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Abstract Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions.

Abstract Genomic surveillance (GS) programmes were crucial in identifying and quantifying the mutating patterns of SARS-CoV-2 during the COVID-19 pandemic. In this work, we develop a Bayesian framework to quantify the relative transmissibility of different variants tailored for regions with limited GS. We use it to study the relative transmissibility of SARS-CoV-2 variants in Chile. Among the 3443 SARS-CoV-2 genomes collected between January and June 2021, where sampling was designed to be representative, the Gamma (P.1), Lambda (C.37), Alpha (B.1.1.7), B.1.1.348, and B.1.1 lineages were predominant. We found that Lambda and Gamma variants’ reproduction numbers were 5% (95% CI: [1%, 14%]) and 16% (95% CI: [11%, 21%]) larger than Alpha’s, respectively. Besides, we observed a systematic mutation enrichment in the Spike gene for all circulating variants, which strongly correlated with variants’ transmissibility during the studied period (r = 0.93, p-value = 0.025). We also characterised the mutational signatures of local samples and their evolution over time and with the progress of vaccination, comparing them with those of samples collected in other regions worldwide. Altogether, our work provides a reliable method for quantifying variant transmissibility under subsampling and emphasises the importance of continuous genomic surveillance.

Objetivo: Traducir y adaptar transculturalmente la escala de dolor anterior de la rodilla (AKPS, por sus siglas en inglés) al español argentino para sujetos con síndrome femoropatelar. Materiales y métodos: Se realizó la traducción de la escala original en inglés siguiendo los lineamientos correspondientes. Se evaluaron 35 sujetos de habla hispana argentina, con edades entre 13 y 45 años y diagnóstico de dolor femoropatelar, mediante la escala traducida. Los sujetos asistieron a cuatro centros de rehabilitación en tres provincias de Argentina. Resultados: Se tradujo la versión original del inglés al español argentino. Se realizó la prueba piloto en 35 sujetos, sin que se registraran dificultades. El tiempo promedio de administración fue de 4 minutos y 10 segundos. Conclusión:Mediante este proceso de traducción y prueba, se obtuvo la adaptación transcultural de la AKPS al español argentino para sujetos con dolor femoropatelar, lo que permitirá evaluar sus propiedades psicométricas en el futuro. Este estudio aporta una herramienta útil para la práctica diaria de los/las terapeutas que participan en la rehabilitación de sujetos con dolor femoropatelar en Argentina.

The presence of skin bacteria capable of forming biofilm, exhibiting antibiotic resistance, and displaying virulence represents a significant challenge in the field of transfusion medicine. This underscores the necessity of enhancing the microbiological safety of blood and blood components against pathogens with virulent characteristics. The aim of this work was to demonstrate bacterial inactivation in plasma by using a photoinactivation method against virulent bacteria and to evaluate coagulation factors before and after treatment. Logarithmic loads of biofilm-producing, antibiotic-resistant, and virulent bacteria isolated from skin (Enterobacter cloacae, Klebsiella ozaenae, and Staphylococcus epidermidis) were used in artificial contamination assays of fresh frozen plasma bags and subjected to photoreduction. FVIII and FI activity were evaluated before and after photoinactivation. The photoinactivation of plasma was demonstrated to be an effective method for the elimination of these bacteria. However, the efficiency of this method was found to be dependent on the bacterial load and the type of test microorganism. Conversely, decay of coagulation factors was observed with net residual activities of 61 and 69% for FVIII and FI, respectively. The photoinactivation system could have a bias in its effectiveness that is dependent on the test pathogen. These findings highlight the importance of employing technologies that increase the safety of the recipient of blood and/or blood components, especially against virulent bacteria, and show the relevance of the role of photoinactivation systems as an option in transfusion practice.

Abstract Previous research has suggested that classical psychedelics can foster significant and enduring changes in personality traits and subjective wellbeing. Despite the lack of evidence for adverse effects on mental health stemming from psychedelic use, concerns persist regarding the capacity of these substances to modulate information processing and attitudes towards factual data. The aim of the present study was to investigate the propensity for accepting alternative facts and the general treatment of knowledge within a sample of 392 participants, 233 of whom reported at least a single incidence of psychedelic use in their lifetime. To do this, we leveraged step-wise methods of linear modelling investigating effects of demographics, psychiatric conditions and concomitant drug use. Our findings revealed a moderate positive association between psychedelic use and beliefs in alternative facts, as well as the specific belief that facts are politically influenced. However, no links were found for favouring intuition over evidence when confirming facts. Among other investigated drugs, only alcohol was negatively associated with beliefs in alternative facts. Taken together, our results support the link between psychedelic use and non-conformist thinking styles, which can be attributed to the psychological effects of the drugs themselves, but may also mirror a common trait related to unconventional beliefs and illicit substance use.

