Spatiotemporally explicit demographic modelling supports a joint effect of historical barriers to dispersal and contemporary landscape composition on structuring genomic variation in a red-listed grasshopper.

Inferring the processes underlying spatial patterns of genomic variation is fundamental to understand how organisms interact with landscape heterogeneity and to identify the factors determining species distributional shifts. Here, we use genomic data (restriction site-associated DNA sequencing) to test biologically informed models representing historical and contemporary demographic scenarios of population connectivity for the Iberian cross-backed grasshopper Dociostaurus hispanicus, a species with a narrow distribution that currently forms highly fragmented populations. All models incorporated biological aspects of the focal taxon that could hypothetically impact its geographical patterns of genomic variation, including (a) spatial configuration of impassable barriers to dispersal defined by topographic landscapes not occupied by the species; (b) distributional shifts resulting from the interaction between the species bioclimatic envelope and Pleistocene glacial cycles; and (c) contemporary distribution of suitable habitats after extensive land clearing for agriculture. Spatiotemporally explicit simulations under different scenarios considering these aspects and statistical evaluation of competing models within an Approximate Bayesian Computation framework supported spatial configuration of topographic barriers to dispersal and human-driven habitat fragmentation as the main factors explaining the geographical distribution of genomic variation in the species, with no apparent impact of hypothetical distributional shifts linked to Pleistocene climatic oscillations. Collectively, this study supports that both historical (i.e., topographic barriers) and contemporary (i.e., anthropogenic habitat fragmentation) aspects of landscape composition have shaped major axes of genomic variation in the studied species and emphasizes the potential of model-based approaches to gain insights into the temporal scale at which different processes impact the demography of natural populations.

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation.

BACKGROUND: Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS-BLED score. MATERIAL AND METHODS: We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS-BLED score if the patient was a simultaneous carrier of the VKORC1 and CYP2C9 polymorphisms related to bleeding, and we called this modified score "GEN|HAS-BLED." During a median follow-up of 7.6 years (IQR 5.6-8.0), all major bleeding events were recorded. RESULTS: During follow-up, 106 (16.2%) patients experienced a major bleeding (2.81%/y; 42 intracranial haemorrhages and 44 gastrointestinal bleeding) and 24 (3.7%) died from major bleeding (0.48%/y). Cox regression analyses demonstrated a significant association between HAS-BLED or GEN|HAS-BLED and major bleeds, both as continuous or categorical scores. Comparison of receiver operating characteristic (ROC) curves shows that original HAS-BLED clinical score had better predictive ability than GEN|HAS-BLED (0.660, 95% CI 0.622-0.696 vs 0.645, 95% CI 0.607-0.682; P = .030). Discrimination and reclassification analyses showed that GEN|HAS-BLED did not improve sensitivity compared with the original score and even showed significant negative reclassification. CONCLUSION: Adding pharmacogenetic factors (ie polymorphisms of the VKORC1 and CYP2C9 genes) to the HAS-BLED score does not improve the prediction or discrimination performance for major bleeding.

Dynamic assessment of CHA2DS2-VASc and HAS-BLED scores for predicting ischemic stroke and major bleeding in atrial fibrillation patients.

INTRODUCTION AND OBJECTIVES: Stroke and bleeding risks in atrial fibrillation (AF) are often assessed at baseline to predict outcomes years later. We investigated whether dynamic changes in CHA2DS2-VASc and HAS-BLED scores over time modify risk prediction. METHODS: We included patients with AF who were stable while taking vitamin K antagonists. During a 6-year follow-up, all ischemic strokes/transient ischemic attacks (TIAs) and major bleeding events were recorded. CHA2DS2-VASc and HAS-BLED were recalculated every 2-years and tested for clinical outcomes at 2-year periods. RESULTS: We included 1361 patients (mean CHA2DS2-VASc and HAS-BLED 4.0±1.7 and 2.9±1.2). During the follow-up, 156 (11.5%) patients had an ischemic stroke/TIA and 269 (19.8%) had a major bleeding event. Compared with the baseline CHA2DS2-VASc, the CHA2DS2-VASc recalculated at 2 years had higher predictive ability for ischemic stroke/TIA during the period from 2 to 4 years. Integrated discrimination improvement (IDI) and net reclassification improvement (NRI) showed improvements in sensitivity and better reclassification. The CHA2DS2-VASc recalculated at 4 years had better predictive performance than the baseline CHA2DS2-VASc during the period from 4 to 6 years, with an improvement in IDI and an enhancement of the reclassification. The recalculated HAS-BLED at 2-years had higher predictive ability than the baseline score for major bleeding during the period from 2 to 4 years, with significant improvements in sensitivity and reclassification. A slight enhancement in sensitivity was observed with the HAS-BLED score recalculated at 4 years compared with the baseline score. CONCLUSIONS: In AF patients, stroke and bleeding risks are dynamic and change over time. The CHA2DS2-VASc and HAS-BLED scores should be regularly reassessed, particularly for accurate stroke risk prediction.

