RESUMEN
BACKGROUND: Plasmodium falciparum malaria is a leading cause of pediatric morbidity and mortality in holoendemic transmission areas. Severe malarial anemia [SMA, hemoglobin (Hb) < 5.0 g/dL in children] is the most common clinical manifestation of severe malaria in such regions. Although innate immune response genes are known to influence the development of SMA, the role of natural killer (NK) cells in malaria pathogenesis remains largely undefined. As such, we examined the impact of genetic variation in the gene encoding a primary NK cell receptor, natural cytotoxicity-triggering receptor 3 (NCR3), on the occurrence of malaria and SMA episodes over time. METHODS: Susceptibility to malaria, SMA, and all-cause mortality was determined in carriers of NCR3 genetic variants (i.e., rs2736191:C > G and rs11575837:C > T) and their haplotypes. The prospective observational study was conducted over a 36 mos. follow-up period in a cohort of children (n = 1,515, aged 1.9-40 mos.) residing in a holoendemic P. falciparum transmission region, Siaya, Kenya. RESULTS: Poisson regression modeling, controlling for anemia-promoting covariates, revealed a significantly increased risk of malaria in carriers of the homozygous mutant allele genotype (TT) for rs11575837 after multiple test correction [Incidence rate ratio (IRR) = 1.540, 95% CI = 1.114-2.129, P = 0.009]. Increased risk of SMA was observed for rs2736191 in children who inherited the CG genotype (IRR = 1.269, 95% CI = 1.009-1.597, P = 0.041) and in the additive model (presence of 1 or 2 copies) (IRR = 1.198, 95% CI = 1.030-1.393, P = 0.019), but was not significant after multiple test correction. Modeling of the haplotypes revealed that the CC haplotype had a significant additive effect for protection against SMA (i.e., reduced risk for development of SMA) after multiple test correction (IRR = 0.823, 95% CI = 0.711-0.952, P = 0.009). Although increased susceptibility to SMA was present in carriers of the GC haplotype (IRR = 1.276, 95% CI = 1.030-1.581, P = 0.026) with an additive effect (IRR = 1.182, 95% CI = 1.018-1.372, P = 0.029), the results did not remain significant after multiple test correction. None of the NCR3 genotypes or haplotypes were associated with all-cause mortality. CONCLUSIONS: Variation in NCR3 alters susceptibility to malaria and SMA during the acquisition of naturally-acquired malarial immunity. These results highlight the importance of NK cells in the innate immune response to malaria.
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Anemia , Malaria Falciparum , Malaria , Humanos , Niño , Anemia/genética , Genotipo , Malaria Falciparum/genética , Alelos , Receptor 3 Gatillante de la Citotoxidad NaturalRESUMEN
BACKGROUND: Epstein Barr virus (EBV)-associated endemic Burkitt's Lymphoma pediatric cancer is associated with morbidity and mortality among children resident in holoendemic Plasmodium falciparum regions in western Kenya. P. falciparum exerts strong selection pressure on sickle cell trait (SCT), alpha thalassemia (-α3.7/αα), glucose-6-phosphate dehydrogenase (G6PD), and merozoite surface protein 2 (MSP-2) variants (FC27, 3D7) that confer reduced malarial disease severity. The current study tested the hypothesis that SCT, (-α3.7/αα), G6PD mutation and (MSP-2) variants (FC27, 3D7) are associated with an early age of EBV acquisition. METHODS: Data on infant EBV infection status (< 6 and ≥ 6-12 months of age) was abstracted from a previous longitudinal study. Archived infant DNA (n = 81) and mothers DNA (n = 70) samples were used for genotyping hemoglobinopathies and MSP-2. The presence of MSP-2 genotypes in maternal DNA samples was used to indicate infant in-utero malarial exposure. Genetic variants were determined by TaqMan assays or standard PCR. Group differences were determined by Chi-square or Fisher's analysis. Bivariate regression modeling was used to determine the relationship between the carriage of genetic variants and EBV acquisition. RESULTS: EBV acquisition for infants < 6 months was not associated with -α3.7/αα (OR = 1.824, P = 0.354), SCT (OR = 0.897, P = 0.881), or G6PD [Viangchan (871G > A)/Chinese (1024 C > T) (OR = 2.614, P = 0.212)] and [Union (1360 C > T)/Kaiping (1388G > A) (OR = 0.321, P = 0.295)]. There was no relationship between EBV acquisition and in-utero exposure to either FC27 (OR = 0.922, P = 0.914) or 3D7 (OR = 0.933, P = 0.921). In addition, EBV acquisition in infants ≥ 6-12 months also showed no association with -α3.7/αα (OR = 0.681, P = 0.442), SCT (OR = 0.513, P = 0.305), G6PD [(Viangchan (871G > A)/Chinese (1024 C > T) (OR = 0.640, P = 0.677)], [Mahidol (487G > A)/Coimbra (592 C > T) (OR = 0.948, P = 0.940)], [(Union (1360 C > T)/Kaiping (1388G > A) (OR = 1.221, P = 0.768)], African A (OR = 0.278, P = 0.257)], or in utero exposure to either FC27 (OR = 0.780, P = 0.662) or 3D7 (OR = 0.549, P = 0.241). CONCLUSION: Although hemoglobinopathies (-α3.7/αα, SCT, and G6PD mutations) and in-utero exposure to MSP-2 were not associated with EBV acquisition in infants 0-12 months, novel G6PD variants were discovered in the population from western Kenya. To establish that the known and novel hemoglobinopathies, and in utero MSP-2 exposure do not confer susceptibility to EBV, future studies with larger sample sizes from multiple sites adopting genome-wide analysis are required.