Abstract Cranial cruciate ligament (CCL) rupture is one of the most commonly diagnosed orthopedic conditions of pet dogs, making estimated lifetime cruciate ligament survival an attractive endpoint for studies attempting to define clinical and genetic correlates of rupture risk reduction. Early life experiences contribute significantly to the origins of adult health outcomes, yet our current understanding of modifiable susceptibility factors that drive the high frequency of CCL rupture remains limited. We reasoned that combining lifetime medical history with standardized late-life assessment of lifetime cruciate ligament survival and detailed phenotyping of each dog for selected risk variables would provide a sensitive approach to identify factors that would differentiate between lifelong avoidance versus susceptibility to ligament rupture. Here, we report results of Kaplan–Meier analysis of estimated lifetime cruciate ligament survival and Cox proportional hazards modeling to assess risk variables in a lifetime cohort study of 123 purebred Rottweilers, a breed at high risk for veterinarian-diagnosed CCL rupture. We show that gonad removal during the 24-month developmental period is adversely associated with three measures of susceptibility—increased incidence of CCL rupture, multiplicity (bilateral rupture), and accelerated time to initial CCL failure. Our analysis reveals two other phenotypes—short adult height and the production of offspring (in females)—are associated with significant CCL rupture risk reduction. Together, the results provide clues to an early endocrine influence on lifetime cruciate ligament survival. Further, we identify two distinct clinical syndromes of CCL failure, providing a disease subtyping framework to advance future progress in genetic epidemiology, pathogenesis, and prediction. By conducting an evaluation of estimated lifetime CCL survival in dogs, we show that cruciate ligament survival may be jeopardized by gonad removal during the developmental period. Avoidance of such early environmental adversity may represent an actionable method for the control of canine CCL disease in certain breeds.

Introducción: Un problema de salud que afecta a la humanidad a nivel global es la drogadicción, una enfermedad crónica del cerebro, con recaídas frecuentes caracterizadas por la búsqueda y el consumo compulsivo de sustancias toxicas. Objetivo: Caracterizar a los pacientes ingresados, en el Servicio de Deshabituación Alcohólica y otras Adicciones del Hospital Psiquiátrico Provincial Docente ¨Crisanto Betancourt Hernández¨. Métodos: Se realizó un estudio descriptivo y retrospectivo, en de la provincia de Mayabeque, en el periodo del 2015 al 2019. La población de estudio fueron 380 pacientes, que ofrecieron su consentimiento para participar. Las variables estudiadas fueron: sexo, edad, procedencia, el diagnóstico y la permanencia institucional. Se utilizó como fuente de información, el libro de registros y las historias clínicas. Se aplicaron métodos teóricos, empíricos y procedimientos estadísticos. Resultados: Predominó el sexo masculino con 94.7 % y el grupo de edad 54 a 59 años con 22.1 %. Existió una mayor demanda institucional de la provincia de Mayabeque, con 86.8 % y del municipio de Güines en el 24.2 %. Prevaleció el diagnóstico en los pacientes de trastornos mentales y del comportamiento, debido al consumo de alcohol en el 95.2 %, con una permanencia institucional superior a 30 días en el 77.6 %. Conclusiones: En los pacientes ingresados prevalece el sexo masculino, en la etapa productiva de la vida, procedentes del municipio de Güines, con diagnóstico de trastrastornos mentales y del comportamiento debido al consumo de alcohol y con una permanencia institucional superior a 30 días.

Abstract Resistance to therapy remains a major obstacle in cancer management. Although treatment with hormone and CDK4/6 inhibitors is successful in luminal breast cancer, resistance to these treatments is frequent, highlighting the need for novel therapeutic strategies to delay disease progression and improve patient survival. Here, we assessed the mechanisms of acquired resistance using T47D and MCF-7 tamoxifen- and palbociclib-resistant cell-line variants in culture and as xenografts, and patient-derived cells (PDCs) obtained from sensitive or resistant patient-derived xenografts (PDXs). In these models, we analyzed the effect of specific kinase inhibitors on survival, signaling and cellular aggressiveness. Our results revealed that mTOR inhibition is more effective than PI3K inhibition in overcoming resistance, irrespective of PIK3CA mutation status, by decreasing cell proliferation and tumor growth, as well as reducing cell migration and stemness. Moreover, a combination of mTOR and CDK4/6 inhibitors may prevent pathway reactivation downstream of PI3K, interfering with the survival of resistant cells and consequent tumor escape. In conclusion, we highlight the benefits of incorporating mTOR inhibitors into the current therapy in ER + breast cancer. This alternative therapeutic strategy not only enhances the antitumor response but may also delay the emergence of resistance and tumor recurrence.

