ROP16-mediated activation of STAT6 enhances cyst development of type III Toxoplasma gondii in neurons.

Toxoplasma gondii establishes a long-lived latent infection in the central nervous system (CNS) of its hosts. Reactivation in immunocompromised individuals can lead to life threatening disease. Latent infection is driven by the ability of the parasite to convert from the acute-stage tachyzoite to the latent-stage bradyzoite which resides in long-lived intracellular cysts. While much work has focused on the parasitic factors that drive cyst development, the host factors that influence encystment are not well defined. Here we show that a polymorphic secreted parasite kinase (ROP16), that phosphorylates host cell proteins, mediates efficient encystment of T. gondii in a stress-induced model of encystment and primary neuronal cell cultures (PNCs) in a strain-specific manner. Using short-hairpin RNA (shRNA) knockdowns in human foreskin fibroblasts (HFFs) and PNCs from transgenic mice, we determined that ROP16's cyst enhancing abilities are mediated, in part, by phosphorylation-and therefore activation-of the host cell transcription factor STAT6. To test the role of STAT6 in vivo, we infected wild-type (WT) and STAT6KO mice, finding that, compared to WT mice, STAT6KO mice have a decrease in CNS cyst burden but not overall parasite burden or dissemination to the CNS. Finally, we found a similar ROP16-dependent encystment defect in human pluripotent stem cell-derived neurons. Together, these findings identify a host cell factor (STAT6) that T. gondii manipulates in a strain-specific manner to generate a favorable encystment environment.

Impact of 13-Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Carriage Rates of Streptococcus pneumoniae in a Rural Community in the Dominican Republic.

BACKGROUND: Invasive pneumococcal disease (IPD) leads to thousands of pediatric deaths annually. Pneumococcal colonization precedes IPD. In 2013, the Dominican Republic introduced the 13-valent pneumococcal conjugate vaccine (PCV13) into its routine infant immunization program, with doses at ages 2, 4, and 12 months. Prevalence of pneumococcal nasopharyngeal colonization was evaluated post-PCV13 introduction. METHODS: A prospective cohort study of 125 children aged 2-35 months was conducted in a rural Dominican Republic community November 2016 through July 2017. Nasopharyngeal swabs and clinical and vaccination data were collected at enrollment and 4-6 months later. Serotypes included in PCV13 were defined as vaccine-type. Colonization rates and serotype distribution were compared at baseline and follow-up, and the association between colonization and vaccination status among the entire cohort was evaluated at each time point. RESULTS: Of 125 children enrolled, 118 (94%) completed follow-up. Overall and vaccine-type pneumococcal colonization rates were 62% and 25%, respectively, at baseline and 60% and 28% at follow-up. Among children age-eligible for 3 doses, 50% and 51% were fully vaccinated at baseline and follow-up, respectively. At baseline assessment, children up-to-date for age for PCV13 were less likely to be colonized with vaccine-type pneumococci than children not up-to-date, and the same was found for fully vaccinated children (3 doses) compared to those not fully vaccinated (odds ratios [ORs], 0.38 [95% confidence interval {CI}, .18-.79], and 0.14 [95% CI, .04-.45], respectively). The same associations were not found at follow-up assessment. CONCLUSIONS: Three years post -PCV13 introduction, vaccine-type colonization rates remained high. Low vaccination coverage for 3 PCV13 doses may have contributed. The protective effect of PCV13 on vaccine-type carriage suggests an increase in PCV13 coverage could lead to substantial declines in pneumococcal vaccine-type carriage.

High Prevalence of Vaccine-Type Infections Among Children with Pneumococcal Pneumonia and Effusion After 13-Valent Pneumococcal Conjugate Vaccine Introduction in the Dominican Republic.

