Evaluation of the malaria elimination policy in Brazil: a systematic review and epidemiological analysis study.

After a centenary fight against malaria, Brazil has seen an opportunity for change with the proposal of the malaria elimination policy set by the Brazilian government, in line with malaria elimination policies in other Latin American countries. Brazilian malaria experts regard eliminating malaria by 2030 to be within reach. Herein we evaluated the likelihood that malaria elimination can be accomplished in Brazil through systematic review of the literature on malaria elimination in Brazil and epidemiological analysis. Fifty-two articles referring to malaria eradication/elimination in Brazil were analyzed to identify challenges and technological breakthroughs for controlling malaria. Monthly deaths (1979-2016) and monthly severe malaria cases (1998-2018) were analyzed according to age groups, geographic region and parasite species. As a result, we observed that the declining malaria burden was mostly attributable to a decline in Plasmodium falciparum-malaria. At the same time, the proportional increase of Plasmodium vivax-malaria in comparison with P. falciparum-malaria was notable. This niche replacement mechanism was discussed in the reviewed literature. In addition, the challenges to P. vivax-malaria elimination outnumbered the available technological breakthroughs. Although accumulated and basic information exists on mosquito vector biology, the lack of specific knowledge about mosquito vector taxonomy and ecology may hamper current attempts at stopping malaria in the country. An impressive reduction in malaria hospitalizations and mortality was seen in Brazil in the past 3 decades. Eliminating malaria deaths in children less than 5 years and P. falciparum severe cases may be achievable goals under the current malaria policy until 2030. However, eliminating P. vivax malaria transmission and morbidity seems unattainable with the available tools. Therefore, complete malaria elimination in Brazil in the near future is unlikely.

Evaluation of the malaria elimination policy in Brazil: a systematic review and epidemiological analysis study

@#After a centenary fight against malaria, Brazil has seen an opportunity for change with the proposal of the malaria elimination policy set by the Brazilian government, in line with malaria elimination policies in other Latin American countries. Brazilian malaria experts regard eliminating malaria by 2030 to be within reach. Herein we evaluated the likelihood that malaria elimination can be accomplished in Brazil through systematic review of the literature on malaria elimination in Brazil and epidemiological analysis. Fifty-two articles referring to malaria eradication/elimination in Brazil were analyzed to identify challenges and technological breakthroughs for controlling malaria. Monthly deaths (1979–2016) and monthly severe malaria cases (1998–2018) were analyzed according to age groups, geographic region and parasite species. As a result, we observed that the declining malaria burden was mostly attributable to a decline in Plasmodium falciparum-malaria. At the same time, the proportional increase of Plasmodium vivax-malaria in comparison with P. falciparum-malaria was notable. This niche replacement mechanism was discussed in the reviewed literature. In addition, the challenges to P. vivax-malaria elimination outnumbered the available technological breakthroughs. Although accumulated and basic information exists on mosquito vector biology, the lack of specific knowledge about mosquito vector taxonomy and ecology may hamper current attempts at stopping malaria in the country. An impressive reduction in malaria hospitalizations and mortality was seen in Brazil in the past 3 decades. Eliminating malaria deaths in children less than 5 years and P. falciparum severe cases may be achievable goals under the current malaria policy until 2030. However, eliminating P. vivax malaria transmission and morbidity seems unattainable with the available tools. Therefore, complete malaria elimination in Brazil in the near future is unlikely.

Effect of intermediate phases on the optical properties of PbI2-rich CH3NH3PbI3 organic-inorganic hybrid perovskite.

Methylammonium lead halide perovskite (CH3NH3PbI3) films, with high PbI2 concentration, were grown by the two-step spin coating method. The influence of the precursor concentration and annealing time on the optical and structural properties of the perovskite films was analyzed by optical absorption, photoluminescence, X-ray diffraction and scanning electron microscopy. The results showed that, in addition to the CH3NH3PbI3 and PbI2 phases, intermediate phases, such as (MA)2(DMF)2Pb3I8, were formed in the films, depending on the time and temperature of annealing, which can tune the optical absorption in the visible spectra. This intermediate phase induced the formation of perovskite nanowires, identified by SEM images, and their growth may be associated with the presence of the DMF solvent remaining in the PbI2 film.

