Addressing the COVID-19 transmission in inner Brazil by a mathematical model.

In 2020, the world experienced its very first pandemic of the globalized era. A novel coronavirus, SARS-CoV-2, is the causative agent of severe pneumonia and has rapidly spread through many nations, crashing health systems and leading a large number of people to death. In Brazil, the emergence of local epidemics in major metropolitan areas has always been a concern. In a vast and heterogeneous country, with regional disparities and climate diversity, several factors can modulate the dynamics of COVID-19. What should be the scenario for inner Brazil, and what can we do to control infection transmission in each of these locations? Here, a mathematical model is proposed to simulate disease transmission among individuals in several scenarios, differing by abiotic factors, social-economic factors, and effectiveness of mitigation strategies. The disease control relies on keeping all individuals' social distancing and detecting, followed by isolating, infected ones. The model reinforces social distancing as the most efficient method to control disease transmission. Moreover, it also shows that improving the detection and isolation of infected individuals can loosen this mitigation strategy. Finally, the effectiveness of control may be different across the country, and understanding it can help set up public health strategies.

Taking the inner route: spatial and demographic factors affecting vulnerability to COVID-19 among 604 cities from inner São Paulo State, Brazil.

Even though the impact of COVID-19 in metropolitan areas has been extensively studied, the geographic spread to smaller cities is also of great concern. We conducted an ecological study aimed at identifying predictors of early introduction, incidence rates of COVID-19 and mortality (up to 8 May 2020) among 604 municipalities in inner São Paulo State, Brazil. Socio-demographic indexes, road distance to the state capital and a classification of regional relevance were included in predictive models for time to COVID-19 introduction (Cox regression), incidence and mortality rates (zero-inflated binomial negative regression). In multivariable analyses, greater demographic density and higher classification of regional relevance were associated with both early introduction and increased rates of COVID-19 incidence and mortality. Other predictive factors varied, but distance from the State Capital (São Paulo City) was negatively associated with time-to-introduction and with incidence rates of COVID-19. Our results reinforce the hypothesis of two patterns of geographical spread of SARS-Cov-2 infection: one that is spatial (from the metropolitan area into the inner state) and another which is hierarchical (from urban centres of regional relevance to smaller and less connected municipalities). Those findings may apply to other settings, especially in developing and highly heterogeneous countries, and point to a potential benefit from strengthening non-pharmaceutical control strategies in areas of greater risk.

The role of intra and inter-hospital patient transfer in the dissemination of heathcare-associated multidrug-resistant pathogens.

Healthcare-associated infections cause significant patient morbidity and mortality, and contribute to growing healthcare costs, whose effects may be felt most strongly in developing countries. Active surveillance systems, hospital staff compliance, including hand hygiene, and a rational use of antimicrobials are among the important measures to mitigate the spread of healthcare-associated infection within and between hospitals. Klebsiella pneumoniae is an important human pathogen that can spread in hospital settings, with some forms exhibiting drug resistance, including resistance to the carbapenem class of antibiotics, the drugs of last resort for such infections. Focusing on the role of patient movement within and between hospitals on the transmission and incidence of enterobacteria producing the K. pneumoniae Carbapenemase (KPC, an enzyme that inactivates several antimicrobials), we developed a metapopulation model where the connections among hospitals are made using a theoretical hospital network based on Brazilian hospital sizes and locations. The pathogen reproductive number, R0 that measures the average number of new infections caused by a single infectious individual, was calculated in different scenarios defined by both the links between hospital environments (regular wards and intensive care units) and between different hospitals (patient transfer). Numerical simulation was used to illustrate the infection dynamics in this set of scenarios. The sensitivity of R0 to model input parameters, such as hospital connectivity and patient-hospital staff contact rates was also established, highlighting the differential importance of factors amenable to change on pathogen transmission and control.

Modelling the dynamics of dengue real epidemics.

In this work, we use a mathematical model for dengue transmission with the aim of analysing and comparing two dengue epidemics that occurred in Salvador, Brazil, in 1995-1996 and 2002. Using real data, we obtain the force of infection, Λ, and the basic reproductive number, R(0), for both epidemics. We also obtain the time evolution of the effective reproduction number, R(t), which results in a very suitable measure to compare the patterns of both epidemics. Based on the analysis of the behaviour of R(0) and R(t) in relation to the adult mosquito control parameter of the model, we show that the control applied only to the adult stage of the mosquito population is not sufficient to stop dengue transmission, emphasizing the importance of applying the control to the aquatic phase of the mosquito.

Modelling the lethargic crab disease.