BACKGROUND: In 2013, the Dominican Republic introduced 13-valent pneumococcal conjugate vaccine (PCV13) using a 3-dose schedule (at 2, 4 and 12 months of age). We evaluated the impact of PCV13 on serotypes causing pneumococcal pneumonia with pleural effusion. METHODS: Surveillance data after PCV13 introduction (July 2014 to June 2016) were compared with data before PCV13 introduction (July 2009 to June 2011). Cases were defined as radiologic evidence of pneumonia with pleural effusion in a child aged <15 years. Pneumococcus was detected in pleural fluid by either culture or polymerase chain reaction, and serotyping was performed. The Ministry of Health's PCV13 uptake data for 2014-2016 were obtained. RESULTS: The prevalence of pneumococcus among cases was similar before and after PCV13 introduction (56.4% and 52.8%, respectively). The proportion of pneumococcal cases caused by vaccine serotypes was 86% for children <2 years old both before and PCV13 introduction. Compared with before PCV13, serotype 14 accounted for a smaller (28% vs 13%, respectively; P = .02) and serotype 1 for a larger (23% vs 37%; P = .09) proportion of pneumococcal cases after PCV13 introduction. National uptake for the first, second, and third PCV13 doses was 94%, 81%, and 28%, respectively, in 2014 and 75%, 61%, and 26% in 2015. DISCUSSION: While the decrease in pneumococcal pneumonia with pleural effusion caused by serotype 14 may reflect an early effect of PCV13 implementation, other vaccine serotypes, including serotype 1, are not well controlled. Better PCV13 coverage for all 3 doses is needed.

mRNA Polyadenylation Machineries in Intestinal Protozoan Parasites.

In humans, mRNA polyadenylation involves the participation of about 20 factors in four main complexes that recognize specific RNA sequences. Notably, CFIm25, CPSF73, and PAP have essential roles for poly(A) site selection, mRNA cleavage, and adenosine residues polymerization. Besides the relevance of polyadenylation for gene expression, information is scarce in intestinal protozoan parasites that threaten human health. To better understand polyadenylation in Entamoeba histolytica, Giardia lamblia, and Cryptosporidium parvum, which represent leading causes of diarrhea worldwide, genomes were screened for orthologs of human factors. Results showed that Entamoeba histolytica and C. parvum have 16 and 12 proteins out of the 19 human proteins used as queries, respectively, while G. lamblia seems to have the smallest polyadenylation machinery with only six factors. Remarkably, CPSF30, CPSF73, CstF77, PABP2, and PAP, which were found in all parasites, could represent the core polyadenylation machinery. Multiple genes were detected for several proteins in Entamoeba, while gene redundancy is lower in Giardia and Cryptosporidium. Congruently with their relevance in the polyadenylation process, CPSF73 and PAP are present in all parasites, and CFIm25 is only missing in Giardia. They conserve the functional domains and predicted folding of human proteins, suggesting they may have the same roles in polyadenylation.

Biological activity of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide against E. histolytica and their analysis as potential thioredoxin reductase inhibitors.

Amoebiasis is caused by the protozoan Entamoeba histolytica that affects millions of people throughout the world. The standard treatment is metronidazole, however, this drug causes several side effects, and is also mutagenic and carcinogenic. Therefore, the search for therapeutic alternatives is necessary. Quinoxaline 1,4-di-N-oxides (QdNOs) derivatives have been shown to exhibit activity against different protozoan. In the present study, the effects of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives on E. histolytica proliferation, morphology, ultrastructure, and oxidative stress were evaluated, also their potential as E. histolytica thioredoxin reductase (EhTrxR) inhibitors was analyzed. In vitro tests showed that 12 compounds from n-propyl and isopropyl series, were more active (IC50 = 0.331 to 3.56 µM) than metronidazole (IC50 = 4.5 µM). The compounds with better biological activity have a bulky, trifluoromethyl and isopropyl group at R1-, R2-, and R3-position, respectively. The main alterations found in trophozoites treated with some of these compounds included changes in chromatin, cell granularity, redistribution of vacuoles with cellular debris, and an increase in reactive oxygen species. Interestingly, docking studies suggested that 7-carboxylate QdNOs derivatives could interact with amino acid residues of the NADPH-binding domain and/or the redox-active site of EhTrxR. Enzymatic assays demonstrated that selected 7-carboxylate QdNOs inhibits EhTrxR disulfide reductase activity, and diaphorase activity shows that these compounds could act as electron acceptor substrates for the enzyme. Taken together, these data indicate that among the mechanisms involved in the antiamoebic effect of the 7-carboxylate QdNOs derivatives studied, is the induction of oxidative stress and the inhibition of EhTrxR activity.