Prescription of transdermal patches in Colombia: A real-world evidence study.

BACKGROUND: Transdermal drug delivery has contributed positively to medical practice. However, prescriptions that do not meet minimum quality criteria and medication errors are common. OBJECTIVE: The objective was to determine how transdermal patches are being prescribed to a group of patients in Colombia, the compliance with established requirements of such prescriptions and the comparisons between correct and incorrect prescriptions. METHODS: This was a cross-sectional study of prescriptions for transdermal patches using data from a population-based drug dispensing database between December 1 and 31, 2019. Medical prescriptions were randomly reviewed, establishing whether the drugs were appropriately prescribed by the manufacturer's indications or national regulations. Descriptive and bivariate analysis was performed. RESULTS: A total of 415 prescriptions were reviewed; the prescription was provided to 412 patients with a median age of 76.9 years, and 63.3% were women. Rivastigmine was the most prescribed transdermal patch (57.8%). 66.3% of all prescriptions did not meet the minimum appropriate prescribing standards, especially those for rivastigmine (97.1%). The 7.0% of all prescriptions had posology errors, especially prescriptions for buprenorphine (43.8%). Older patients (84.4% vs 52.5%), from the Pacific region (34.4% vs 23.7%), with manual formulations (22.1% vs 0.8%), dementia (49.0% vs 6.8%), and in management with lipid-lowering drugs (41.8% vs 30.5%), presented incorrect transdermal patch formulations more frequently (p < 0.05). CONCLUSION: The high proportion of inappropriately prescribed transdermal patches should draw the attention of those responsible for health care to improve the training of physicians and create prescription quality verification systems.

Potentially Inappropriate Prescriptions of Antipsychotics for Patients With Dementia.

Dementias are neurodegenerative and progressive diseases of the central nervous system. The objective of this study was to determine the frequency of potentially inappropriate prescriptions of antipsychotics in a group of patients diagnosed with dementia in Colombia. This was a cross-sectional study based on a population database for drug dispensing that identified prescriptions of antidementia drugs, antipsychotics, and other drugs for patients with a diagnosis of dementia. Descriptive statistics and bivariate and multivariate analyses were performed. A total of 11,372 patients with dementia were identified; 66.6% were women, and the mean age was 80.5 ± 9.6 years. Alzheimer's disease was the most frequent diagnosis (76.6%). A total of 69.0% of patients received antidementia drugs. A total of 37.1% of patients received some antipsychotic, especially atypical antipsychotics (31.0%). Increased age, being treated with memantine, simultaneously presenting with anxiety, depression, and psychotic disorders, and concomitantly receiving anticonvulsants, bronchodilators and benzodiazepines were associated with a greater probability of being prescribed antipsychotics. More than one-third of patients with dementia received antipsychotic prescriptions, which are considered potentially inappropriate because they can worsen cognitive decline and favor the occurrence of adverse events.