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Infecciones por Virus de Epstein-Barr , Hemoglobinopatías , Malaria Falciparum , Malaria , Niño , Animales , Humanos , Lactante , Herpesvirus Humano 4/genética , Merozoítos , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/genética , Kenia/epidemiología , Malaria/epidemiología , Malaria/genética , Polimorfismo GenéticoRESUMEN
This commentary presents a virtual special issue on the global growth of community psychology (CP), particularly, but not exclusively, as reflected in the American Journal of Community Psychology (AJCP). CP exists in at least 50 countries all over the world, in many of those for over 25 years. Yet, aside from several early Israeli articles, AJCP rarely published work from or about countries outside the US and Canada until the early 2000s, when the number of international articles began to rise sharply. The focus of CP developed differently in different continents. CP in Australia and New Zealand initially followed North America's emphasis on improving social service systems, but has since focused more on environmental and indigenous cultural and decolonial issues that are as salient in those countries as in North America, but have drawn much more attention. CP came later to most of Asia, where it also tended to follow the North American path, but starting in Japan, India, and Hong Kong and now in China and elsewhere, it is establishing its own way. The other two global hotspots for CP for over 40 years have been Europe and Latin America. The level and focus of CP in Europe varies in each country, with some focused on applied developmental psychology and/or community services and others advancing critical and liberation psychology. CP in Latin America evolved from social psychology, but like CP in Sub-Saharan Africa, is also more explicitly political due to a history of political oppression, social activism, and the limitations of individualistic psychology to focus on social change, overcoming poverty, and interventions by (not just for) community members. Despite those differences, CP literature over the past 23 years suggests an increasingly common interest in social justice, multinational collaborations, and decoloniality. There is still a need for more truly (bidirectional) cross-cultural, comparative work for mutual learning, sharing of ideas, methods, and intervention practices, and for CP to develop in countries and communities throughout the globe where it could have the greatest impact.
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Psicología Social , Psicología , Estados Unidos , Humanos , América Latina , América del Norte , Europa (Continente) , CanadáRESUMEN
Leishmaniasis is an infectious disease caused by parasites of the genus Leishmania and transmitted by the bite of a sand fly. To date, most available drugs for treatment are toxic and beyond the economic means of those affected by the disease. Protein disulfide isomerase (PDI) is a chaperone protein that plays a major role in the folding of newly synthesized proteins, specifically assisting in disulfide bond formation, breakage, or rearrangement in all non-native proteins. In previous work, we demonstrated that Leishmania major PDI (LmPDI) has an essential role in pathogen virulence. Furthermore, inhibition of LmPDI further blocked parasite infection in macrophages. In this study, we utilized a computer-aided approach to design a series of LmPDI inhibitors. Fragment-based virtual screening allowed for the understanding of the inhibitors' modes of action on LmPDI active sites. The generated compounds obtained after multiple rounds of virtual screening were synthesized and significantly inhibited target LmPDI reductase activity and were shown to decrease in vitro parasite growth in human monocyte-derived macrophages. This novel cheminformatics and synthetic approach led to the identification of a new series of compounds that might be optimized into novel drugs, likely more specific and less toxic for the treatment of leishmaniasis.
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Antiinfecciosos/síntesis química , Inhibidores Enzimáticos/química , Hexaclorofeno/síntesis química , Leishmania major/enzimología , Leishmaniasis/tratamiento farmacológico , Proteína Disulfuro Isomerasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Antiinfecciosos/farmacología , Dominio Catalítico , Diseño Asistido por Computadora , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Hexaclorofeno/farmacología , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
Data on 105 countries from the Global Development of Applied Community Studies project and a geographic information system (ArcGIS) were used to map and identify spatial patterns in the international growth of community psychology, as measured by professional associations and conferences, graduate and undergraduate programs and courses, and publications. Our primary aim was to analyze the field's global development, emphasizing professional training and research products, in the context of geographic proximity and theories of knowledge transfer and knowledge spillover. The results of Hot Spot Analysis and Cluster and Outlier Analysis spatially confirmed our hypothesis, revealing statistically significant hot spots of the strength of community psychology in the countries sharing borders. Hierarchical regression analysis found that the strength of community psychology in neighboring countries significantly predicted the development of community psychology beyond the influence of population size, Human Development Index, freedom score, and a history of grassroots activism. Implications for theory, research, and international professional and student exchanges are discussed.