Effectiveness of 13-pneumococcal conjugate vaccine (PCV13) against invasive pneumococcal disease in children in the Dominican Republic.

BACKGROUND: Limited data are available on the effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in resource-poor settings and PCV naïve populations. The Dominican Republic introduced PCV13 in September 2013 using a 2 + 1 schedule (2, 4, and 12 months) without a catch-up campaign. We evaluated PCV13 effectiveness against vaccine-type (VT) invasive pneumococcal disease (IPD) among children in the Dominican Republic. METHODS: We conducted a matched case-control study. A case-patient was defined as VT-IPD identified by culture or polymerase chain reaction (PCR) from a normally sterile-site in a hospitalized child who was age-eligible to have received ≥1 PCV13 dose. Four age- and neighborhood-matched controls were enrolled for each case-patient. We collected demographic, vaccination history, and risk factor data. Conditional logistic regression was performed. Vaccine effectiveness was calculated as (1- adjusted matched odds ratio for vaccination) X 100%. RESULTS: We enrolled 39 case-patients and 149 matched-controls. Most case-patients had pneumonia with pleural effusion (64%), followed by meningitis (28%) and septicemia (13%). The most common pneumococcal serotypes identified included 14 (18%), 3 (13%), 19A (10%), and 1 (8%). Fewer case-patients had ≥1 PCV13 dose as compared to controls (61.5% vs. 80.0%; p = 0.006). Adjusting for malnutrition and socioeconomic status, VE of ≥1 PCV13 dose compared to no doses was 67.2% (95% CI: 2.3% to 90.0%). Only 44% of controls were up-to-date for PCV13, suggesting low vaccine coverage in the population. CONCLUSIONS: We found that PCV13 provided individual protection against VT-IPD in this resource-poor setting with a PCV-naïve population, despite low PCV13 coverage. Expanding vaccination coverage might increase PCV13 impact.

Characterization of a triple-recombinant, reassortant rotavirus strain from the Dominican Republic.

We report the genome of a novel human triple-recombinant G4P[6-8_R] mono-reassortant strain identified in a stool sample from the Dominican Republic during routine facility-based rotavirus strain surveillance. The strain was designated as RVA/Human-wt/DOM/2013840364/2013/G4P[6-8_R], with a genomic constellation of G4-P[6-8_R]-I1-R1-C1-M1-(A1-A8_R)-N1-(T1-T7_R)-E1-H1. Recombinant gene segments NSP1 and NSP3 were generated as a result of recombination between genogroup 1 rotavirus A1 human strain and a genotype A8 porcine strain and between genogroup 1 rotavirus T1 human strain and a genotype T7 bovine strain, respectively. Analyses of the RNA secondary structures of gene segment VP4, NSP1 and NSP3 showed that all the recombinant regions appear to start in a loop (single-stranded) region and terminate in a stem (double-stranded) structure. Also, the VP7 gene occupied lineage VII within the G4 genotypes consisting of mostly porcine or porcine-like G4 strains, suggesting the occurrence of reassortment. The remaining gene segments clustered phylogenetically with genogroup 1 strains. This exchange of whole or partial genetic materials between rotaviruses by recombination and reassortment contributes directly to their diversification, adaptation and evolution.

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors.

Development of heat shock protein 90 (Hsp90) C-terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti-proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Šapart along with angles of 180°.

Barriers to Leisure-Time Physical Activities in Individuals with Spinal Cord Injury.

This study investigated the personal, environmental, and activity barriers to leisure-time physical activities (LTPAs) among individuals with spinal cord injury (SCI). A survey instrument was administered to 85 participants with SCI. Personal barriers to LTPAs included issues involving motivation, pain, scheduling, and financial resources. Environmental barriers marked the issues regarding availability and accessibility to specialized programs, activities, and professional services. Activity barriers included limitations in equipment, training, and personal skills required by the selected activities. Significant negative correlations were found between these barriers and the levels of physical activity and satisfaction with physical activity. While working with clients with SCI, occupational therapists should identify those LTPA barriers and possible solutions in order to establish individualized action plans for enhancing participation in LTPAs.

Overweight, Obesity, Hypertriglyceridemia, and Insulin Resistance Are Positively Associated with High Serum Copper Levels in Mexican Adults.