The lethargic crab disease (LCD) is an emergent infirmity that has decimated native populations of the mangrove land crab (Ucides cordatus, Decapoda: Ocypodidae) along the Brazilian coast. Several potential etiological agents have been linked with LCD, but only in 2005 was it proved that it is caused by an ascomycete fungus. This is the first attempt to develop a mathematical model to describe the epidemiological dynamics of LCD. The model presents four possible scenarios, namely, the trivial equilibrium, the disease-free equilibrium, endemic equilibrium, and limit cycles arising from a Hopf bifurcation. The threshold values depend on the basic reproductive number of crabs and fungi, and on the infection rate. These scenarios depend on both the biological assumptions and the temporal evolution of the disease. Numerical simulations corroborate the analytical results and illustrate the different temporal dynamics of the crab and fungus populations.

Porosity and tortuosity relations as revealed by a mathematical model of biofilm structure.

A biofilm is assumed to be submerged in a fluid with given viscosity and low Reynolds number. The interaction between fluid and bacteria is modeled through streamlines. We use finite-difference and boundary element numerical schemes to predict streamlines within the biofilm. The results show that this approach can provide information about prior distribution and geometry of the biofilm structure. Theoretical values of porosity and tortuosity are computed and compared with published data.

Support for involvement of neuregulin 1 in schizophrenia pathophysiology.

Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population ("Hap(ICE)"), and two haplotypes located in the 3' end of NRG1 (all P<0.05). However, association was not detected with Hap(ICE) itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.

Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11.

As part of an extensive study in the Portuguese Island population of families with multiple patients suffering from bipolar disorder and schizophrenia, we performed an initial genome-wide scan of 16 extended families with bipolar disorder that identified three regions on chromosomes 2, 11, and 19 with genome-wide suggestive linkage and several other regions, including chromosome 6q, also approached suggestive levels of significance. Dick et al. [2003: Am J Hum Genet 73:107-114] recently reported in a study of 250 families with bipolar disorder a maxLOD score of 3.61 near marker D6S1021 on chromosome 6q. This study replicates this finding having detected a peak NPL = 2.02 (P = 0.025) with the same marker D6S1021(104.7 Mb). Higher-density mapping provided additional support for loci on chromosome 6 including marker D6S1021 with an NPL = 2.59 (P = 0.0068) and peaking at marker D6S1639 (125 Mb) with an NPL = 3.06 (P = 0.0019). A similar pattern was detected with higher-density mapping of chromosome 11 with an NPL = 3.15 (P = 0.0014) at marker D11S1883 (63.1 Mb). Simulations at the density of our fine mapping data indicate that less than 1 scan out of 10 would find two such scores genome-wide in the same scan by chance. Our findings provide additional support for a susceptibility locus for bipolar disorder on 6q, as well as, suggesting the importance of denser scans. Published 2004 Wiley-Liss, Inc.

Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22.

We performed a linkage analysis on 25 extended multiplex Portuguese families segregating for bipolar disorder, by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the GeneChip Human Mapping 10K Array (HMA10K). Of these families, 12 were used for a direct comparison of the HMA10K with the traditional 10-cM microsatellite marker set and the more dense 4-cM marker set. This comparative analysis indicated the presence of significant linkage peaks in the SNP assay in chromosomal regions characterized by poor coverage and low information content on the microsatellite assays. The HMA10K provided consistently high information and enhanced coverage throughout these regions. Across the entire genome, the HMA10K had an average information content of 0.842 with 0.21-Mb intermarker spacing. In the 12-family set, the HMA10K-based analysis detected two chromosomal regions with genomewide significant linkage on chromosomes 6q22 and 11p11; both regions had failed to meet this strict threshold with the microsatellite assays. The full 25-family collection further strengthened the findings on chromosome 6q22, achieving genomewide significance with a maximum nonparametric linkage (NPL) score of 4.20 and a maximum LOD score of 3.56 at position 125.8 Mb. In addition to this highly significant finding, several other regions of suggestive linkage have also been identified in the 25-family data set, including two regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), as well as regions on chromosomes 4 (91 Mb, NPL = 2.97), 16 (20 Mb, NPL = 2.89), and 20 (60 Mb, NPL = 2.99). We conclude that at least some of the linkage peaks we have identified may have been largely undetected in previous whole-genome scans for bipolar disorder because of insufficient coverage or information content, particularly on chromosomes 6q22 and 11p11.

Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis.

Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island populations, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31-5q35 with strong linkage (NPL=3.09, P=0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL=3.10 for significant linkage. Additional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 additional families. The combined set of 40 families had a peak NPL=3.28 (P=0.00066) at markers D5S2112-D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia (peak NPL=3.03, P=0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases. Molecular Psychiatry (2004) 9, 213-218. doi:10.1038/sj.mp.4001418 Published online 30 December 2003

Estudo farmacognóstico de Croton rhamnifolius H.B.K. e Croton rhamnifolioides Pax & Hoffm. (Euphorbiaceae) / Pharmacognostic study of Croton rhamnifolius H.B.K. and Croton rhamnifolioides Pax & Hoffm. (Euphorbiaceae)

Aspectos farmacognósticos de Croton rhamnifolius H.B.K. e C. rhamnifolioides Pax & Hoffm. foram comparados. Evocou-se a armacogeografia do gênero em Pernambuco, bem como a farmacoetimologia, farmacoetnologia, farmacobotânica e a farmacoquímica das espécies citadas. Este estudo permitiu localizar os taxa nesse Estado, conhecer seus nomes vulgares e suas utilizações, segundo a população local. Comparou-se também as características botânicas e finalizou-se com um estudo fitoquímico, que evidenciou os protocolos extrativos, e a caracterização dos principais grupos de substância presentes nos dois taxa: polifenóis, terpenóides, alcalóides e açúcares redutores.

The pharmacognostical aspects of Croton rhamnifolius H.B.K. and C. rhamnifolioides Pax & Hoffm. have been compared. The parameters applied for such comparison were the pharmacogeography concerning this genus in Pernambuco, as well as the pharmacoetymology, the pharmacoethnology, the pharmacobotany and the pharmacochemistry, all of which related to both species above mentioned. Not only was the present study able to ascertain the species’ rate regarding the State, but also to determine its medical usage and denomination among the locals. The botanical characteristics were compared and a phytochemical analysis was carried out in order to establish the extractive rocedures and also the main molecule’s rate found on both: terpenoids, alkaloids, polyphenols and reducting sugars.

Identification of candidate genes for psychosis in rat models, and possible association between schizophrenia and the 14-3-3eta gene.

Although the genetic contribution to schizophrenia is substantial, positive findings in whole-genome linkage scans have not been consistently replicated. We analyzed gene expression in various rat conditions to identify novel candidate genes for schizophrenia. Suppression subtraction hybridization (SSH), with polyA mRNA from temporal and frontal cortex of rats, was used to identify differentially expressed genes. Expression of mRNA was compared between adult Lewis and Fischer 344 (F344) rats, adult and postnatal day 6 (d6) F344, and adult F344 treated with haloperidol or control vehicle. These groups were chosen because each highlights a particular aspect of schizophrenia: differences in strain vulnerability to behavioral analogs of psychosis; factors that may relate to disease onset in relation to CNS development; and improvement of symptoms by haloperidol. The 14-3-3 gene family, as represented by 14-3-3gamma and 14-3-3zeta isoforms in the SSH study, and SNAP-25 were among the candidate genes. Genetic association between schizophrenia and the 14-3-3eta gene, positioned close to a genomic locus implicated in schizophrenia, and SNAP-25 genes was analyzed in 168 schizophrenia probands and their families. These findings address three different genes in the 14-3-3 family. We find a significant association with schizophrenia for two polymorphisms in the 14-3-3eta gene: a 7 bp variable number of tandem repeats in the 5' noncoding region (P=0.036, 1 df), and a 3' untranslated region SNP (753G/A) that is an RFLP visualized with Ava II (P=0.028). There was no significant genetic association with SNAP-25. The candidate genes identified may be of functional importance in the etiology, pathophysiology or treatment response of schizophrenia or psychotic symptoms. This is to our knowledge the first report of a significant association between the 14-3-3eta-chain gene and schizophrenia in a family-based sample, strengthening prior association reports in case-control studies and microarray gene expression studies.

Evolution of protein synthesis in a lattice model of replicators.

The traditional chemical-kinetics approach to the study of prebiotic evolution cannot explain the evolution of protein synthesis in a homogeneous population of self-replicating molecules, because the invasion of a resident population of simpler, template-directed replicators by mutant protein-assisted replicators is deemed impossible. Approaching this problem in a spatial cellular automaton framework, we argue here that in such a setting evolution of protein synthesis is a likely event. In addition, we show that the onset of invasion may be viewed as a nonequilibrium phase transition, that can be characterized quantitatively by a set of critical exponents.

Phase transitions in a model for the formation of herpes simplex ulcers.

The critical properties of a cellular automaton model describing the spreading of infection of the herpes simplex virus in corneal tissue are investigated through the dynamic Monte Carlo method. The model takes into account different cell susceptibilities to the viral infection, as suggested by experimental findings. In a two-dimensional square lattice the sites are associated with two distinct types of cells, namely, permissive and resistant to the infection. While a permissive cell becomes infected in the presence of a single infected cell in its neighborhood, a resistant cell needs to be surrounded by at least R>1 infected or dead cells in order to become infected. The infection is followed by the death of the cells resulting in ulcers whose forms may be dendritic (self-limited clusters) or amoeboid (percolating clusters) depending on the degree of resistance R of the resistant cells as well as on the density of permissive cells in the healthy tissue. We show that a phase transition between these two regimes occurs only for R>/=5 and, in addition, that the phase transition is in the universality class of the ordinary percolation.