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Análisis de Regresión , Humanos , Factores SocioeconómicosRESUMEN
BACKGROUND: Convalescent plasma (CP) is a potentially important therapy for coronavirus disease 2019 (COVID-19). However, knowledge regarding neutralizing antibody (NAb) titers in donor plasma and their impact in patients with acute COVID-19 remains largely undetermined. We measured NAb titers in CP and in patients with acute COVID-19 before and after transfusion through the traditional Food and Drug Administration investigational new drug pathway. METHODS: We performed a single-arm interventional trial measuring NAb and total antibody titers before and after CP transfusion over a 14-day period in hospitalized patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection. RESULTS: NAb titers in the donor CP units were low (<1:40 to 1:160) and had no effect on recipient neutralizing activity 1 day after transfusion. NAb titers were detected in 6 of 12 patients on enrollment and in 11 of 12 at ≥2 time points. Average titers peaked on day 7 and declined toward day 14 (Pâ =â .004). Nab titers and immunoglobulin G levels were correlated in donor plasma units (ρâ =â 0.938; Pâ <â .001) and in the cumulative patient measures (ρâ =â 0.781; Pâ <â .001). CONCLUSIONS: CP infusion did not alter recipient NAb titers. Prescreening of CP may be necessary for selecting donors with high titers of neutralizing activity for infusion into patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04434131.
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Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Betacoronavirus/inmunología , Donantes de Sangre , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Neumonía Viral/epidemiología , Neumonía Viral/terapia , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus/genética , COVID-19 , Estudios de Cohortes , Infecciones por Coronavirus/virología , Femenino , Humanos , Inmunización Pasiva , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , New Mexico/epidemiología , Pandemias , Neumonía Viral/virología , ARN Viral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/inmunología , Resultado del Tratamiento , Sueroterapia para COVID-19RESUMEN
Cyclooxygenase-2 [(COX-2) or prostaglandin endoperoxide H2 synthase-2 (PTGS-2)] induces the production of prostaglandins as part of the host-immune response to infections. Although a number of studies have demonstrated the effects of COX-2 promoter variants on autoimmune and inflammatory diseases, their role in malaria remains undefined. As such, we investigated the relationship between four COX-2 promoter variants (COX-2 -512 C > T, -608 T > C, -765 G > C, and -1195 A > G) and susceptibility to malaria and severe malarial anemia (SMA) upon enrollment and longitudinally over a 36-month follow-up period. All-cause mortality was also explored. The investigation was carried out in children (n = 1081, age; 2-70 months) residing in a holoendemic Plasmodium falciparum transmission region of western Kenya. At enrollment, genotypes/haplotypes (controlling for anemia-promoting covariates) did not reveal any strong effects on susceptibility to either malaria or SMA. Longitudinal analyses showed decreased malaria episodes in children who inherited the -608 CC mutant allele (RR = 0.746, P = 1.811 × 10-4) and -512C/-608T/-765G/-1195G (CTGG) haplotype (RR = 0.856, P = 0.011), and increased risk in TTCA haplotype carriers (RR = 1.115, P = 0.026). Over the follow-up period, inheritance of the rare TTCG haplotype was associated with enhanced susceptibility to both malaria (RR = 1.608, P = 0.016) and SMA (RR = 5.714, P = 0.004), while carriage of the rare TTGG haplotype increased the risk of malaria (RR = 1.755, P = 0.007), SMA (RR = 8.706, P = 3.97 × 10-4), and all-cause mortality (HR = 110.000, P = 0.001). Collectively, these results show that SNP variations in the COX-2 promoter, and their inherited combinations, are associated with the longitudinal risk of malaria, SMA, and all-cause mortality among children living in a high transmission area for P. falciparum.