Recently, the role of trace elements in the pathophysiology of obesity, insulin resistance (IR), and metabolic diseases has been explored. In this cross-sectional study, we aimed to assess the association of overweight, obesity, and cardiometabolic traits with serum copper (Cu) levels in 346 Mexican adults. Serum Cu level was measured by inductively coupled plasma mass spectrometry (ICP-MS). Anthropometrical data were collected, and biochemical parameters were measured. The triglyceride-glucose (TyG) index was used as a surrogate marker to evaluate IR. Overweight and obesity status was positively associated with the serum Cu level (ß = 19.434 ± 7.309, p = 0.008). Serum Cu level was observed to have a positive association with serum triglycerides level (ß = 0.160 ± 0.045, p < 0.001) and TyG (ß = 0.001 ± 0.001, p < 0.001). Additionally, high serum Cu level was positively associated with overweight and obesity status (odds ratio [OR] = 1.9, 95% confidence interval [95% CI] 1.1-3.4, p = 0.014), hypertriglyceridemia (OR = 3.0, 95% CI 1.7-5.3, p < 0.001), and IR (OR = 2.6, 95% CI 1.4-4.6, p = 0.001). In conclusion, our results suggest that overweight, obesity, hypertriglyceridemia, and IR are positively associated with serum Cu levels in Mexican adults.

Taxanes for the treatment of breast cancer during pregnancy: an international cohort study.

INTRODUCTION: The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy. METHODS: This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data. RESULTS: A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%). CONCLUSION: Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated.

Serum levels of anti-inflammatory/proinflammatory adipocytokines, and copper levels in overweight and obese women in an adult Mexican population.

BACKGROUND: An imbalance between adipokines and micronutrient concentrations, such as those of copper (Cu), has been linked to dysregulation of energy homeostasis leading to weight gain and the development of other comorbidities; however, information on this issue remains limited. Our aim was to investigate the correlation between Cu status and serum adipokine levels and their relationship in normal-weight, overweight, and obese adult women. METHODS: Sixty patients were evaluated and classified according to their body mass index (BMI) and biochemical parameters; adipokines and Cu were measured at fasting. RESULTS: Leptin (Lep) and resistin (Res) levels were elevated, whereas adiponectin (Adpn) and ghrelin (Ghr) values were decreased in overweight and obese women (p = 0.001). The mean Adpn/Lep ratio was <0.5 in overweight and obese subjects, while the Lep/Ghr ratio increased significantly in relation to weight gain, suggesting an inverse link between the ratios of these hormones in the regulation of obesity. The analysis revealed a positive association between BMI and Cu levels in obese women. Moreover, a negative association between Cu and Res in normal-weight subjects was found. CONCLUSIONS: Circulating fasting Res levels are negatively associated with serum Cu concentration in normal-weight adult women. We also observed a close relationship between Adpn/Lep and Lep/Ghr ratios with obesity. However, more observational studies are required to confirm these results in future research.

Bioactivity of Natural Polyphenols as Antiparasitic Agents and their Biochemical Targets.

BACKGROUND: Leishmaniasis and trypanosomiasis are diseases that affect public health worldwide due to their high incidence, morbidity, and mortality. Available treatments are costly, prolonged, and toxic, not to mention the problem of parasite resistance. The development of alternative treatments is justified and polyphenols show promising activity. OBJECTIVE: The main aim of this mini-review was to analyze the most promising phenolic compounds with reported antileishmanial and antitrypanosomal activity as well as their mechanisms of action. RESULTS: We found that the mode of action of these natural compounds, mainly lignans, neolignans, and flavonoids depends on the organism they act on and includes macrophage activation, induction of morphological changes such as chromatin condensation, DNA fragmentation, accumulation of acidocalcisomes, and glycosomes, Golgi damage and mitochondrial dysfunction as well as negative regulation of mitochondrial enzymes and other essential enzymes for parasite survival such as arginase. This gives a wide scope for future research toward the rational development of anti-kinetoplastid drugs. CONCLUSION: Although the specific molecular targets, bioavailability, route of administration, and dosages of some of these natural compounds need to be determined, polyphenols and their combinations represent a very promising and safe strategy to be considered for use against Leishmania spp and Trypanosoma spp. In addition, these compounds may provide a scaffold for developing new, more potent, and more selective antiprotozoal agents.