Characterization of sexually transmitted infections, their pharmacological treatment, and recurrence in a Colombian population. / Caracterización de las infecciones de transmisión sexual, su tratamiento farmacológico y la recurrencia en una población colombiana

INTRODUCTION: Sexually transmitted infections are a public health problem worldwide. Their inadequate antimicrobial management has been associated with a higher risk of recurrence. OBJECTIVE: To characterize the main sexually transmitted infections, the adherence to clinical practice guidelines, and the factors associated with recurrence in Colombia. MATERIALS AND METHODS: We conducted an observational study to identify the main sexually transmitted infections, the sociodemographic variables, and the pharmacological management in a patient cohort from a population database of 6.5 million people affiliated with the Colombian health system. We made a multivariate analysis to identify the variables associated with recurrence. RESULTS: We detected 3,158 patients with a mean age of 41.8 ± 14.5 years, of whom 63.1% were men. We found 4.030 episodes of sexually transmitted infections, predominantly urethral syndrome (27.5%). Only 13.6% of patients with urethral syndrome, ulcerative syndrome, or genital warts were managed in compliance with clinical practice guidelines and 20.6% were dispensed condoms; 16.7% of patients had recurrences and being male (OR=1.32; 95%CI 1.08-1.63), <30 years old (OR=1.72; 95%CI 1.40-2.13), being treated in municipalities other than capital cities (OR=1.43; 95%CI 1.06-1.94), and having received inadequate treatment for the first episode (OR=1.93; 95%CI 1.52-2.39) were associated with recurrence. CONCLUSIONS: The majority of patients with sexually transmitted infections were not treated in compliance with clinical practice guidelines and those who did not have adequate management had a higher risk of recurrence.

Introducción. Las infecciones de transmisión sexual constituyen actualmente un problema de salud pública en el mundo. Su inadecuado tratamiento antimicrobiano se ha relacionado con un mayor riesgo de recurrencias. Objetivo. Caracterizar las principales infecciones de transmisión sexual, el cumplimiento de las guías de práctica clínica de Colombia y los factores asociados con las recurrencias. Materiales y métodos. Se hizo un estudio observacional para determinar las principales infecciones de transmisión sexual, las variables sociodemográficas y el tratamiento farmacológico en una cohorte de pacientes registrados en una base de datos poblacional de 6,5 millones de personas afiliadas al Sistema de Salud de Colombia. Se hizo un análisis multivariado para establecer las variables asociadas con las recurrencias. Resultados. Se detectaron 3.158 pacientes; su edad media era de 41,8 ±14,5 años y 63,1 % de ellos correspondía a hombres; se encontraron 4.030 episodios de infecciones de transmisión sexual con predominio del síndrome uretral (27,5 %). El 13,6 % de los pacientes con síndrome uretral, ulceroso o con verrugas genitales se manejó según las guías de práctica clínica. El 20,6 % tenía acceso a condones y el 16,7 % presentó recurrencias. Ser hombre (OR=1,32; IC95% 1,08-1,63), tener <30 años (OR=1,72; IC95% 1,40-2,13), ser tratado en municipios distintos a ciudades capitales (OR=1,43; IC95% 1,06-1,94) y haber recibido un tratamiento inadecuado en el primer episodio (OR=1,93; IC95% 1,52-2,39) fueron factores asociados con las recurrencias. Conclusiones. La mayoría de los pacientes con infecciones de transmisión sexual no fueron tratados según las guías de práctica clínica y quienes no tuvieron un manejo adecuado presentaban mayor riesgo de recurrencias.

Anticoagulant therapy in patients with congenital FXI deficiency.

The bleeding phenotype of factor XI (FXI) deficiency is unpredictable. Bleeding is usually mild and mostly occurs after injury. Although FXI deficiency renders antithrombotic protection, some patients might eventually develop thrombosis or atrial fibrillation, requiring anticoagulant therapy. There is almost no evidence on the bleeding risk in this scenario. Our retrospective study of 269 white FXI-deficient subjects (1995-2021) identified 15 cases requiring anticoagulation. They harbored 8 different F11 variants, mainly in heterozygosis (1 case was homozygote), and had mild to moderate deficiency (FXI:C: 20% to 70%). Two subjects (13.3%) had bleeding history before anticoagulation. Atrial fibrillation was the main indication (12/15; 80%). Fourteen patients started therapy with vitamin K antagonists (VKA), but 4 subjects were on direct oral anticoagulants (DOACs) at the end of follow-up. Over >1000 months of anticoagulation, 2 mild bleeding episodes in 2 patients (13.3%, 95% confidence interval: 3.7% to 37.9%) were recorded. No major/fatal events were reported. "Pre-post" bleeding localization and severity did not change despite treatment. On VKA, drug dosing and management were also standard, unaltered by FXI deficiency. We provide the largest description of anticoagulant use in FXI deficiency, and the first cases receiving DOACs. Although further studies are needed, our observations suggest that moderate FXI deficiency does not interfere with anticoagulant management nor bleeding risk.