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Anemia/genética , Ciclooxigenasa 2/genética , Malaria Falciparum/genética , Malaria/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Anemia/mortalidad , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Lactante , Kenia , Estudios Longitudinales , Malaria/inmunología , Malaria/mortalidad , Malaria/transmisión , Malaria Falciparum/inmunología , Malaria Falciparum/mortalidad , Malaria Falciparum/transmisión , Masculino , RiesgoRESUMEN
BACKGROUND: Sulfadoxine-pyrimethamine (SP) is the only anti-malarial drug formulation approved for intermittent preventive treatment in pregnancy (IPTp). However, mutations in the Plasmodium falciparum dhfr (Pfdhfr) and dhps (Pfdhps) genes confer resistance to pyrimethamine and sulfadoxine, respectively. Here, the frequencies of SP resistance-associated mutations from 2005 to 2018 were compared in samples from Kenyan children with malaria residing in a holoendemic transmission region. METHODS: Partial sequences of the Pfdhfr and Pfdhps genes were amplified and sequenced from samples collected in 2005 (n = 81), 2010 (n = 95), 2017 (n = 43), and 2018 (n = 55). The frequency of known mutations conferring resistance to pyrimethamine and sulfadoxine were estimated and compared. Since artemisinin-based combination therapy (ACT) is the current first-line treatment for malaria, the presence of mutations in the propeller domain of P. falciparum kelch13 gene (Pfk13) linked to ACT-delayed parasite clearance was studied in the 2017/18 samples. RESULTS: Among other changes, the point mutation of Pfdhps S436H increased in frequency from undetectable in 2005 to 28% in 2017/18. Triple Pfdhfr mutant allele (CIRNI) increased in frequency from 84% in 2005 to 95% in 2017/18, while the frequency of Pfdhfr double mutant alleles declined (allele CICNI from 29% in 2005 to 6% in 2017/18, and CNRNI from 9% in 2005 to undetectable in 2010 and 2017/18). Thus, a multilocus Pfdhfr/Pfdhps genotype with six mutations (HGEAA/CIRNI), including Pfdhps S436H, increased in frequency from 2010 to 2017/18. Although none of the mutations associated with ACT-delayed parasite clearance was observed, the Pfk13 mutation A578S, the most widespread Pfk13 SNP found in Africa, was detected in low frequency (2.04%). CONCLUSIONS: There were changes in SP resistance mutant allele frequencies, including an increase in the Pfdhps S436H. Although these patterns seem consistent with directional selection due to drug pressure, there is a lack of information to determine the actual cause of such changes. These results suggest incorporating molecular surveillance of Pfdhfr/Pfdhps mutations in the context of SP efficacy studies for intermittent preventive treatment in pregnancy (IPTp).
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Antimaláricos/farmacología , Resistencia a Medicamentos/genética , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas Protozoarias/genética , Tetrahidrofolato Deshidrogenasa/genética , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Kenia , Mutación , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/metabolismo , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
Mutations in the Plasmodium falciparumk13 (Pfk13) gene are linked to delayed parasite clearance in response to artemisinin-based combination therapies (ACTs) in Southeast Asia. To explore the evolutionary rate and constraints acting on this gene, k13 orthologs from species sharing a recent common ancestor with P. falciparum and Plasmodium vivax were analyzed. These comparative studies were followed by genetic polymorphism analyses within P. falciparum using 982 complete Pfk13 sequences from public databases and new data obtained by next-generation sequencing from African and Haitian isolates. Although k13 orthologs evolve at heterogeneous rates, the gene was conserved across the genus, with only synonymous substitutions being found at residues where mutations linked to the delayed parasite clearance phenotype have been reported. This suggests that those residues were under constraint from undergoing nonsynonymous changes during evolution of the genus. No fixed nonsynonymous differences were found between Pfk13 and its orthologs in closely related species found in African apes. This indicates that all nonsynonymous substitutions currently found in Pfk13 are younger than the time of divergence between P. falciparum and its closely related species. At the population level, no mutations linked to delayed parasite clearance were found in our samples from Africa and Haiti. However, there is a high number of single Pfk13 mutations segregating in P. falciparum populations, and two predominant alleles are distributed worldwide. This pattern is discussed in terms of how changes in the efficacy of natural selection, affected by population expansion, may have allowed for the emergence of mutations tolerant to ACTs.