Proteomic and Functional Analysis of the Effects of Quinoxaline Derivatives on Entamoeba histolytica.

Quinoxalines are heterocyclic compounds that contain a benzene ring and a pyrazine ring. The oxidation of both nitrogen of the pyrazine ring results in quinoxaline derivatives (QdNO), which exhibit a variety of biological properties, including antiparasitic activity. However, its activity against Entamoeba histolytica, the protozoan that causes human amebiasis, is poorly understood. Recently, our group reported that various QdNOs produce morphological changes in E. histolytica trophozoites, increase reactive oxygen species, and inhibit thioredoxin reductase activity. Notably, T-001 and T-017 derivatives were among the QdNOs with the best activity. In order to contribute to the characterization of the antiamebic effect of QdNOs, in this work we analyzed the proteomic profile of E. histolytica trophozoites treated with the QdNOs T-001 and T-017, and the results were correlated with functional assays. A total number of 163 deregulated proteins were found in trophozoites treated with T-001, and 131 in those treated with T-017. A set of 21 overexpressed and 24 under-expressed proteins was identified, which were mainly related to cytoskeleton and intracellular traffic, nucleic acid transcription, translation and binding, and redox homeostasis. Furthermore, T-001 and T-017 modified the virulence of trophozoites, since they altered their erythrophagocytosis, migration, adhesion and cytolytic capacity. Our results show that in addition to alter reactive oxygen species, and thioredoxin reductase activity, T-001 and T-017 affect essential functions related to the actin cytoskeleton, which eventually affects E. histolytica virulence and survival.

Current status of quinoxaline and quinoxaline 1,4-di-N-oxides derivatives as potential antiparasitic agents.

Parasitic diseases are a public health problem, especially in developing countries where millions of people are affected every year. Current treatments have several drawbacks: emerging resistance to the existing drugs, lack of efficacy, and toxic side effects. Therefore, new antiparasitic drugs are urgently needed to treat and control diseases that affect human health, such as malaria, Chagas disease, leishmaniasis, amebiasis, giardiasis schistosomiasis, and filariasis, among others. Quinoxaline is a compound containing a benzene ring and a pyrazine ring. The oxidation of both pyrazine ring nitrogens allows the obtention of quinoxaline 1,4-di-N-oxides (QdNOs) derivatives. By modifying the chemical structure of these compounds, it is possible to obtain a wide variety of biological properties. This review investigated the activity of quinoxaline derivatives and QdNOs against different protozoan parasites and helminths. We also cover the structure-activity relationship (SAR) and summarize the main findings related to their mechanisms of action from published works in recent years. However, further studies are needed to determine specific molecular targets. This review aims to highlight the new development of antiparasitic drugs with better pharmacological profiles than current treatments.

Efficacy of Individualized Homeopathy in Treatment-Resistant Depression.

Treatment-resistant major depression (TRD), defined as an insufficient response to at least two antidepressant treatments, is usually treated with antidepressants, psychotherapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation or combinations of these. However, the response rate is modest and, on many occasions, insufficient or nonexistent. Here, we describe the case of a 19-year-old woman with a history of TRD, treated for depression since the age of five years. Her symptoms were resistant to fluoxetine, escitalopram, atomoxetine, and psychotherapy. Individualized homeopathic treatment with Staphisagria, Nux vomica, Arsenicum album, and Lachesis trigonocephalus was started. Posology was carried out in 200CH dynamizations. Treatment was prescribed for four months. This led to an immediate improvement in mood and a sustained and gradual reduction of depressive symptoms and, consequently, a reduction and then cessation of medication with antidepressants and psychotherapy. At follow-up eight months later, the patient is free of depression and medication. This case study reconfirms the usefulness of homeopathy in the treatment of depression. It also suggests that individualized homeopathic treatment may be useful in cases of treatment-resistant depression.

The direct effect of pneumococcal conjugate vaccines on invasive pneumococcal disease in children in the Latin American and Caribbean region (SIREVA 2006-17): a multicentre, retrospective observational study.

