Sensitivity to prior independence via Farlie-Gumbel-Morgenstern model

Statistical Methods

Update on Dihydropteroate Synthase (DHPS) Mutations in Pneumocystis jirovecii

A Pneumocystis jirovecii is one of the most important microorganisms that cause pneumonia in immunosupressed individuals. The guideline for treatment and prophylaxis of Pneumocystis pneumonia (PcP) is the use of a combination of sulfa drug-containing trimethroprim and sulfamethoxazole. In the absence of a reliable method to culture Pneumocystis, molecular techniques have been developed to detect mutations in the dihydropteroate synthase gene, the target of sulfa drugs, where mutations are related to sulfa resistance in other microorganisms. The presence of dihydropteroate synthase (DHPS) mutations has been described at codon 55 and 57 and found almost around the world. In the current work, we analyzed the most common methods to identify these mutations, their geographical distribution around the world, and their clinical implications. In addition, we describe new emerging DHPS mutations. Other aspects, such as the possibility of transmitting Pneumocystis mutated organisms between susceptible patients is also described, as well as a brief summary of approaches to study these mutations in a heterologous expression system

Geographical variation in serological responses to recombinant Pneumocystis jirovecii major surface glycoprotein antigens

AbstractThe use of recombinant fragments of the major surface glycoprotein (Msg) of Pneumocystis jirovecii has proven useful for studying serological immune responses of blood donors and human immunodeficiency virus (HIV)-positive (HIV+) patients. Here, we have used ELISA to measure antibody titres to Msg fragments (MsgA, MsgB, MsgC1, MsgC3, MsgC8 and MsgC9 in sera isolated in the USA (n=200 and Spain (n=326), to determine whether geographical location affects serological responses to these antigens. Blood donors from Seville exhibited a significantly greater antibody titre to MsgC8, and significantly lower responses to MsgC3 and MsgC9, than did Cincinnati (USA) donors. Spanish blood donors (n=162 also exhibited elevated responses to MsgC1, MsgC8 and MsgC9 as compared with Spanish HIV+ (n=patients. HIV+ patients who had Pneumocystis pneumonia (PcP+) exhibited a higher response to MsgC8 than did HIV+ PcP- patients. These data show that geographical location plays a role in responsiveness to Msg fragments. Additionally, these fragments have utility in differentiating HIV+ PcP and HIV+ PcP+ among patient populations

High prevalence of Pneumocystis jirovecii pneumonia among Mozambican children < 5 years of age admitted to hospital with clinical severe pneumonia

We aimed to describe Pneumocystis jirovecii pneumonia (PCP) prevalence and features in children from sub-Saharan Africa, and to investigate PCP-associated risk factors. During 2006-2007 we used molecular methods to test children younger than 5 years old admitted with severe pneumonia to a hospital in Southern Mozambique for Pneumocystis infection. We recruited 834 children. PCP prevalence was 6.8% and HIV prevalence was 25.7%. The in-hospital and delayed mortality were significantly higher among children with PCP (20.8% vs. 10.2 %, p=0.021, and 11.5% vs. 3.6%, p=0.044, respectively). Clinical features were mostly overlapping between the two groups. Independent risk factors for PCP were age less than a year (OR 6.34, 95%CI 1.86-21.65), HIV infection (OR 2.99, 95%CI 1.16-7.70), grunting (OR 2.64, 95%CI 1.04-6.73), and digital clubbing (OR 10.75, 95%CI 1.21-95.56). PCP is a common and life-threatening cause of severe pneumonia in Mozambican children. Mother-to-child HIV transmission prevention should be strengthened. Better diagnostic tools are needed

Primeros datos del magmatismo pérmico medio-superior del SE de la Cordillera Ibérica: caracterización y comparación con magmatismos contemporáneos del Tethys occidental