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Antimaláricos/farmacología , Artemisininas/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Proteínas Protozoarias/genética , Resistencia a Medicamentos/genética , Filogenia , Plasmodium vivax/efectos de los fármacos , Plasmodium vivax/genética , Polimorfismo Genético/genéticaRESUMEN
BACKGROUND: Severe malarial anemia (SMA) is a leading cause of malaria-related morbidity and mortality in children. The genetic factors that influence development of SMA and inefficient erythropoiesis, a central pathogenic feature of SMA, are only partially understood. METHODS: We performed a pilot Genome-wide Association Study (GWAS) on children with Plasmodium falciparum. The GWAS was performed using the Illumina® Infinium® HD Super Assay in conjunction with Illumina's® Human Omni2.5-8v1 BeadChip (with > 2.45 M markers). Data were analyzed using single SNP logistic regression analysis with an additive model of inheritance controlling for covariates. Results from our pilot global genomics study identified that variation in interleukin (IL)-7 was associated with enhanced risk of SMA. To validate this finding, we investigated the relationship between genotypes and/or haplotypes of two single nucleotide polymorphisms (SNPs) in IL7 [72194 T/C and - 2440 A/G] and susceptibility to both SMA and inefficient erythropoiesis [i.e., reticulocyte production index (RPI) < 2.0 in anemic children (Hb < 11.0 g/dL). Children presenting with P. falciparum malaria (< 3 years, n = 883) were stratified into two groups: Uncomplicated malaria (UM, n = 718) and SMA (n = 165). RESULTS: Regression modeling, controlling for anemia-related confounders, revealed that carriage of the TC genotype at position 72194 T/C was associated with enhanced susceptibility to inefficient erythropoiesis (OR = 1.90; 95% CI 1.09-3.30; P = 0.02) as was homozygous CC (OR 5.14; 95% CI = 1.20-21.99; P = 0.03). Consistent with this finding, individuals with the CA (72194C/-2440A) haplotype had an increased risk of inefficient erythropoiesis (OR = 1.90; 95% CI = 1.10-3.30; P = 0.02), whereas TA haplotype carriers had marginal protection against inefficient erythropoiesis (OR = 0.24; 95% CI = 0.06-1.21; P = 0.05). These observations were supported by Cochran-Armitage trend test for inefficient erythropoiesis (CA > TA > CG; P < 0.01). Although none of the genotype and/or haplotypic variants were significantly associated with SMA, the direction of the risk profiles were consistent with the erythropoiesis results. CONCLUSION: Taken together, variation in IL7 is associated with erythropoietic responses in children with falciparum malaria, a central physiological feature contributing to development of SMA.
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Eritropoyesis/genética , Variación Genética , Interleucina-7/genética , Malaria Falciparum/complicaciones , Anemia/etiología , Anemia/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos , Humanos , Lactante , Kenia , Masculino , Proyectos Piloto , Plasmodium falciparum/patogenicidad , Polimorfismo de Nucleótido SimpleRESUMEN
This project examines the connections between community psychology and faith-based community development. We investigate whether and how 4 major principles of community psychology-neighboring, sense of community, empowerment, and citizen participation-are found in the theory and philosophy of practice of the Christian Community Development Association (CCDA), a national faith-based community development network. We employ content analysis of four official CCDA publications to identify whether and how these four principles are embedded in the organization's espoused principles of practice. Our findings are as follows: (a) All four principles are found within CCDA theory and philosophy of practice, with the greatest emphasis on neighboring and sense of community and a less robust application of empowerment and citizen participation; (b) CCDA primarily focuses on the individual-level impact of these principles; and (c) CCDA Bases their application of these principles in Christian scripture and tradition. Our results indicate that the field could be strengthened by examining religious approaches to these principles and considering how organizations engage these concepts in both the theory and the practice. Additionally, faith-based organizations may foster a more effective application of these concepts in their social change efforts by partnering with community researchers and practitioners.
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Cristianismo , Redes Comunitarias , Empoderamiento , Conducta Social , Participación Social , Planificación Social , Adulto , Humanos , Psicología , Investigación CualitativaRESUMEN
OBJECTIVES: This study compared 29 drugs for risk of psychiatric hospitalization in bipolar disorders, addressing the evidence gap on the >50 drugs used by US patients for treatment. METHODS: The Truven Health Analytics MarketScan® database was used to identify 190 894 individuals with bipolar or schizoaffective disorder who filled a prescription for one of 29 drugs of interest: lithium, first- or second-generation antipsychotics, mood-stabilizing anticonvulsants, and antidepressants. Competing risks regression survival analysis was used to compare drugs for risk of psychiatric hospitalization, adjusting for patient age, sex, comorbidities, and pretreatment medications. Other competing risks were ending monotherapy and non-psychiatric hospitalization. RESULTS: Three drugs were associated with significantly lower risk of psychiatric hospitalization than lithium: valproate (relative risk [RR] = 0.80, P = 3.20 × 10-4 ), aripiprazole (RR = 0.80, P = 3.50 × 10-4 ), and bupropion (RR = 0.80, P = 2.80 × 10-4 ). Eight drugs were associated with significantly higher risk of psychiatric hospitalization: haloperidol (RR = 1.57, P = 9.40 × 10-4 ), clozapine (RR = 1.52, P = .017), fluoxetine (RR = 1.17, P = 3.70 × 10-3 ), sertraline (RR = 1.17, P = 3.20 × 10-3 ), citalopram (RR = 1.14, P = .013), duloxetine (RR = 1.24, P = 5.10 × 10-4 ), venlafaxine (RR = 1.33; P = 1.00 × 10-6 ), and ziprasidone (RR = 1.25; P = 6.20 × 10-3 ). CONCLUSIONS: This largest reported retrospective observational study on bipolar disorders pharmacotherapy to date demonstrates that the majority of patients end monotherapy within 2 months after treatment start. The risk of psychiatric hospitalization varied almost two-fold across individual medications. The data add to the evidence favoring lithium and mood stabilizer use in short-term bipolar disorder management. The findings that the dopaminergic drugs aripiprazole and bupropion had better outcomes than other members of their respective classes and that antidepressant outcomes may vary by baseline mood polarity merit further investigation.