The interruption of bacteriological surveillance due to the COVID-19 pandemic brought serious consequences, such as the collapse of health systems and the possible increase in antimicrobial resistance. Therefore, it is necessary to know the rate of resistance and its associated mechanisms in bacteria causing hospital infections during the pandemic. The aim of this work was to show the phenotypic and molecular characteristics of antimicrobial resistance in ESKAPE bacteria in a Mexican tertiary care hospital in the second and third years of the pandemic. For this purpose, during 2021 and 2022, two hundred unduplicated strains of the ESKAPE group (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii) were collected from various clinical sources and categorized by resistance according to the CLSI. An analysis of variance (ANOVA) complemented by the Tukey test was performed to search for changes in antimicrobial susceptibility profiles during the study period. Finally, the mechanisms of resistance involved in carbapenem resistance were analyzed, and the search for efflux pumps and high-risk sequence types in A. baumannii was performed by multilocus analysis (MLST). The results showed no changes in K. pneumoniae resistance during the period analyzed. Decreases in quinolone resistance were identified in E. coli (p = 0.039) and P. aeruginosa (p = 0.03). Interestingly, A. baumannii showed increases in resistance to penicillins (p = 0.004), aminoglycosides (p < 0.001, p = 0.027), carbapenems (p = 0.027), and folate inhibitors (p = 0.001). Several genes involved in carbapenem resistance were identified (blaNDM, blaVIM, blaOXA, blaKPC, blaOXA-40, and blaOXA-48) with a predominance of blaOXA-40 and the adeABCRS efflux pump in A. baumannii. Finally, MLST analysis revealed the presence of globally distributed sequence types (ST369 and ST758) related to hospital outbreaks in other parts of the world. The results presented demonstrate that the ESKAPE group has played an important role during the COVID-19 pandemic as nosocomial antibiotic-resistant pathogens and in particular A. baumannii MDR as a potential reservoir of resistance genes. The implications of the increases in antimicrobial resistance in pathogens of the ESKAPE group and mainly in A. baumannii during the COVID-19 pandemic are analyzed and discussed.

Dissemination of carbapenemase-encoding plasmids by horizontal gene transfer in multidrug-resistant bacteria is the major driver of rising carbapenem-resistance, but the conjugative mechanics and evolution of clinically relevant plasmids are not yet clear. We performed whole-genome sequencing on 1,215 clinical Enterobacterales isolates collected in Singapore during 2010–2015. We identified 1,126 carbapenemase-encoding plasmids and discovered pKPC2 is becoming the dominant plasmid in Singapore, overtaking an earlier dominant plasmid, pNDM1. pKPC2 frequently conjugates with many Enterobacterales species, including hypervirulent Klebsiella pneumoniae, and maintains stability in vitro without selection pressure and minimal adaptive sequence changes. Furthermore, capsule and decreasing taxonomic relatedness between donor and recipient pairs are greater conjugation barriers for pNDM1 than pKPC2. The low fitness costs pKPC2 exerts in Enterobacterales species indicate previously undetected carriage selection in other ecological settings. The ease of conjugation and stability of pKPC2 in hypervirulent K. pneumoniae could fuel spread into the community.

Abstract Black carbon aerosol emissions are recognized as contributors to global warming and air pollution. There remains, however, a lack of techniques to remotely measure black carbon aerosol particles with high range and time resolution. This article presents a direct and contact-free remote technique to estimate the black carbon aerosol number and mass concentration at a few meters from the emission source. This is done using the Colibri instrument based on a novel technique, referred to here as Picosecond Short-Range Elastic Backscatter Lidar (PSR-EBL). To address the complexity of retrieving lidar products at short measurement ranges, we apply a forward inversion method featuring radiometric lidar calibration. Our method is based on an extension of a well-established light-scattering model, the Rayleigh–Debye–Gans for Fractal-Aggregates (RDG-FA) theory, which computes an analytical expression of lidar parameters. These parameters are the backscattering cross-sections and the lidar ratio for black carbon fractal aggregates. Using a small-scale Jet A-1 kerosene pool fire, we demonstrate the ability of the technique to quantify the aerosol number and mass concentration with centimetre range-resolution and millisecond time-resolution.

Abstract Background Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone–rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype–phenotype correlations. Results Genetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone–rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype–phenotype correlation in these patients. Conclusions The authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone–rod and cone dystrophies.