A multiple basic to intermediate sill is reported for the first time in the south-eastern Iberian Ranges. It is composed of several tabular to irregular levels intercalated within the fluvial sediments of the Alcotas Formation (Middle-Upper Permian). The sill could represent the youngest Paleozoic subvolcanic intrusion in the Iberian Ranges. The igneous rocks are classified as basaltic andesites. They show a subophitic microstructure constituted by plagioclase (An62 – An6), augite (En48Wo44Fs7 –En46Wo39Fs15), pseudomorphosed olivine, minor amounts of oxides (magnetite and ilmenite) and accessory F-apatite. According to the mineralogy and whole-rock composition, their geochemical affinity is transitional from subalkaline to alkaline. Radiometric dating of the sill is not feasible due to its significant alteration. Field criteria, however, suggest an emplacement coeval to the deposition of the Alcotas Formation (Middle-Upper Permian). This hypothesis is supported by the transitional affinity of these rocks, similar to other Middle-Upper Permian magmatisms in the western Tethys, e.g., from the Pyrenees. Taking into account their isotopic signature (εSr: -6.8 to -9.2; εNd: +1.7 to +8.3), an enriched mantle source with the involvement of a HIMU component has been identified. This interpretation is supported by the trace element contents. Some of these HIMU characteristics have been recognised in the Middle-Upper Permian magmatisms of the Central Pyrenees (Anayet Basin) and the High Atlas (Argana Basin). However, none of these source features are shared with other Middle-Upper Permian magmatisms of the western Tethys (Catalonian Coastal Ranges, Corsica-Sardinia and southern France), nor with the Lower Permian magmatism of the Iberian Ranges. These differences support the presence of a heterogeneous mantle in the western Tethys during the Permian.Se describe por primera vez en el sudeste de la Cordillera Ibérica un sill múltiple de carácter básico a intermedio. Está compuesto por varios cuerpos tabulares a irregulares intercalados entre los sedimentos de origen fluvial de la Formación Alcotas (Pérmico Medio-Superior). El sill podría representar la intrusión subvolcánica paleozoica más reciente en la Cordillera Ibérica. Estas rocas subvolcánicas se clasifican como andesitas basálticas. Muestran una textura subofítica constituida por plagioclasa (An62 – An6), augita (En48Wo44Fs7 –En46Wo39Fs15), pseudomorfos de olivino, minerales opacos (magnetita e ilmenita) y F-apatito accesorio. De acuerdo con su composición mineral y de roca total, su afinidad geoquímica es transicional entre subalcalina y alcalina. La datación radiométrica del sill no es posible debido a su elevado grado de alteración. No obstante, los criterios de campo sugieren un emplazamiento contemporáneo con el depósito de la Formación Alcotas (Pérmico Medio-Superior). Esta hipótesis está apoyada por la afinidad transicional de estas rocas, similar a otros episodios magmáticos del Pérmico Medio-Superior en el Tethys occidental, como los que afloran en los Pirineos. Teniendo en cuenta su signatura isotópica (εSr: -6.8 a -9.2; εNd: +1.7 a +8.3), se propone un origen a partir de un manto enriquecido, con la participación de un componente de tipo HIMU. Esta interpretación está apoyada por sus contenidos en elementos traza. Algunas de estas características del protolito han sido reconocidas en los magmatismos del Pérmico Medio-Superior del Pirineo (cuenca del Anayet) y del Alto Atlas (cuenca de Argana), pero no son habituales en otros magmatismos de edad Pérmico Medio-Superior del Tethys occidental (Cadenas Costero Catalanas, Córcega-Cerdeña y Sur de Francia), ni en el magmatismo Pérmico Inferior de la Cordillera Ibérica. Estas diferencias apoyan la presencia de un manto heterogéneo en el Tethys occidental durante el Pérmico

Transition between Variscan and Alpine cycles in the Pyrenean-Cantabrian Mountains (N Spain): Geodynamic evolution of near-equator European Permian basins