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Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Antipsicóticos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Compuestos de Litio/uso terapéutico , Adulto , Antimaníacos/uso terapéutico , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/tratamiento farmacológico , Estudios Retrospectivos , RiesgoRESUMEN
OBJECTIVES: As part of a series of Patient-Centered Outcomes Research Institute-funded large-scale retrospective observational studies on bipolar disorder (BD) treatments and outcomes, we sought the input of patients with BD and their family members to develop research questions. We aimed to identify systemic root causes of patient-reported challenges with BD management in order to guide subsequent studies and initiatives. METHODS: Three focus groups were conducted where patients and their family members (total n = 34) formulated questions around the central theme, "What do you wish you had known in advance or over the course of treatment for BD?" In an affinity mapping exercise, participants clustered their questions and ranked the resulting categories by importance. The research team and members of our patient partner advisory council further rated the questions by expected impact on patients. Using a Theory of Constraints systems thinking approach, several causal models of BD management challenges and their potential solution were developed with patients using the focus group data. RESULTS: A total of 369 research questions were mapped to 33 categories revealing 10 broad themes. The top priorities for patient stakeholders involved pharmacotherapy and treatment alternatives. Analysis of causal relationships underlying 47 patient concerns revealed two core conflicts: for patients, whether or not to take pharmacotherapy, and for mental health services, the dilemma of care quality vs quantity. CONCLUSIONS: To alleviate the core conflicts identified, BD management requires a coordinated multidisciplinary approach including: improved access to mental health services, objective diagnostics, sufficient provider visit time, evidence-based individualized treatment, and psychosocial support.
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Trastorno Bipolar , Servicios de Salud Mental/normas , Adulto , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/psicología , Trastorno Bipolar/terapia , Participación de la Comunidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Necesidades , Prioridad del Paciente , Mejoramiento de la Calidad , Estudios Retrospectivos , Encuestas y Cuestionarios , Estados UnidosRESUMEN
BACKGROUND: Improved understanding of the molecular mechanisms involved in pediatric severe malarial anemia (SMA) pathogenesis is a crucial step in the design of novel therapeutics. Identification of host genetic susceptibility factors in immune regulatory genes offers an important tool for deciphering malaria pathogenesis. The IL-23/IL-17 immune pathway is important for both immunity and erythropoiesis via its effects through IL-23 receptors (IL-23R). However, the impact of IL-23R variants on SMA has not been fully elucidated. METHODS: Since variation within the coding region of IL-23R may influence the pathogenesis of SMA, the association between IL-23R rs1884444 (G/T), rs7530511 (C/T), and SMA (Hb < 6.0 g/dL) was examined in children (n = 369, aged 6-36 months) with P. falciparum malaria in a holoendemic P. falciparum transmission area. RESULTS: Logistic regression analysis, controlling for confounding factor of anemia, revealed that individual genotypes of IL-23R rs1884444 (G/T) [GT; OR = 1.34, 95% CI = 0.78-2.31, P = 0.304 and TT; OR = 2.02, 95% CI = 0.53-7.74, P = 0.286] and IL-23R rs7530511 (C/T) [CT; OR = 2.6, 95% CI = 0.59-11.86, P = 0.202 and TT; OR = 1.66, 95% CI = 0.84-3.27, P = 0.142] were not associated with susceptibility to SMA. However, carriage of IL-23R rs1884444T/rs7530511T (TT) haplotype, consisting of both mutant alleles, was associated with increased susceptibility to SMA (OR = 1.12, 95% CI = 1.07-4.19, P = 0.030). CONCLUSION: Results presented here demonstrate that a haplotype of non-synonymous IL-23R variants increase susceptibility to SMA in children of a holoendemic P. falciparum transmission area.