Using voice to create inpatient progress notes: effects on note timeliness, quality, and physician satisfaction.

OBJECTIVES: We describe the evaluation of a system to create hospital progress notes using voice and electronic health record integration to determine if note timeliness, quality, and physician satisfaction are improved. MATERIALS AND METHODS: We conducted a randomized controlled trial to measure effects of this new method of writing inpatient progress notes, which evolved over time, on important outcomes. RESULTS: Intervention subjects created 709 notes and control subjects created 1143 notes. When adjusting for clustering by provider and secular trends, there was no significant difference between the intervention and control groups in the time between when patients were seen on rounds and when progress notes were viewable by others (95% confidence interval -106.9 to 12.2 min). There were no significant differences in physician satisfaction or note quality between intervention and control. DISCUSSION: Though we did not find support for the superiority of this system (Voice-Generated Enhanced Electronic Note System [VGEENS]) for our 3 primary outcomes, if notes are created using voice during or soon after rounds they are available within 10 min. Shortcomings that likely influenced subject satisfaction include the early state of our VGEENS and the short interval for system development before the randomized trial began. CONCLUSION: VGEENS permits voice dictation on rounds to create progress notes and can reduce delay in note availability and may reduce dependence on copy/paste within notes. Timing of dictation determines when notes are available. Capturing notes in near-real-time has potential to apply NLP and decision support sooner than when notes are typed later in the day, and to improve note accuracy.

Dengue hospitalisations in Brazil: annual wave from West to East and recent increase among children.

The number of dengue epidemics in Brazil has increased dramatically in the last 15 years. In this study, we analysed the seasonal patterns in the incidence of hospitalisations due to dengue across the different states of Brazil and compared these with the corresponding climatic patterns. We discovered that the seasonality of dengue hospitalisations in Brazil has a clear zonal gradient, characterised by the progression of primary peaks from West to East during the first half of the year, which may be associated with the increased vapour pressure and rainfall during this period, leading to increased mosquito abundance and activity. We also found that the proportion of children among hospitalised individuals was especially high during the peak outbreaks in 2007/2008 and 2010. This may be due to the emergence and spread of the new DENV-2 Southeast Asian genotype lineage II from 2007, which has probably arrived from the Caribbean and may have caused an increase in incidence and severity of the disease, particularly among children. Our findings may allow health systems to improve control interventions and contribute to reducing dengue morbidity and mortality by using integrated vector control in conjunction with early diagnosis and prompt supportive care.

Using voice to create hospital progress notes: Description of a mobile application and supporting system integrated with a commercial electronic health record.

We describe the development and design of a smartphone app-based system to create inpatient progress notes using voice, commercial automatic speech recognition software, with text processing to recognize spoken voice commands and format the note, and integration with a commercial EHR. This new system fits hospital rounding workflow and was used to support a randomized clinical trial testing whether use of voice to create notes improves timeliness of note availability, note quality, and physician satisfaction with the note creation process. The system was used to create 709 notes which were placed in the corresponding patient's EHR record. The median time from pressing the Send button to appearance of the formatted note in the Inbox was 8.8 min. It was generally very reliable, accepted by physician users, and secure. This approach provides an alternative to use of keyboard and templates to create progress notes and may appeal to physicians who prefer voice to typing.

Risk of obstructive sleep apnea in patients with type 2 diabetes mellitus.

BACKGROUND AND OBJECTIVES: Type 2 diabetes mellitus (DM) and obstructive sleep apnea (OSA) share several clinical findings: obesity, hypertension, and impaired glucose tolerance. OSA may be an under-recognized comorbidity of DM. The purpose of this study is to estimate the proportion of patients with type 2 DM at risk for OSA and describe factors associated with that risk. METHODS: This cross-sectional study enrolled 297 adults, ages 18 years and older, with type 2 DM from a university-based Family Medicine Center. Participants completed a research questionnaire recording sociodemographic information, medical history, and clinical data including medications and hemoglobin A1C. OSA risk was determined using the Berlin Questionnaire. Relationships between risk of OSA and sociodemographic and clinical variables were evaluated using bivariate analyses and covariate adjusted logistic regression models. RESULTS: Thirty-seven participants (12.5%) had a prior diagnosis of OSA. Based on the Berlin Questionnaire, 124 (48.6%) of the remaining patients were classified as high risk for OSA. Patients less than age 60 years were at increased risk for OSA, adjusted OR=2.67 (1.57, 4.54; 95% CI). Non-Hispanic whites, adjusted OR=1.76 (1.01, 3.06; 95% CI), and patients with symptoms of depression, adjusted OR=2.64 (1.60, 4.52; 95% CI), were also at higher risk. Gender and hemoglobin A1C were not associated with increased risk of OSA. CONCLUSIONS: Nearly half of adults with type 2 DM may be at high risk for OSA, and many may be undiagnosed. In a primary care setting, the Berlin Questionnaire is an easily applied screening instrument that identifies patients at increased risk of OSA who may benefit from further diagnostic studies and treatment of OSA.

An exploration of spatial patterns of seasonal diarrhoeal morbidity in Thailand.

Studies of temporal and spatial patterns of diarrhoeal disease can suggest putative aetiological agents and environmental or socioeconomic drivers. Here, the seasonal patterns of monthly acute diarrhoeal morbidity in Thailand, where diarrhoeal morbidity is increasing, are explored. Climatic data (2003-2006) and Thai Ministry of Health annual reports (2003-2009) were used to construct a spatially weighted panel regression model. Seasonal patterns of diarrhoeal disease were generally bimodal with aetiological agents peaking at different times of the year. There is a strong association between daily mean temperature and precipitation and the incidence of hospitalization due to acute diarrhoea in Thailand leading to a distinct spatial pattern in the seasonal pattern of diarrhoea. Model performance varied across the country in relation to per capita GDP and population density. While climatic factors are likely to drive the general pattern of diarrhoeal disease in Thailand, the seasonality of diarrhoeal disease is dampened in affluent urban populations.

Spatio-temporal patterns of diarrhoeal mortality in Mexico.

Diarrhoeal mortality rates in Mexican children dramatically declined during the 1980s and 1990s, concomitant with a temporal shift in peak deaths from summer to autumn-winter. The spatial dynamics of these patterns have not previously been studied. We first describe the seasonal features of paediatric diarrhoeal mortality in Mexico as a whole, then across individual states. While no geographical gradients in the magnitude of diarrhoeal mortality rates have been detected in recent years, we identified a distinct spatial pattern in the timing of peak mortality rate. In the 1980s the summer peak mortality was earliest around Mexico's capital and later in states to the southeast and northwest. Our results suggest that the direction and timing of those annual waves are related to the mean monthly precipitation and mean daily temperature. This pattern has disintegrated in recent years as the summer peak has diminished.

The 'ghosts' that pester studies on learning in mosquitoes: guidelines to chase them off.

The identification of memory and learning in medically important mosquito species has been of epidemiological interest mainly because of the implications of learning on the pattern of contact between vectors and hosts. Empirical results either showing or suggesting the existence of cognitive abilities in mosquitoes have been reported in a number of experimental studies, mainly based on the observation of individual fidelity towards subsets of specific resources, such as hosts, resting sites or breeding sites. A closer inspection of the design of these experiments shows that, with the exception of recent studies providing stronger evidence of learning in the genus Culex (Diptera: Culicidae), methodological shortcomings still hinder the possibility of eliminating alternative interpretations for these findings, in some cases because the experiments were not specifically designed to identify the phenomenon, but mostly because of a lack of appropriate controls or replication. By highlighting these limitations, while acknowledging the practical difficulties that are inherent to the field, we aim to help expel from future research the 'ghosts' that still preclude the achievement of more definite conclusions about the prevalence of memory and learning in this group of insects.

Viral inactivation of intramuscular immune serum globulins.

A new process for the production of intramuscular immunoglobulin products is described which includes viral inactivation through solvent-detergent treatment. Removal of solvent-detergent was accomplished by precipitation, filtration and diafiltration. Process-scale preparations had appropriate antibody potency levels, and improved IgG integrity relative to traditional IGIM products. Moreover, acceptable results were obtained in all in vitro and in vivo pre-clinical toxicology testing, as well as clinical evaluation. Scaled-down experiments demonstrated that the new process provides effective viral inactivation. Taken together, these results indicate that the new products should have the same efficacy of the previous IGIM products albeit with safety and processing improvements.

Nutritional control of pregnant women on chronic hemodialysis.

The authors describe their experience in the follow-up of four patients with chronic renal failure who became pregnant while being treated with chronic hemodialysis. The outcomes were successful and each gave birth to healthy babies. The adequate nutritional condition previous to the pregnancies added more safety to their management. Special dedication to the nutritional control enabled a good outcome of their pregnancies. It stressed the importance of the intervention of the nutritionist-dietitian in the follow-up of nephrologic patients and the integration of a multidisciplinary staff.

Biosynthesis of monoterpenes: partial purification, characterization, and mechanism of action of 1,8-cineole synthase.

Geranyl pyrophosphate: 1,8-cineole cyclase (cineole synthase) catalyzes the conversion of geranyl pyrophosphate to the symmetrical monoterpene ether 1,8-cineole (1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane) by a process thought to involve the initial isomerization of the substrate to the tertiary allylic isomer, linalyl pyrophosphate, and cyclization of this bound intermediate to the alpha-terpinyl carbocation that is subsequently captured by water and undergoes heterocyclization to the remaining double bond. The enzyme was isolated from the secretory cells of the glandular trichomes of Salvia officinalis (garden sage) and partially purified, and the properties of this monoterpene cyclase, previously determined in crude cell-free extracts, were reexamined. These properties (pH optimum, divalent metal ion requirement, molecular weight, pI) were similar to those determined previously with the exception of substrate utilization; geranyl pyrophosphate was shown to be a more efficient substrate than the cis-isomer, neryl pyrophosphate, in the absence of competing phosphatase activity that contaminated earlier preparations of this enzyme. As with other monoterpene cyclases of herbaceous species, cineole synthase was inhibited by cysteine- and histidine-directed reagents, and protection against inactivation was provided by the substrate-metal ion complex. Studies with 18O-labeled acyclic precursors and H(2)18O, followed by mass spectrometric analysis of the product, confirmed that water was the sole source of the ether oxygen atom of 1,8-cineole. The electrophilic nature of the coupled isomerization-cyclization reaction was examined with a series of substrate and intermediate analogues. The overall stereochemistry of the cyclization of geranyl pyrophosphate to the symmetrical monoterpene was established by determining the enantioselectivity for (3R)- or (3S)-linalyl pyrophosphate as an alternative substrate and by oxidation of [3-3H]1,8-cineole, derived from [1-3H]geranyl pyrophosphate, to (+/-)-3-keto-1,8-cineole and radio-GLC separation of diastereomeric ketal derivatives to determine the labeled enantiomer.

Irreversible inactivation of monoterpene cyclases by a mechanism-based inhibitor.