BACKGROUND: Streptococcus pneumoniae isolated from patients with invasive pneumococcal disease has been subjected to laboratory-based surveillance in Latin American and Caribbean countries since 1993. Invasive pneumococcal diseases remain a major cause of death and disability worldwide, particularly in children. We therefore aimed to assess the direct effect of pneumococcal conjugate vaccines (PCVs) on the distribution of pneumococcal serotypes causing invasive pneumococcal disease in children younger than 5 years before and after PCV introduction. METHODS: We did a multicentre, retrospective observational study in eight countries that had introduced PCV (ie, PCV countries) in the Latin American and Caribbean region: Argentina, Brazil, Chile, Colombia, Dominican Republic, Mexico, Paraguay, and Uruguay. Cuba and Venezuela were also included as non-PCV countries. Isolate data for Streptococcus pneumoniae were obtained between 2006 and 2017 from children younger than 5 years with an invasive pneumococcal disease from local laboratories or hospitals. Species' confirmation and capsular serotyping were done by the respective national reference laboratories. Databases from the Sistema Regional de Vacunas (SIREVA) participating countries were managed and cleaned in a unified database using Microsoft Excel 2016 and the program R (version 3.6.1). Analysis involved percentage change in vaccine serotypes between pre-PCV and post-PCV periods and the annual reporting rate of invasive pneumococcal diseases per 100 000 children younger than 5 years, which was used as a population reference to calculate percentage vaccine type reduction. FINDINGS: Between 2006 and 2017, 12 269 isolates of invasive pneumococcal disease were collected from children younger than 5 years in the ten Latin American and Caribbean countries. The ten serotypes included in ten-valent pneumococcal conjugate vaccine (PCV10) decreased significantly (p<0·0001) after any PCV introduction, except for the Dominican Republic. The percentage change for the ten vaccine serotypes in PCV10 countries was -91·6% in Brazil (530 [72·9%] of 727 before, 27 [6·1%] of 441 after); -85·0% in Chile (613 [72·6%] of 844 before, 44 [10·9%] of 404] after); -84·7% in Colombia (231 [63·1%] of 366 before, 34 [9·7%] of 352 after); and -73·8% in Paraguay (127 [77·0%] of 165 before, 22 [20·2%] of 109 after). In the 13-valent pneumococcal conjugate vaccine (PCV13) countries, the percentage change for the 13 vaccine serotypes was -59·6% in Argentina (853 [85·0%] of 1003 before, 149 [34·3%] of 434 after); -16·5% in the Dominican Republic (95 [80·5%] of 118 before, 39 [67·2%] of 58 after); -43·7% in Mexico (202 [73·2%] of 276 before, 63 [41·2%] of 153 after); and -45·9% in Uruguay (138 [80·7%] of 171 before, 38 [43·7%] of 87 after). Annual reporting rates showed a reduction from -82·5% (6·21 before vs 1·09 after per 100 000, 95% CI -61·6 to -92·0) to -94·7% (1·15 vs 0·06 per 100 000, -89·7 to -97·3) for PCV10 countries, and -58·8% (2·98 vs 1·23 per 100 000, -21·4 to -78·4) to -82·9% (7·80 vs 1·33 per 100 000, -76·9 to -87·4) for PCV13 countries. An increase in the amount of non-vaccine types was observed in the eight countries after PCV introduction together with an increase in their percentage in relation to total invasive strains in the post-PCV period. INTERPRETATION: SIREVA laboratory surveillance was able to confirm the effect of PCV vaccine on serotypes causing invasive pneumococcal disease in the eight PCV countries. Improved monitoring of the effect and trends in vaccine type as well as in non-vaccine type isolates is needed, as this information will be relevant for future decisions associated with new PCVs. FUNDING: None. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

Molecular characterization of Latin American invasive Streptococcus pneumoniae serotype 19A isolates.

Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, especially among children and the elderly. S. pneumoniae serotype 19A has emerged as a major cause of invasive disease in many countries, regardless of whether pneumococcal conjugate vaccines are used. The aim of this study was molecular characterization of invasive S. pneumoniae serotype 19A isolates recovered between 2000 and 2015 from 13 National Laboratories through the laboratory-based surveillance of invasive S. pneumoniae program SIREVA II in Latin American countries. The isolates were submitted with antimicrobial susceptibility tests and were genotyped by a combination of pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Of the 185 isolates assayed, notable rates of resistance to penicillin (MIC ≥ 0.125 µg/mL; 68.6%), tetracycline (63.7%), trimethoprim-sulfamethoxazole (63.2%), and erythromycin (43.2%) were observed, while 44.3% of isolates were multidrug resistant. The most frequently observed sequence types (ST) were ST320 (32.4%), ST199 (14.1%), ST172 (10.8%) and ST5204 (7.1%). The distribution of STs indicated regional differences in the epidemiology of the clonal groups. The present study showed a diverse genetic background of the pneumococcal population in Latin American countries. Continuous surveillance of the pneumococcal serotype 19A population in the region will be necessary to obtain information about geographical differences and changes in the spread and the establishment of particular clones.

Assessment of the impact of inpatient infectious events in pediatric patients with newly diagnosed acute leukemia at Dr. Robert Reid Cabral Children's Hospital, Dominican Republic.

Survival rates for pediatric acute leukemia vary dramatically worldwide. Infections are a leading cause of morbidity and mortality, and the impact is amplified in low and middle-income countries. Defining the epidemiology of infection in a specific health care setting is paramount to developing effective interventions. This study aimed to define the epidemiology of and outcomes from infection in children with acute leukemia treated in a large public pediatric hospital in the Dominican Republic. A retrospective cohort was assembled of children newly diagnosed with acute leukemia between July 1, 2015 to June 30, 2017 at Hospital Infantil Dr. Robert Reid Cabral in Santo Domingo. Patients were identified from the Pediatric Oncology Network Database (PONDTM) and hospital admissions from the Oncology admissions logbook. Medical records and microbiology results were reviewed to identify all inpatient invasive infections. Distance from a child's home to the hospital was determined using ArcGIS by Esri. Infection rates were described in discrete time periods after diagnosis and risk factors for invasive infection were explored using negative binomial regression. Overall, invasive infections were common and a prominent source of death in this cohort. Rates were highest in the first 60 days after diagnosis. Gastroenteritis/colitis, cellulitis, and pneumonia were most frequent, with bacteremia common early on. Multidrug resistant bacteria were prevalent among a small number of positive cultures. In a multivariate negative binomial regression model, age ≥ 10 years and distance from the hospital > 100 km were each protective against invasive infection in the first 180 days after diagnosis, findings that were unexpected and warrant further investigation. Over one-third of patient deaths were related to infection. Interventions aimed at reducing infection should target the first 60 days after diagnosis, improved supportive care inside and outside the hospital, and increased antimicrobial stewardship and infection prevention and control measures.

Contrast sensitivity visual acuity in REM sleep behavior disorder: a comparison with and without Parkinson disease.

STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is characterized by dream enactment behavior and is a premotoric sign associated with parkinsonism and dementia. We previously found contrast sensitivity visual acuity (CSVA) deficiencies in earliest stages of Parkinson disease (PD), plausibly associated with alpha-synuclein deposits in the inner retinal layers. We speculated that individuals with REM sleep behavior without clinical signs of parkinsonism might also show similar deficiencies. METHODS: Twenty-three patients with RBD and 28 healthy control patients. Eleven with PD and 12 with idiopathic RBD (iRBD). Twelve patients with RBD were re-evaluated after 1 year. Evaluations consisted of CSVA SLOAN low contrast acuity charts, optical coherence topography, Unified Parkinson's Disease Rating Scale (UPDRS), and general neurologic and ophthalmologic examinations. Data analyzed between groups using a one-way analysis of variance, and a paired samples t test for returning patients. RESULTS: Participants were classified into three groups: controls (n = 28), iRBD (n = 12), and RBD+PD (n = 11). Analysis of variance revealed CSVA scores were statistically significantly different between the three groups F2, 50 = 7.037, P = .002. Longitudinal analysis of RBD group showed CSVA decreased significantly at 1 year (P = .0141). To date, PD has developed in three individuals with iRBD based on progression of their UPDRS scores. CONCLUSIONS: CSVA is reduced in individuals with RBD and declines over time. It is plausible that patients with iRBD may show early loss in dopaminergic lateral inhibition in the retina, evidenced by their progressive loss of CSVA. This may represent a global loss of dopaminergic neurons similar to PD.