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Anemia/genética , Haplotipos , Malaria Falciparum/complicaciones , Polimorfismo de Nucleótido Simple , Receptores de Interleucina/genética , Anemia/etiología , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Kenia , Malaria Falciparum/transmisión , Masculino , MutaciónRESUMEN
BACKGROUND: Naturally-acquired immunity to Plasmodium falciparum malaria develops after several episodes of infection. Fc gamma receptors (FcγRs) bind to immunoglobulin G (IgG) antibodies and mediate phagocytosis of opsonized microbes, thereby, linking humoral and cellular immunity. FcγR polymorphisms influence binding affinity to IgGs and consequently, can influence clinical malaria outcomes. Specifically, variations in FcγRIIA -131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 modulate immune responses through altered binding preferences to IgGs and immune complexes. Differential binding, in turn, changes ability of immune cells to respond to infection through production of inflammatory mediators during P. falciparum infection. METHODS: We determined the association between haplotypes of FcγRIIA-131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 variants and severe malarial anemia (SMA; hemoglobin < 6.0 g/dL, any density parasitemia) in children (n = 274; aged 6-36 months) presenting for their first hospital visit with P. falciparum malaria in a holoendemic transmission region of western Kenya. FcγRIIA-131Arg/His and FcγRIIIA-176F/V genotypes were determined using TaqMan® SNP genotyping, while FcγRIIIBNA1/NA2 genotypes were determined using restriction fragment length polymorphism. Hematological and parasitological indices were measured in all study participants. RESULTS: Carriage of FcγRIIA-131Arg/FcγRIIIA-176F/FcγRIIIBNA2 haplotype was associated with susceptibility to SMA (OR = 1.70; 95% CI; 1.02-2.93; P = 0.036), while the FcγRIIA-131His/ FcγRIIIA-176F/ FcγRIIIB NA1 haplotype was marginally associated with enhanced susceptibility to SMA (OR: 1.80, 95% CI; 0.98-3.30, P = 0.057) and higher levels of parasitemia (P = 0.009). Individual genotypes of FcγRIIA-131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 were not associated with susceptibility to SMA. CONCLUSION: The study revealed that haplotypes of FcγRs are important in conditioning susceptibility to SMA in immune-naive children from P. falciparum holoendemic region of western Kenya.
Asunto(s)
Anemia/genética , Malaria/complicaciones , Polimorfismo Genético , Receptores de IgG/genética , Anemia/etiología , Preescolar , Estudios Transversales , Femenino , Proteínas Ligadas a GPI/genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Lactante , Kenia , Malaria/genética , Malaria Falciparum/sangre , Malaria Falciparum/complicaciones , Masculino , Carga de Parásitos , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Using a mixed-method analysis, we propose and test a framework for predicting the international development of community psychology (CP) and community development (CD) as two examples of applied community-based research (CBR) disciplines aiming to link local knowledge generation with social change. Multiple regressions on an international sample of 91 countries were used to determine the relative influences of preexisting grassroots activism, population size, social and economic development, and civil liberties on estimates of the current strength of CP and CD based on Internet search and review of training courses and programs, published articles and journals, and professional organizations and conferences in these countries. Our results provide support for the proposed model and suggest that grassroots activism positively accounts for the development of CP and CD, above and beyond the influences of the other predictors. Brief qualitative case-study analyses of Chile (high CP, low CD) and Ghana (high CD, low CP) explore the limitations of our quantitative model and the importance of considering other historical, sociopolitical, cultural, and geographic factors for explaining the development of CP, CD, and other applied community studies.
Asunto(s)
Países en Desarrollo , Psicología Social , Planificación Social , Chile , Ghana , Humanos , Investigación Cualitativa , Análisis de RegresiónRESUMEN
Severe malarial anemia [SMA, hemoglobin (Hb) <5.0 g/dL] is a leading cause of global morbidity and mortality among children residing in Plasmodium falciparum transmission regions. Exploration of molecular pathways through global gene expression profiling revealed that SMA was characterized by decreased HSPA1A, a heat shock protein (Hsp) 70 coding gene. Hsp70 is a ubiquitous chaperone that regulates Nuclear Factor-kappa B (NF-κB) signaling and production of pro-inflammatory cytokines known to be important in malaria pathogenesis (e.g., IL-1ß, IL-6 and TNF-α). Since the role of host Hsp70 in malaria pathogenesis is unexplored, we investigated Hsp70 and molecular pathways in children with SMA. Validation experiments revealed that leukocytic HSP70 transcripts were reduced in SMA relative to non-severe malaria, and that intraleukocytic hemozoin (PfHz) was associated with lower HSP70. HSP70 was correlated with reticulocyte production and Hb. Since glutamine (Gln) up-regulates Hsp70, modulates NF-κB activation, and attenuates over-expression of pro-inflammatory cytokines, circulating Gln was measured in children with malaria. Reduced Gln was associated with increased risk of developing SMA. Treatment of cultured peripheral blood mononuclear cells (PBMCs) with PfHz caused a time-dependent decrease in Hsp70 transcripts/protein, and NF-κB activation. Gln treatment of PBMCs overcame PfHz-induced suppression of HSP70 transcripts/protein, reduced NF-κB activation, and suppressed over-expression of IL-1ß, IL-6 and TNF-α. Findings here demonstrate that SMA is characterized by reduced intraleukocytic HSP70 and circulating Gln, and that PfHz-induced suppression of HSP70 can be reversed by Gln. Thus, Gln supplementation may offer important immunotherapeutic options for futures studies in children with SMA.