Multicenter collaborative study for standardization of Candida albicans genotyping using a polymorphic microsatellite marker.

Microsatellite-based genotyping for Candida albicans can give discrepant results between laboratories when expressed in fragment sizes, because their determination depends on electrophoretic conditions. The interlaboratory reproducibility was assessed in six laboratories provided with an allelic ladder. Despite variations in size determinations, alleles were correctly assigned, making data transportable between laboratories.

Insights into the neutral and adaptive processes shaping the spatial distribution of genomic variation in the economically important Moroccan locust (Dociostaurus maroccanus).

Understanding the processes that shape neutral and adaptive genomic variation is a fundamental step to determine the demographic and evolutionary dynamics of pest species. Here, we use genomic data obtained via restriction site-associated DNA sequencing to investigate the genetic structure of Moroccan locust (Dociostaurus maroccanus) populations from the westernmost portion of the species distribution (Iberian Peninsula and Canary Islands), infer demographic trends, and determine the role of neutral versus selective processes in shaping spatial patterns of genomic variation in this pest species of great economic importance. Our analyses showed that Iberian populations are characterized by high gene flow, whereas the highly isolated Canarian populations have experienced strong genetic drift and loss of genetic diversity. Historical demographic reconstructions revealed that all populations have passed through a substantial genetic bottleneck around the last glacial maximum (~21 ka BP) followed by a sharp demographic expansion at the onset of the Holocene, indicating increased effective population sizes during warm periods as expected from the thermophilic nature of the species. Genome scans and environmental association analyses identified several loci putatively under selection, suggesting that local adaptation processes in certain populations might not be impeded by widespread gene flow. Finally, all analyses showed few differences between outbreak and nonoutbreak populations. Integrated pest management practices should consider high population connectivity and the potential importance of local adaptation processes on population persistence.

Using high-throughput sequencing to investigate the factors structuring genomic variation of a Mediterranean grasshopper of great conservation concern.

Inferring the demographic history of species is fundamental for understanding their responses to past climate/landscape alterations and improving our predictions about the future impacts of the different components of ongoing global change. Estimating the time-frame at which population fragmentation took place is also critical to determine whether such process was shaped by ancient events (e.g. past climate/geological changes) or if, conversely, it was driven by recent human activities (e.g. habitat loss). We employed genomic data (ddRAD-Seq) to determine the factors shaping contemporary patterns of genetic variation in the Iberian cross-backed grasshopper Dociostaurus crassiusculus, an endangered species with limited dispersal capacity and narrow habitat requirements. Our analyses indicate the presence of two ancient lineages and three genetic clusters resulted from historical processes of population fragmentation (~18-126 ka) that predate the Anthropocene. Landscape genetic analyses indicate that the limits of major river basins are the main geographical feature explaining large-scale patterns of genomic differentiation, with no apparent effect of human-driven habitat fragmentation. Overall, our study highlights the importance of detailed phylogeographic, demographic and spatially-explicit landscape analyses to identify evolutionary significant units and determine the relative impact of historical vs. anthropogenic factors on processes of genetic fragmentation in taxa of great conservation concern.

Characterization of sexually transmitted infections, their pharmacological treatment, and recurrence in a Colombian population / Caracterización de las infecciones de transmisión sexual, su tratamiento farmacológico y la recurrencia en una población colombiana