Abstract Metabolic energy consumption has long been thought to play a major role in the aging process (Pearl, The rate of living. University of London Press, London, 1928). Across species, a gram of tissue expends approximately the same amount of energy during the lifespan on average (Speakman, J Exp Biol 208:1717–1730, 2005). Energy restriction has also been shown to increase the maximum lifespan (McCay et al. J Nutr 10:63–79, 1935) and to retard age-associated changes (Weindruch and Walford, The retardation of aging and disease by dietary restriction. CC Thomas, Springfield, 1988). However, there are significant exceptions to universal energy consumption during the lifespan, mainly found by interclass comparison (Ramsey et al. Free Rad Biol Med 29:946–968, 2000; Atanasov, Trakia J Sci 10(3):1–14, 2012). Here, we present a universal relation that relates lifespan energy consumption to several physiological variables, such as body mass, temperature and the ratio of heart rate to respiratory rate, which have been shown to be valid for $$\sim 300$$ ∼ 300 species representing different classes of living organisms, from unicellular organisms to the largest mammals. This relation has an average scattered pattern restricted to factors of 2, with 95% ( $$2-\sigma$$ 2 - σ ) of the organisms having departures of less than a factor of $$\pi$$ π from the relation, despite the difference of $$\sim 20$$ ∼ 20 orders of magnitude in body mass, reducing any possible interclass variation in the relation to only a geometrical factor. This result can be interpreted as supporting evidence for the existence of an approximately constant total number $${\mathrm{N}}_{{\mathrm{r}}} \sim 10^8$$ N r ∼ 10 8 of respiration cycles per lifetime for all organisms studied, effectively predetermining the extension of life through the basic energetics of respiration (quantified by $${\mathrm{t}}_{{\mathrm{life}}} = \mathrm{N}_\mathrm{r}/\mathrm{f}_{{\mathrm{resp}}}$$ t life = N r / f resp ); this is an incentive to conduct future studies on the relation of such a constant number $${\mathrm{N}}_{\mathrm{r}}$$ N r of cycles per lifetime due to the production rates of free radicals and oxidants or alternative mechanisms, which may yield definite constraints on the origin of aging.

Ranaviruses have been associated with amphibian, fish and reptile mortality events worldwide and with amphibian population declines in parts of Europe. Xenopus laevis is a widespread invasive amphibian species in Chile. Recently, Frog virus 3 (FV3), the type species of the Ranavirus genus, was detected in two wild populations of this frog near Santiago in Chile, however, the extent of ranavirus infection in this country remains unknown. To obtain more information about the origin of ranavirus in Chile, its distribution, species affected, and the role of invasive amphibians and freshwater fish in the epidemiology of ranavirus, a surveillance study comprising wild and farmed amphibians and wild fish over a large latitudinal gradient (2,500 km) was carried out in 2015–2017. In total, 1,752 amphibians and 496 fish were tested using a ranavirus-specific qPCR assay, and positive samples were analyzed for virus characterization through whole genome sequencing of viral DNA obtained from infected tissue. Ranavirus was detected at low viral loads in nine of 1,011 X. laevis from four populations in central Chile. No other amphibian or fish species tested were positive for ranavirus, suggesting ranavirus is not threatening native Chilean species yet. Phylogenetic analysis of partial ranavirus sequences showed 100% similarity with FV3. Our results show a restricted range of ranavirus infection in central Chile, coinciding with X. laevis presence, and suggest that FV3 may have entered the country through infected X. laevis, which appears to act as a competent reservoir host, and may contribute to the spread the virus locally as it invades new areas, and globally through the pet trade.

Summary: Background: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications. Methods: 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition. Findings: We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. Interpretation: Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection. Funding: NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.

Tropical forests on karstic relief (tropical karst forest) are among the most species-rich biomes. These forests play pivotal roles as global climate regulators and for human wellbeing. Their long-term conservation could be central to global climate mitigation and biodiversity conservation. In Mexico, karst landscapes occupy 20% of the total land surface and are distributed mainly in the southeast of the country, along the eastern slope, and in the Yucatan Peninsula. Within each of these areas, the following types of karst occur: coastal karst, plain karst, hill karst, and mountain karst (low, medium, high). Mountain karst cover 2.07% of Mexico's land surface and are covered by tropical rainforests, montane cloud forests, and tropical deciduous forests. These are probably one of the most diverse biomes in Mexico. However, the mountain karst forests of Mexico have received little attention, and very little is known about their diversity. Here, we evaluated the vascular plant species richness within the mountain karst forests of Mexico. We assembled the first, largest, and most comprehensive datasets of Mexican mountain karst forest species, from different public databases (CONABIO, GBIF, IBdata-UNAM), which included a critical review of all data. We compiled a list of the families, genera, and species present within the mountain karst forests of Mexico. Taxa that best characterize these forests were identified based on their spatial correlation with this biome. We explored biodiversity patterns, identifying areas with the highest species richness, endemism centers, and areas of relatively low sampling intensity. We found that within the mountain karst forests of Mexico there are representatives of 11,771 vascular plant species (253 families and 2,254 genera), ca. 50% of the Mexican flora. We identified 372 species endemic to these forests. According to preliminary IUCN red list criteria, 2,477 species are under some category of conservation risk, of which 456 (3.8%) are endangered. Most of the Mexican mountain karst forests have been extensively explored and six allopatric, species-rich areas were identified. Compared to other regions in the world, the mountain karst forests of Mexico are one of the most diverse biomes. They contain more species than some entire montane systems in Mexico such as Sierra Madre Oriental, and Sierra Madre del Sur. Also, the mountain karst forests of Mexico are most diverse than similar forests of South America and Asia, even if considering the effect of different sampling areas. The fact that mountain karst forests are embedded in areas of high biotic diversity, probably contributes to their great floristic diversity. Thus, the mountain karst forests of Mexico are an important source of diversity and shelters a large percentage of the Mexican flora.