In the northern Iberian Peninsula, the Pyrenean-Cantabrian orogenic belt extends E-W for ca. 1000 km between the Atlantic Ocean and Mediterranean Sea. This orogen developed from the collision between Iberia and Eurasia, mainly in Cenozoic times. Lower-middle Permian sediments crop out in small, elongated basins traditionally considered independent from each other due to misinterpretations on incomplete lithostratigraphic data and scarce radiometric ages. Here, we integrate detailed stratigraphic, sedimentary, tectonic, paleosol and magmatic data from well-dated lithostratigraphic units. Our data reveal a similar geodynamic evolution across the Pyrenean-Cantabrian Ranges at the end of the Variscan cycle. Lower-middle Permian basins started their development under an extensional regime related to the end of the Variscan Belt collapse, which stars in late Carboniferous times in the Variscan hinterland. This orogenic collapse transitioned to Pangea breakup at the middle Permian times in the study region. Sedimentation occurred as three main tectono-sedimentary extensional phases. A first phase (Asselian-Sakmarian), which may have even started at the end of the Carboniferous (Gzhelian) in some sections, is mainly represented by alluvial sedimentation associated with calc-alkaline magmatism. A second stage (late Artinskian-early Kungurian), represented by al-luvial, lacustrine and palustrine sediments with intercalations of calc-alkaline volcanic beds, shows a clear up-ward aridification trend probably related to the late Paleozoic icehouse-greenhouse transition. The third and final stage (Wordian-Capitanian) comprised of alluvial deposits with intercalations of alkaline and mafic beds, rarely deposited in the Cantabrian Mountains, and underwent significant pre-and Early Mesozoic erosion in some segments of the Pyrenees. This third stage can be related to a transition towards the Pangea Supercontinent breakup, not generalized until the Early/Middle Triassic at this latitude because the extensional process stopped about 10 Myr (Pyrenees) to 30 Myr (Cantabrian Mountains). When compared to other well-dated basins near the paleoequator, the tectono-sedimentary and climate evolution of lower-middle Permian basins in Western and Central Europe shows common features. Specifically, we identify coeval periods with magmatic activity, extensional tectonics, high subsidence rates and thick sedi-mentary record, as well as prolonged periods without sedimentation. This comparison also identifies some evolutionary differences between Permian basins that could be related to distinct locations in the hinterland or foreland of the Variscan orogen. Our data provide a better understanding of the major crustal re-equilibration and reorganization that took place near the equator in Western-Central Europe during the post-Variscan period

New lithostratigraphy for the Cantabrian Mountains: A common tectono-stratigraphic evolution for the onset of the Alpine cycle in the W Pyrenean realm, N Spain

The Pyrenean-Cantabrian Orogen arose through the collision of the Iberian and Eurasian plates, mostly in Cenozoic times. This orogen comprises two main mountain ranges, the Pyrenees to the east, and the Cantabrian Mountains to the west. To date, the early Alpine tectono-sedimentary phases preserved in the Cantabrian Mountains, of Permian and Triassic age, have been considered independently from the same phases in neighbouring basins of SW Europe, and even from the eastern part of the same orogeny (the Pyrenean orogeny). In consequence, the beginning of the Alpine cycle in the Cantabrian Mountains has been interpreted within a specific geodynamic context, far from the general evolutionary phases of the western Peri-Tethys basins. Through detailed field work, including geological mapping, sedimentology, lithostratigraphy and petrology of volcanic rocks, and new palaeontological data, here we define several new lithostratigraphical formations and five new tectono-sedimentary cycles (TS I-V) for the initial phases of evolution of the Mesozoic Basque-Cantabrian Basin, interrupted by periods of tectonic stability. To complete this information, we include data from an onshore borehole (Villabona Mine) and two offshore boreholes constrained by 2D reflection seismic profiles acquired in the North Iberian continental platform. The main tectono-sedimentary cycles, related to the deposition of five major identified lithostratigraphic units, can be described as follows: TS I (late Gzelian-early Asselian), relating to the late Variscan deformation and preserved in a single outcrop in all the Cantabrian Mountains (San Tirso Formation). This formation is constituted by medium-distal alluvial fan deposits in which humid intervals predominate, forming some thin coal beds. TS II (Asselian-Sakmarian), a post-Variscan extensional phase with associated calc-alkaline magmatism, represented by profuse volcanic and volcanosedimentary intercalations in the early Permian sedimentary basins (Acebal Formation) and small plutons in surrounding areas. TS III (Kungurian), or reactivation of the post-Variscan extension leading to alluvial and lacustrine carbonate sedimentation in arid climate conditions, which do not change during the rest of the Permian and Triassic periods (Sotres Formation). A generalized karstification in the basin represents the end of Permian deposition, followed by an interruption in sedimentation longer than 30 Myr. The Permian tectono-sedimentary cycles (TS II and TS III) are contemporary with Variscan belt collapse and the basins are controlled by extensional reactivation of NE-SW and E-W Variscan structures, and NW-SE late Variscan structures. TS IV (late Anisian–middle Carnian), renewed sedimentation in more extensive basins, precursors of the great Mesozoic Basque-Cantabrian Basin. This cycle is represented by fluvial deposits (Cicera Formation, or Buntsandstein facies), which are interrupted by the first Mesozoic marine ingression (Rueda Formation, or Muschelkalk facies). TS V (Norian-Rhaetian), or shallow marine carbonate deposits (Transición Formation) related to increasingly compartmentalized sub-basins, controlled by normal faults. This final TS is broadly connected with different basins of the western Peri-Tethys domain. The identification of units TS I-V in the Cantabrian Mountains along with the volcanic character of TS II, all indicate the development of a common post-Variscan to early Alpine tectono-sedimentary evolution for the whole Pyrenean-Cantabrian realm