Abstract | Introduction: Sexually transmitted infections are a public health problem worldwide. Their inadequate antimicrobial management has been associated with a higher risk of recurrence. Objective: To characterize the main sexually transmitted infections, the adherence to clinical practice guidelines, and the factors associated with recurrence in Colombia. Materials and methods: We conducted an observational study to identify the main sexually transmitted infections, the sociodemographic variables, and the pharmacological management in a patient cohort from a population database of 6.5 million people affiliated with the Colombian health system. We made a multivariate analysis to identify the variables associated with recurrence. Results: We detected 3,158 patients with a mean age of 41.8 ± 14.5 years, of whom 63.1% were men. We found 4.030 episodes of sexually transmitted infections, predominantly urethral syndrome (27.5%). Only 13.6% of patients with urethral syndrome, ulcerative syndrome, or genital warts were managed in compliance with clinical practice guidelines and 20.6% were dispensed condoms; 16.7% of patients had recurrences and being male (OR=1.32; 95%CI 1.08-1.63), <30 years old (OR=1.72; 95%CI 1.40-2.13), being treated in municipalities other than capital cities (OR=1.43; 95%CI 1.06-1.94), and having received inadequate treatment for the first episode (OR=1.93; 95%CI 1.52-2.39) were associated with recurrence. Conclusions: The majority of patients with sexually transmitted infections were not treated in compliance with clinical practice guidelines and those who did not have adequate management had a higher risk of recurrence.

Resumen | Introducción. Las infecciones de transmisión sexual constituyen actualmente un problema de salud pública en el mundo. Su inadecuado tratamiento antimicrobiano se ha relacionado con un mayor riesgo de recurrencias. Objetivo. Caracterizar las principales infecciones de transmisión sexual, el cumplimiento de las guías de práctica clínica de Colombia y los factores asociados con las recurrencias. Materiales y métodos. Se hizo un estudio observacional para determinar las principales infecciones de transmisión sexual, las variables sociodemográficas y el tratamiento farmacológico en una cohorte de pacientes registrados en una base de datos poblacional de 6,5 millones de personas afiliadas al Sistema de Salud de Colombia. Se hizo un análisis multivariado para establecer las variables asociadas con las recurrencias. Resultados. Se detectaron 3.158 pacientes; su edad media era de 41,8 ±14,5 años y 63,1 % de ellos correspondía a hombres; se encontraron 4.030 episodios de infecciones de transmisión sexual con predominio del síndrome uretral (27,5 %). El 13,6 % de los pacientes con síndrome uretral, ulceroso o con verrugas genitales se manejó según las guías de práctica clínica. El 20,6 % tenía acceso a condones y el 16,7 % presentó recurrencias. Ser hombre (OR=1,32; IC95% 1,08-1,63), tener <30 años (OR=1,72; IC95% 1,40-2,13), ser tratado en municipios distintos a ciudades capitales (OR=1,43; IC95% 1,06-1,94) y haber recibido un tratamiento inadecuado en el primer episodio (OR=1,93; IC95% 1,52-2,39) fueron factores asociados con las recurrencias. Conclusiones. La mayoría de los pacientes con infecciones de transmisión sexual no fueron tratados según las guías de práctica clínica y quienes no tuvieron un manejo adecuado presentaban mayor riesgo de recurrencias.

Multiple opportunistic fungal infections in an individual with severe HIV disease: A case report.

BACKGROUND: Fungal infections have been commonly diagnosed in individuals with advanced HIV disease. Cryptococcosis, pneumocystosis, and histoplasmosis are the most frequent systemic mycoses in people suffering from HIV/AIDS. CASE REPORT: We report a case of multiple fungal infections in an advanced AIDS-patient. A 33-year-old HIV-positive man from Brazil was hospitalized due to diarrhea, dyspnea, emaciation, hypoxemia, extensive oral thrush, and a CD4+ T lymphocyte count of 20cells/mm(3). Honeycombed-structures consistent with Pneumocystis jirovecii were observed by direct immunofluorescence in induced sputum. Cryptococcus neoformans was recovered from respiratory secretion and cerebrospinal fluid cultures. Histopathology of the bone marrow also revealed the presence of Histoplasma capsulatum. Molecular assays were performed in a sputum sample. Nested-PCR confirmed the presence of P. jirovecii and H. capsulatum; qPCR multiplex was positive for C. neoformans and H. capsulatum. With the treatment of antifungal drugs the patient progressed satisfactorily. CONCLUSIONS: The diagnosis of several systemic mycoses demonstrates the vulnerability of advanced AIDS-patients. Thus, the detection of AIDS cases in the early stages of infection is necessary for a prompt and adequate introduction of HAART therapy, and the use of prophylaxis to control opportunistic infections.