Monoterpene synthases (cyclases) catalyze the divalent metal ion-dependent transformation of geranyl pyrophosphate to representative of the various monocyclic and bicyclic skeletal types by an electrophilic reaction mechanism involving coupled isomerization and cyclization steps. An analogue of the geranyl substrate, in which the terminal gem-dimethyl groups were joined to form a cyclopropyl function (6-cyclopropylidene-3E-methyl-hex-2-en-l-yl pyrophosphate) was shown to be a potent inhibitor of (-)-4S-limonene synthase from Mentha spicata and of several other monoterpene cyclases from diverse plant species. Inhibition was concentration and time dependent (pseudo-first-order kinetics), as well as absolutely contingent on the presence of the divalent metal ion cofactor. A double reciprocal plot of kinactivation versus inhibitor concentration gave an apparent Ki of approximately 0.3 microM and a maximum rate of inactivation of about 0.3 min-1 with limonene synthase. As expected for an active-site-directed process, the natural substrate, geranyl pyrophosphate, afforded protection against inactivation by the cyclopropylidene analogue. Selectivity of the inhibition was demonstrated with [1-3H]6-cyclopropylidene-3E-methyl-hex-2-en-1-yl pyrophosphate by specific labeling of limonene synthase in crude enzyme extracts as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, radio-fluorography, and immunoblotting. The radioactive cyclase-inactivator complex was formed with 1:1 stoichiometry and was stable to extended dialysis and boiling in 2% sodium dodecyl sulfate, suggesting irreversible covalent modification of the enzyme involving a chemical reaction between cyclase and inhibitor. Thermally denatured limonene synthase and synthase that had been inactivated with the histidine-directed reagent diethylpyrocarbonate or the cysteine-directed reagent p-hydroxymercuribenzoate (two reagents known to modify the active site of the enzyme and inhibit catalysis) were not labeled when treated with the [1-3H]-analogue, indicating that the functional enzyme was necessary to effect complex formation. All of the evidence is consistent with the analogue serving as a mechanism-based inactivator that must undergo both ionization-dependent isomerization and cyclization steps to reveal an allylic cation which alkylates the protein. In addition to furnishing supporting evidence for the electrophilic reaction sequence, this mechanism-based inactivator provides a powerful new approach for the examination of cyclase active sites.

4S-limonene synthase from the oil glands of spearmint (Mentha spicata). cDNA isolation, characterization, and bacterial expression of the catalytically active monoterpene cyclase.

The committed step in the biosynthesis of monoterpenes in mint (Mentha) species is the cyclization of geranyl pyrophosphate to the olefin (-)-4S-limonene catalyzed by limonene synthase (cyclase). Internal amino acid sequences of the purified enzyme from spearmint oil glands were utilized to design three distinct oligonucleotide probes. These probes were subsequently employed to screen a spearmint leaf cDNA library, and four clones were isolated. Three of these cDNA isolates were full-length and were functionally expressed in Escherichia coli, yielding a peptide that is immunologically recognized by polyclonal antibodies raised against the purified limonene synthase from spearmint and that is catalytically active in generating from geranyl pyrophosphate a product distribution identical to that of the native enzyme (principally limonene with small amounts of the coproducts alpha- and beta-pinene and myrcene). The longest open reading frame is 1800 nucleotides and the deduced amino acid sequence contains a putative plastidial transit peptide of approximately 90 amino acids and a mature protein of about 510 residues corresponding to the native enzyme. Several nucleotide differences in the 5'-untranslated region of all three full-length clones suggest the presence of several limonene synthase genes and/or alleles in the allotetraploid spearmint genome. Sequence comparisons with a sesquiterpene cyclase, epi-aristolochene synthase from tobacco, and a diterpene cyclase, casbene synthase from castor bean, demonstrated a significant degree of similarity between these three terpenoid cyclase types, the first three examples of this large family of catalysts to be described from higher plants.

Production and characterization of polyclonal antibodies in rabbits to 4S-limonene synthase from spearmint (Mentha spicata).

Limonene synthase, a monoterpene cyclase from the oil glands of spearmint (Mentha spicata) leaves that catalyzes the conversion of geranyl pyrophosphate to (-)-4S-limonene, was purified, and polyclonal antibodies were generated in rabbits against the sodium dodecyl sulfate-denatured protein. Immunoblotting analysis revealed that the antibodies were very specific for denatured limonene synthase from all Mentha species tested. However, no immunological cross-reactivity was observed with denatured limonene synthases from Valencia oranges (Citrus sinensis, Rutaceae) or wormseed (Chenopodium ambrosioides, Chenopodiaceae). Furthermore, the antibody preparation did not detectably cross-react with other monoterpene cyclases from related angiosperm species of the Lamiaceae, Asteraceae, and Umbellifereae, or from conifer species, and no cross-reactivity was demonstrated toward several sesquiterpene cyclases of higher plant and fungal origin. Although the antibody preparation was highly selective for denatured limonene cyclase from Mentha, the antibodies did not recognize the native protein in several different types of experiments. Nevertheless, specificity for the target enzyme was unambiguously demonstrated when the antibody preparation was shown to cross-react with the cyclase protein expressed in Escherichia coli that harbored the corresponding limonene synthase cDNA gene from M. spicata.