High prevalence of Pneumocystis jirovecii pneumonia among Mozambican children <5 years of age admitted to hospital with clinical severe pneumonia

We aimed to describe Pneumocystis jirovecii pneumonia (PCP) prevalence and features in children from sub-Saharan Africa and to investigate PCP-associated risk factors. During 2006–2007 we used molecular methods to test children younger than 5 years old admitted with severe pneumonia to a hospital in southern Mozambique for Pneumocystis infection. We recruited 834 children. PCP prevalence was 6.8% and HIV prevalence was 25.7%. The in-hospital and delayed mortality were significantly higher among children with PCP (20.8% vs. 10.2%, p 0.021, and 11.5% vs. 3.6%, p 0.044, respectively). Clinical features were mostly overlapping between the two groups. Independent risk factors for PCP were age less than a year (odds ratio (OR) 6.34, 95% confidence interval (CI) 1.86–21.65), HIV infection (OR 2.99, 95% CI 1.16–7.70), grunting (OR 2.64, 95% CI 1.04–6.73) and digital clubbing (OR 10.75, 95% CI 1.21–95.56). PCP is a common and life-threatening cause of severe pneumonia in Mozambican children. Mother-to-child HIV transmission prevention should be strengthened. Better diagnostic tools are needed.This work was supported by the World Health Organization (WHO-C6-181-489). QB has a fellowship from the program Miguel Servet of the ISCIII (Plan Nacional de I+D+I 2008–2011, grant CP11/00269). LM has a fellowship from the program Río Hortega of the ISCIII (CM13/00260).Peer reviewe

A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia

We hypothesized that a common SNP in the 3' untranslated region of the upstream transcription factor 1 (USF1), rs3737787, may affect lipid traits by influencing gene expression levels, and we investigated this possibility utilizing the Mexican population, which has a high predisposition to dyslipidemia. We first associated rs3737787 genotypes in Mexican Familial Combined Hyperlipidemia (FCHL) case/control fat biopsies, with global expression patterns. To identify sets of co-expressed genes co-regulated by similar factors such as transcription factors, genetic variants, or environmental effects, we utilized weighted gene co-expression network analysis (WGCNA). Through WGCNA in the Mexican FCHL fat biopsies we identified two significant Triglyceride (TG)-associated co-expression modules. One of these modules was also associated with FCHL, the other FCHL component traits, and rs3737787 genotypes. This USF1-regulated FCHL-associated (URFA) module was enriched for genes involved in lipid metabolic processes. Using systems genetics procedures we identified 18 causal candidate genes in the URFA module. The FCHL causal candidate gene fatty acid desaturase 3 (FADS3) was associated with TGs in a recent Caucasian genome-wide significant association study and we replicated this association in Mexican FCHL families. Based on a USF1-regulated FCHL-associated co-expression module and SNP rs3737787, we identify a set of causal candidate genes for FCHL-related traits. We then provide evidence from two independent datasets supporting FADS3 as a causal gene for FCHL and elevated TGs in Mexicans

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality