the distribution of malaria genetics across seven sites within the Democratic Republic of Congo (DRC) and two nearby countries, Ghana and Kenya, in order to understand how the relatedness of malaria parasites varies across space, and whether there are barriers to the flow of malaria parasites within the DRC or across borders. Parasite DNA was retrieved from dried blood spots from 7 Demographic and Health Survey sample clusters in the DRC. Malaria genetic characteristics of parasites from Ghana and Kenya were also obtained. For each of 9 geographic sites (7 DRC, 1 Ghana and 1 Kenya), a pair-wise RST statistic was calculated, indicating the genetic distance between malaria parasites found in those locations. Mapping genetics across the spatial extent of the study area indicates a complex genetic landscape, where relatedness between two proximal sites may be relatively high (RST > 0.64) or low (RST < 0.05), and where distal sites also exhibit both high and low genetic similarity. Mantel’s tests suggest that malaria genetics differ as geographic distances increase. Principal Coordinate Analysis suggests that genetically related samples are not co-located. Barrier analysis reveals no significant barriers to gene flow between locations. Malaria genetics in the DRC have a complex and fragmented landscape. Limited exchange of genes across space is reflected in greater genetic distance between malaria parasites isolated at greater geographic distances. There is, however, evidence for close genetic ties between distally located sample locations, indicating that movement of malaria parasites and flow of genes is being driven by factors other than distance decay. This research demonstrates the contributions that spatial disease ecology and landscape genetics can make to understanding the evolutionary dynamics of infectious diseases

Malaria Transmission and Spillover across the Peru-Ecuador Border: A Spatiotemporal Analysis.

Border regions have been implicated as important hot spots of malaria transmission, particularly in Latin America, where free movement rights mean that residents can cross borders using just a national ID. Additionally, rural livelihoods largely depend on short-term migrants traveling across borders via the Amazon's river networks to work in extractive industries, such as logging. As a result, there is likely considerable spillover across country borders, particularly along the border between Peru and Ecuador. This border region exhibits a steep gradient of transmission intensity, with Peru having a much higher incidence of malaria than Ecuador. In this paper, we integrate 13 years of weekly malaria surveillance data collected at the district level in Peru and the canton level in Ecuador, and leverage hierarchical Bayesian spatiotemporal regression models to identify the degree to which malaria transmission in Ecuador is influenced by transmission in Peru. We find that increased case incidence in Peruvian districts that border the Ecuadorian Amazon is associated with increased incidence in Ecuador. Our results highlight the importance of coordinated malaria control across borders