The lissencephaly 1 protein, LIS1, is mutated in type-1 lissencephaly and is a key regulator of cytoplasmic dynein-1. At a molecular level, current models propose that LIS1 activates dynein by relieving its autoinhibited form. Previously we reported a 3.1 Å structure of yeast dynein bound to Pac1, the yeast homologue of LIS1, which revealed the details of their interactions (Gillies et al., 2022). Based on this structure, we made mutations that disrupted these interactions and showed that they were required for dynein’s function in vivo in yeast. We also used our yeast dynein-Pac1 structure to design mutations in human dynein to probe the role of LIS1 in promoting the assembly of active dynein complexes. These mutations had relatively mild effects on dynein activation, suggesting that there may be differences in how dynein and Pac1/LIS1 interact between yeast and humans. Here, we report cryo-EM structures of human dynein-LIS1 complexes. Our new structures reveal the differences between the yeast and human systems, provide a blueprint to disrupt the human dynein-LIS1 interactions more accurately, and map type-1 lissencephaly disease mutations, as well as mutations in dynein linked to malformations of cortical development/intellectual disability, in the context of the dynein-LIS1 complex.

Abstract Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3–4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4–6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P

Introducción: Entre las drogas depresoras se encuentra el alcohol que inhibe los centros corticales y libera la subcorteza, con el resultado responsable de conductas primarias instintivo- afectivas. Objetivo: Explorar la depresión oculta en pacientes alcohólicos ingresados para deshabituación. Métodos: Se realizó un estudio descriptivo, transversal y prospectivo, en el Servicio de Deshabituación del Hospital Psiquiátrico, ¨Crisanto Betancourt Hernández¨, en Mayabeque, en el primer semestre del 2019. De un universo de 76 pacientes, se seleccionó una muestra de 38, mediante la aplicación de muestreo probabilístico, simple, aleatorio, con intervalo de selección de uno cada dos que cumplieron los criterios de inclusión y exclusión. Se consideraron como variables: el grupo etario, estado civil; características depresivas ocultas, indicadores de depresión y rasgo o estado de esta. La información se obtuvo mediante la observación, entrevistas; revisión de historias clínicas, aplicación de una encuesta para explorar la depresión oculta y su comportamiento; según el Inventario de Depresión Rasgo – Estado Resultados: Predominó el grupo de 41 a 50 años 47 %, estado civil casado 34 %. Las características de depresión fueron la tristeza oculta 71 %, el desánimo y la culpabilidad 55 %; la tristeza oculta a familiares y amigos 53 %. En los indicadores de depresión prevalecieron los trastornos del sueño 66 % y la depresión como estado en el 60 %. Conclusiones: En el grupo de pacientes predomina la quinta década de la vida, casados; sobresale la tristeza oculta como manifestación de depresión, los trastornos del sueño como indicador y la depresión como estado.

Abstract Statins are the cornerstone of therapy for individuals with hyperlipidemia. The aim of this study was to analyze the undesirable effects of mild, moderate and high doses of rosuvastatin in CD-1 male mice who received a cholesterol-rich diet, focusing on the morphological and functional changes on hepatocyte mitochondria. In a mouse model we studied the combined administration of a cholesterol-rich diet along with mild and moderate doses of rosuvastatin (1, 2.5 or 5 mg/kg/day) during several days. After the animals were sacrificed, liver mitochondria were isolated for microscopic studies and to analyze the respiratory function. The respiratory control (state-3/state-4) was evaluated in mice who received high doses of rosuvastatin. Rosuvastatin doses higher than 20 mg/kg/day induced premature death in mice with a hypercholesterolemic diet, but not in mice with a cholesterol-free diet. Doses from 2.5 to 5 mg/kg/day also induced morphological and functional alterations in mitochondria but these hypercholesterolemic animals survived longer. Giving 1 mg/kg/day, which is close to the maximal therapeutic dose for humans, did not affect mitochondrial architecture or respiratory function after two months of treatment. We analyzed the effect of rosuvastatin on hepatic tissue because it is where statins are mainly accumulated and it is the main site of endogenous cholesterol synthesis. Our results contribute to understand the side effects of rosuvastatin in hypercholesterolemic mice, effects that could also affect humans who are intolerant to statins.