Purification of 4S-limonene synthase, a monoterpene cyclase from the glandular trichomes of peppermint (Mentha x piperita) and spearmint (Mentha spicata).

The p-menthane monoterpenes of the Mentha species are biosynthesized from geranyl pyrophosphate via the monocyclic olefin 4S-limonene. A monoterpene cyclase was isolated from both Mentha x piperita (peppermint) and Mentha spicata (spearmint) that catalyzes the cyclization of geranyl pyrophosphate to 4S-limonene. This enzyme, 4S-limonene synthase, was purified to apparent homogeneity by dye ligand, anion exchange, and hydrophobic interaction chromatography. Since the monoterpenes of Mentha are synthesized and secreted in modified epidermal hairs called glandular trichomes, an extract of isolated glandular trichome cells was used as the source of this enzyme. A combination of gel permeation chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that purified 4S-limonene synthase had a native molecular weight of 56,000 and was monomeric. The principal product of the enzyme was enantiomerically pure (-)-4S-limonene, and a catalytic constant of 0.3/s was determined. The basic properties of 4S-limonene synthase from both M. x piperita and M. spicata are identical and, in general, are similar to those of other monoterpene, sesquiterpene, and diterpene cyclases isolated from microorganisms and higher plants.

Purification and characterization of the monoterpene cyclase gamma-terpinene synthase from Thymus vulgaris.

The monoterpene cyclase, gamma-terpinene synthase, from Thymus vulgaris (thyme) leaves was purified to apparent homogeneity by isoelectric focusing and dye-ligand, anion-exchange, hydrophobic interaction, and gel permeation chromatography. The enzyme has a native molecular weight of 96,000 as determined by gel permeation chromatography, and exhibited a specific activity of 538 nmol/h.mg protein (turnover number of approximately 0.01/s). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed the enzyme to be composed of two apparently identical subunits of Mr approximately 55,000. The protein was very hydrophobic, and possessed a pI value of 4.85 as determined by isoelectric focusing. Maximum activity was observed at pH 6.8 in the presence of 20 mM Mg2+; 5 mM Mn2+ could support catalysis, albeit at a much lower rate. The Km value for the substrate, geranyl pyrophosphate, was 2.6 microM. Cyclase activity was inhibited by cysteine- and histidine-directed reagents. Purified gamma-terpinene synthase also possessed the ability to cyclize geranyl pyrophosphate to small amounts of alpha-thujene and to lesser quantities of myrcene, alpha-terpinene, limonene, linalool, terpinen-4-ol, and alpha-terpineol, all of which appear to be coproducts of the reaction sequence leading to gamma-terpinene. In general properties, the gamma-terpinene synthase from thyme leaves resembles other monoterpene cyclases as well as sesquiterpene and diterpene cyclases.

Chicken erythrocyte beta-globin chromatin: enhanced solubility is a direct consequence of induced histone hyperacetylation.

Chicken immature red blood cells were incubated for 1 hour in Swim's medium containing 3H-acetate and 10 mM n-butyrate. During the incubation period, the small percentage of dynamically acetylated and deacetylated histone is radiolabeled and hyperacetylated. A second effect of the n-butyrate incubation is to shift a small subset of nucleohistone into a soluble form. This chromatin is predominantly polynucleosome size (approximately dimer to pentamer) and can be separated from soluble mononucleosomes by 5-30% sucrose gradient centrifugation. The soluble polynucleosomes are 25-30 fold enriched for adult beta-globin (beta A) DNA and contain the hyperacetylated histones. We have tested whether histone hyperacetylation is responsible for the enhanced beta-globin chromatin solubility by in vitro deacetylation of the soluble chromatin histones. This procedure converts the beta-globin polynucleosomes to an insoluble form, demonstrating that histone hyperacetylation is in fact directly responsible for the increased solubility of the beta A chromatin.