Evidence for linkage disequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families.

Recent studies have suggested that the alpha 7-nicotinic receptor gene (CHRNA7) may play a role in the pathogenesis of schizophrenia. The alpha 7-nicotinic receptor gene (CHRNA7) is involved in P50 auditory sensory gating deficits, and the genomic locus for this gene lies in the chromosome 15q13-14 regions. The human gene is partially duplicated (exons 5-10) with four novel upstream exons. The marker D15S1360 has been shown to be significantly linked with the phenotype of abnormal P50 suppression in schizophrenia families. The marker L76630 is 3 kb in the 3' direction from the last exon of the CHRNA7 gene and is located in the duplicated region. The function of the two L76630 copies is unknown. We genotyped three polymorphic markers D15S1360, D15S165, and L76630 that are localized in a genomic fragment containing the CHRNA7 in 31 Azorean schizophrenia families/trios (including 41 schizophrenia individuals and 97 unaffected families members). An overall analysis utilizing the family-based association test revealed significant linkage disequilibrium between L76630 and schizophrenia (P = 0.0004). Using the extended transmission disequilibrium test and limiting the analysis to one triad per family, transmission disequilibrium of D15S1360 was near significance (P = 0.078). The 15q13 region overlaps with the location of two well-known genomically imprinted disorders: Angelman syndrome and Prader-Willi syndrome. Therefore, we investigated maternal and paternal meioses. We found significant transmission disequilibrium for D15S1360 through paternal transmission (P = 0.0006) in our schizophrenia families. The L76630 marker showed a significant disequilibrium in maternal transmissions (P = 0.028). No parent-of-origin effect was found in D15S165. Overall, our results suggest that the CHRNA7 may play a role in schizophrenia in these families. A parent of origin effect may be present and requires further study.

[Associated and prognosis in apparent life threatening events (ALTE)] / Patologias associadas e prognóstico de eventos com aparente risco de vida (ALTE).

OBJECTIVE: To verify the etiology and prognosis of ALTE in infancy and its possible relationship to Sudden Infant Death Syndrome (SIDS). METHODS: We studied a group of infants that presented ALTE episodes and were evaluated in our hospital. First we reviewed their clinical history and polysomnographies, then we sent a letter to the families with questions regarding the outcome. RESULTS: 56 patients were included. 92% had ALTE during their first 6 months and 83% in the first trimester. Symptomatic ALTE predominated (71%). The disease most frequently associated was gastroesophageal reflux, followed by neurological diseases. The follow up showed 51.5% of normal outcome, 4 children repeated ALTE, no cases of SIDS were registered. CONCLUSIONS: Our results showed that multifactorial etiologies can be associated to ALTE, and the outcome is generally related to the associated disease. We did not observe any relationship between ALTE and SIDS considering a predominantly symptomatic ALTE population.

Selection of homogeneous populations for genetic study: the Portugal genetics of psychosis project.

Molecular genetic studies of psychiatric disorders must face the possibility that despite the significant contribution of genetic factors to the expression of syndromes like schizophrenia, these syndromes may be a heterogeneous collection of genetic and non-genetic illnesses. These illnesses may be etiologically distinct from each other and still share many clinical features in common. Linkage studies of families with multiple affected members tend to favor the selection of genetic forms of a syndrome but can still represent a heterogeneous set of different genetic illnesses. To limit the potential genetic heterogeneity of a study sample, we selected a population that was geographically isolated and was historically relatively genetically homogeneous. We then assessed the relative level of homogeneity utilizing a surname analysis of the population of the Azores, mainland Portugal, rural USA, and urban USA. The average number of families with the same last name corrected for population size in the Azores is 30.88, in Coimbra it is 21.42, compared to 1.13 in a rural American population and 0.38 in an urban American population. The results of this analysis indicate that the Azores have the highest degree of homogeneity, and mainland Portugal has a high degree of homogeneity.

Anorexia nervosa and bulimia: a prevalence study.

We determined the prevalence of anorexia nervosa and bulimia in a large sample of students attending a secondary school on the island of São Miguel (Azores) using the Diagnostic Interview for Children and Adolescents, which enabled us to collect the information necessary to make DSM-III diagnoses. Although the prevalence of anorectic and bulimic behaviour was rather high, the partial syndrome of anorexia nervosa was found in only 0.48% of the students (0.76% for girls and 0.17% for boys) and the syndrome of bulimia in only 0.16% (0.30% of the girls; there were no boys with bulimia). The overall prevalence of eating disorders, including partial syndromes, was rather low (0.64%). These results stand in sharp contrast to reports that eating disorders are common and probably getting more common. The low prevalence found in the present survey is probably due to the absence of sociocultural pressures to control eating and weight.