Resumen Introducción y objetivo. El proceso de cicatrización, cuando se ve perturbado o interrumpido, puede conllevar una reparación cutánea descontrolada como la observada en los queloides. Son reconocidos como tumores fibroproliferativos únicos en humanos, lesiones difíciles de tratar debido a que la mayoría de los enfoques terapéuticos siguen siendo clínicamente insatisfactorios. Sin embargo, estudios recientes sugieren que la toxina botulínica tipo A (TBA) influye en la apoptosis y proliferación celular, razón por lo cual nos planteamos demostrar si la TBA intralesional produce mejoría no solo clínica, sino también histológica en el queloide. Material y método. Seleccionamos 11 queloides y realizamos biopsias de los mismos, además de medición previa y en 3 controles posteriores a la aplicaciónn de TBA. Hacemos descripción histopatológica de los cambios observados a los 3 meses mediante el Sofware Image Pro Plus, versión 5.0 (Olympus®) y tinciones con hematoxilina-eosina (H/E) y tricrómico de Masson. Aplicamos tratamiento estadístico mediante análisis de las características demográficas y clínicas. A las variables nominales se le determinaron frecuencia y porcentajes, por lo que elaboramos tablas descriptivas. Con las variables cuantitativas trabajamos con medidas de tendencia central (media). Para la comparación y el análisis de las variables utilizamos medidas de tendencia central (media), coeficiente de relación de Pearson y desviación estándar. Resultados. La edad promedio fue de 31 años, el sexo predominante fue el femenino (63%), la etiología más frecuente fue postraumática (35%), predominó el tipo de piel IV (50%), clínicamente hubo mejoría significativa de altura y anchura del queloide confirmada mediante coeficiente de relación de Pearson con un -0.91 y -0.88 respectivamente, así como del dolor, prurito, coloración y consistencia; también reducción del diámetro de la epidermis verificado por desviación estándar y cambios en la dermis en cuanto a distribución del colágeno, vascularización, infiltrado inflamatorio y unión dermoepidermica se refiere. Conclusiones. Dados los resultados obtenidos en nuestro estudio desde el punto de vista clínico e histopatológico, planteamos la TBA como una nueva opción terapéutica para el tratamiento del queloide.

La atención al enfermo mental ha estado centrada en el hospital psiquiátrico, eje fundamental del tratamiento a enfermedades mentales.Con la reorientación de la psiquiatría, los hospitales psiquiátricos desarrollan una labor comunitaria coordinada entre el nivel de atención primario y el secundario. El Hospital Psiquiátrico ¨Crisanto Betancourt Hernández¨, representa a este tipo de entidad, lo que motiva a explorar su evolución histórica. Las referencias se obtienen de las entrevistas a los fundadores, los vecinos, la exploración de documentos, las fotos, los reconocimientos y las condecoraciones .Se constata que ha crecido en la calidad de los servicios, la transformación de nuevas instalaciones; la reducción de camas acorde al desarrollo de la reorientación de la especialidad, la proyección comunitaria en el primer nivel de atención; la formación del personal idóneo para la realización de esta labor y su superación científica.

Resumen Introducción y objetivo. Para la reconstrucción del maxilar se han descrito múltiples clasificaciones y algoritmos de manejo. Actualmente, el más aceptado es el planteado por Cordeiro y Santamaría. Presentamos nuestra experiencia en reconstrucción microquirúrgica del maxilar con colgajos libres de peroné y ánterolateral de muslo, con el objetivo de que se consideren herramientas de primera elección en la reconstrucción de defectos clasificados como tipo II y III. Material y método. Estudio retrospectivo descriptivo, serie de casos, en el que presentamos 7 casos clínicos de reconstrucción de maxilar con colgajo libre de peroné y ánterolateral de muslo realizados en el Hospital Universitario de La Samaritana (HUS) en Bogotá, Colombia, entre enero de 2018 y febrero de 2019. Resultados. Para la reconstrucción de los defectos IIa, IIb y IIIa utilizamos el colgajo libre de peroné. En maxilectomías clasificadas como IIIb implementamos el colgajo ánterolateral de muslo quimérico con vasto lateral. La supervivencia de los colgajos fue del 100%. Conclusiones. El colgajo libre de peroné es nuestra principal opción reconstructiva en los defectos por maxilectomías IIa, IIb y IIIa, mientras que el colgajo ánterolateral de muslo quimérico con vasto lateral es nuestro colgajo de elección en defectos tipo IIIb

ABSTRACT Objective To determine the rate of complications associated with the use of temporary pacemakers in patients in the waiting list for the definitive pacemaker implantation in a public hospital located in São Paulo, SP, Brazil. Methods Retrospective observational study based on data extracted from medical records of patients admitted to Hospital Municipal Dr. Moyses Deutsch, Hospital Israelita Albert Einstein from January 2014 to December 2018. Patients aged 18 years or older, diagnosed with high degree atrioventricular block upon admission and with indications for definitive pacemaker implantation were included. All-cause mortality, clinical and surgical complications and length of hospital stay while waiting for the procedure were defined as primary outcomes. Results The sample comprised 66 patient allocated to one of two groups: with and without the need of temporary pacemaker while in hospital (n=45 and n=21, respectively). The rate of complications was higher in patients who used a temporary pacemaker (p