RESUMEN
OBJECTIVES: Thyroid abnormalities in patients with bipolar disorder (BD) have been linked to lithium treatment for decades, yet other drugs have been less well studied. Our objective was to compare hypothyroidism risk for lithium versus the anticonvulsants and second-generation antipsychotics commonly prescribed for BD. METHODS: Administrative claims data on 24,574 patients with BD were analyzed with competing risk survival analysis. Inclusion criteria were (i) one year of no prior hypothyroid diagnosis nor BD drug treatment, (ii) followed by at least one thyroid test during BD monotherapy on lithium carbonate, mood-stabilizing anticonvulsants (lamotrigine, valproate, oxcarbazepine, or carbamazepine) or antipsychotics (aripiprazole, olanzapine, risperidone, or quetiapine). The outcome was cumulative incidence of hypothyroidism per drug, in the presence of the competing risk of ending monotherapy, adjusted for age, sex, physician visits, and thyroid tests. RESULTS: Adjusting for covariates, the four-year cumulative risk of hypothyroidism for lithium (8.8%) was 1.39-fold that of the lowest risk therapy, oxcarbazepine (6.3%). Lithium was non-statistically significantly different from quetiapine. While lithium conferred a higher risk when compared to all other treatments combined as a group, hypothyroidism risk error bars overlapped for all drugs. Treatment (p = 3.86e-3), age (p = 6.91e-10), sex (p = 3.93e-7), and thyroid testing (p = 2.79e-87) affected risk. Patients taking lithium were tested for hypothyroidism 2.26-3.05 times more frequently than those on other treatments. CONCLUSIONS: Thyroid abnormalities occur frequently in patients with BD regardless of treatment. Therefore, patients should be regularly tested for clinical or subclinical thyroid abnormalities on all therapies and treated as indicated to prevent adverse effects of hormone imbalances on mood.
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Antimaníacos/efectos adversos , Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Hipotiroidismo/inducido químicamente , Adulto , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Compuestos de Litio/efectos adversos , Compuestos de Litio/uso terapéutico , Masculino , Riesgo , Análisis de SupervivenciaRESUMEN
Bacteremia and malaria coinfection is a common and life-threatening condition in children residing in sub-Saharan Africa. We previously showed that coinfection with Gram negative (G[-]) enteric Bacilli and Plasmodium falciparum (Pf[+]) was associated with reduced high-density parasitemia (HDP, >10,000 parasites/µL), enhanced respiratory distress, and severe anemia. Since inflammatory mediators are largely unexplored in such coinfections, circulating cytokines were determined in four groups of children (n = 206, aged <3 yrs): healthy; Pf[+] alone; G[-] coinfected; and G[+] coinfected. Staphylococcus aureus and non-Typhi Salmonella were the most frequently isolated G[+] and G[-] organisms, respectively. Coinfected children, particularly those with G[-] pathogens, had lower parasite burden (peripheral and geometric mean parasitemia and HDP). In addition, both coinfected groups had increased IL-4, IL-5, IL-7, IL-12, IL-15, IL-17, IFN-γ, and IFN-α and decreased TNF-α relative to malaria alone. Children with G[-] coinfection had higher IL-1ß and IL-1Ra and lower IL-10 than the Pf[+] group and higher IFN-γ than the G[+] group. To determine how the immune response to malaria regulates parasitemia, cytokine production was investigated with a multiple mediation model. Cytokines with the greatest mediational impact on parasitemia were IL-4, IL-10, IL-12, and IFN-γ. Results here suggest that enhanced immune activation, especially in G[-] coinfected children, acts to reduce malaria parasite burden.
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Bacteriemia/microbiología , Bacteriemia/parasitología , Coinfección/sangre , Coinfección/microbiología , Coinfección/parasitología , Malaria Falciparum/microbiología , Malaria Falciparum/parasitología , Bacteriemia/sangre , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Inflamación/sangre , Inflamación/microbiología , Inflamación/parasitología , Interferón-alfa/sangre , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-12/sangre , Interleucina-15/sangre , Interleucina-17/sangre , Interleucina-4/sangre , Interleucina-5/sangre , Interleucina-7/sangre , Malaria Falciparum/sangre , Masculino , Salmonella/patogenicidad , Staphylococcus aureus/patogenicidad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The findings on the association between Social Networking Sites and civic engagement are mixed. The present study aims to evaluate a theoretical model linking the informational use of Internet-based social media (specifically, Facebook) with civic competencies and intentions for future civic engagement, taking into account the mediating role of civic discussions with family and friends and sharing the news online. Participants were 114 Italian high school students aged 14-17 years (57 % boys). Path analysis was used to evaluate the proposed theoretical model. Results showed that Facebook informational use was associated with higher levels of adolescent perceived competence for civic action, both directly and through the mediation of civic discussion with parents and friends (offline). Higher levels of civic competencies, then, were associated with a stronger intention to participate in the civic domain in the future. Our findings suggest that Facebook may provide adolescents with additional tools through which they can learn civic activities or develop the skills necessary to participate in the future.