Al momento actual, una nueva epidemia, azota a la humanidad con consecuencias catastróficas, afectando a 184 países, la COVID-19; la misma se hará sentir no solo para la economía y la salud, por la pérdida de vidas humanas sino también desde el punto de vista psicológico y social. Mediante la revisión de artículos, de fuentes autorizadas y de sitios Web de reconocido prestigio científico se pretende dotar a los profesionales de la salud de herramientas sobre los importantes aspectos psicológicos, en los diferentes momentos evolutivos de la enfermedad, y su repercusión social. Se concluye que es una necesidad la orientación profesional encaminada a enfrentar los trastornos psicológicos que ocasiona el azote de la COVI-19, que abarque todas las esferas de la vida social dirigida a disminuir las secuelas de la pandemia en la salud mental y contribuir al restablecimiento del equilibrio biopsicosocial en las personas.

Abstract Background Lipodystrophy syndromes are a group of disorders characterized by a loss of adipose tissue once other situations of nutritional deprivation or exacerbated catabolism have been ruled out. With the exception of the HIV-associated lipodystrophy, they have a very low prevalence, which together with their large phenotypic heterogeneity makes their identification difficult, even for endocrinologists and pediatricians. This leads to significant delays in diagnosis or even to misdiagnosis. Our group has developed an algorithm that identifies the more than 40 rare lipodystrophy subtypes described to date. This algorithm has been implemented in a free mobile application, LipoDDx®. Our aim was to establish the effectiveness of LipoDDx®. Forty clinical records of patients with a diagnosis of certainty of most lipodystrophy subtypes were analyzed, including subjects without lipodystrophy. The medical records, blinded for diagnosis, were evaluated by 13 physicians, 1 biochemist and 1 dentist. Each evaluator first gave his/her results based on his/her own criteria. Then, a second diagnosis was given using LipoDDx®. The results were analysed based on a score table according to the complexity of each case and the prevalence of the disease. Results LipoDDx® provides a user-friendly environment, based on usually dichotomous questions or choice of clinical signs from drop-down menus. The final result provided by this app for a particular case can be a low/high probability of suffering a particular lipodystrophy subtype. Without using LipoDDx® the success rate was 17 ± 20%, while with LipoDDx® the success rate was 79 ± 20% (p

Background: people who work outdoors are exposed to long periods of ultraviolet radiation; such is the case of street vendors. Objectives: determine the knowledge and habits of solar exposition in itinerant traders around a Chiclayo market. Materials and methods: A questionnaire were applied to 291 itinerant merchants located around the Mercado Modelo of Chiclayo, who evaluated sun exposure habits, photo protection measures, a history of sunburn and skin cancer, as well as knowledge of ultraviolet radiation and sources of information. Results: the following results were found: the age ranges were 18-25 (42.3%), 36-54 (38.1%), 55 -78 (19.6%). At the level of education, 13.1% have completed primary school, 32.6% have full secondary and 8.2% complete. At the time of the study, 71.9% had been working as street traders for more than 3 years. The phototype of the participants were phototype I (0.3%), phototype II (4.5%), phototype III (24.7%), phototype IV (48.8%), phototype V (19.6%), phototype VI (2.15). A 90 ± 3.5 %% recognizes that causes skin cancer, 53.6% recognizes that a feature of skin aging by radiation are spots and warts, 56% responded that solar radiation causes cataracts, a 52,92 % replied that white-skinned people are more sensitive to the sun's rays. 59.5% of traders indicated that they go to work from Monday to Sunday, 39.4% work 5-6 days a week, and 4.1% work 4 or less days a week. A 48.5% of them declared to expose themselves more than 6 hours to the solar rays, 24.7% are exposed of 3 - 6 hours a day, while 8.6% registered the shortest time of solar exposure (0 - 2 hours). 75.3% did not use sunscreen, 24.7% of merchants used sunscreen at the time of being surveyed as a measure of photo protection; of them, 63.9% said that a family member recommended their use, 94.4% use it 1-2 times a day, 38.9% only apply it when they go to work, 52.8% use it on their face , neck, ears and hands, and half of them (50.0%) get it from a catalog. Conclusions: the knowledge and habits of solar exposition in itinerant traders were equal or inferior to that described in other studies. It was found that the knowledge is from regular to adequate and poor habits.

Summary: The antiretroviral treatment (ART) developed to control HIV infection led to a revolution in the prognosis of people living with HIV (PLWH). PLWH underwent from suffering severe disease and often fatal complications at young ages to having a chronic condition and a life expectancy close to the general population. Nevertheless, chronic age-related diseases increase as PLWH age. The harmful effect of HIV infection on the individual's immune system adds to its deterioration during ageing, exacerbating comorbidities. In addition, PLWH are more exposed to risk factors affecting ageing, such as coinfections or harmful lifestyles. The ART initiation reverses the biological ageing process but only partially, and additionally can have some toxicities that influence ageing. Observational studies suggest premature ageing in PLWH. Therefore, there is considerable interest in the early prediction of unhealthy ageing through validated biomarkers, easy to implement in HIV-clinical settings. The most promising biomarkers are second-generation epigenetic clocks and integrative algorithms.

Introducción La participación es la interacción dinámica y compleja entre la condición de salud del individuo, las funciones corporales, las actividades que puede realizar y los factores ambientales. Medirla ayuda a comprender el impacto de la discapacidad. Objetivos: Describir las actividades y participación en sujetos con patologías neurológicas, dados de alta de internación para rehabilitación. Secundariamente comparar las características clínico-demográficas y la participación entre usuarios de silla de ruedas respecto a personas no usuarias. Material y método Estudio observacional, prospectivo, transversal, multicéntrico. Basado en una encuesta a mayores de 18 años con patologías de origen neurológico dados de alta de rehabilitacion de 6 centros de Argentina. Resultados Respondieron 282 personas, 69% hombres con una media de edad de 50 años y dados de alta hace 22 meses. El diagnóstico más frecuente fue el accidente cerebrovascular. La autopercepción de la participación fue de 49 sobre 90, y los que no utilizan silla de ruedas refieren mayor nivel de participación. La mayor satisfacción fue en áreas de relaciones interpersonales. El 50% requiere de asistencia para utilizar los transportes en la comunidad. El 61% no trabaja ni estudia, así como tampoco realizan actividades deportivas (65%). Al 61% de los usuarios de silla de ruedas no pueden ir a lugares de la comunidad por ser inaccesibles. Conclusión Se observó menor participación en actividades comunitarias, principalmente por barreras arquitectónicas y por dificultades para usar el transporte en usuarios de silla de ruedas. La familia ocupa un lugar central para que puedan integrarse en la comunidad.

La hernia de Amyand se define como la presencia de un apéndice vermiforme dentro de un saco herniario inguinal. Menos del 1 % de las publicaciones médicas sobre hernias en el mundo corresponde a este padecimiento, y los reportes en Latinoamérica y el Caribe son escasos. Este artículo describe el caso de un varón de 78 años con un cuadro clínico de cinco meses de evolución aproximadamente. El paciente refiere que sentía una masa en la región inguinal derecha de crecimiento progresivo. Luego se asoció un dolor (de escala 8/10) durante los dos días previos al ingreso en el departamento de urgencias. Durante la operación en la región inguinal derecha, se abre el saco herniario que muestra partes del colon derecho, el ciego y el apéndice (edematosos), por lo que se decide realizar una apendicectomía y la reconstrucción con una malla de polipropileno.

The lissencephaly 1 gene, LIS1, is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator known to bind directly to dynein’s motor domain, and by doing so alters dynein’s mechanochemistry. Lis1 is required for the formation of fully active dynein complexes, which also contain essential cofactors: dynactin and an activating adaptor. Here, we report the first high-resolution structure of the yeast dynein–Lis1 complex. Our 3.1 Å structure reveals, in molecular detail, the major contacts between dynein and Lis1 and between Lis1’s ß-propellers. Structure-guided mutations in Lis1 and dynein show that these contacts are required for Lis1’s ability to form fully active human dynein complexes and to regulate yeast dynein’s mechanochemistry and in vivo function.

Purpose: To report a case of severe mpox in a newly diagnosed HIV patient concerning for Immune Reconstitution Inflammatory Syndrome (IRIS) and/or tecovirimat resistance and to describe the management approach in the setting of refractory disease. Case: 49-year-old man presented with 2 weeks of perianal lesions. He tested positive for mpox PCR in the emergency room and was discharged home with quarantine instructions. Three weeks later, the patient returned with disseminated firm, nodular lesions in the face, neck, scalp, mouth, chest, back, legs, arms, and rectum, with worsening pain and purulent drainage from the rectum. The patient reported being on 3 days of tecovirimat treatment, which was prescribed by the Florida department of health (DOH). During this admission, he was found to be HIV positive. A pelvic CT scan revealed a 2.5 cm perirectal abscess. Treatment with tecovirimat was continued for 14 days, along with an empiric course of antibiotics for treatment of possible superimposed bacterial infection upon discharge. He was seen in the outpatient clinic and initiated antiretroviral therapy (ART) with TAF/emtricitabine/bictegravir. Two weeks after starting ART, the patient was readmitted for worsening mpox rash and rectal pain. Urine PCR also returned positive for chlamydia, for which the patient was prescribed doxycycline. He was discharged on a second course of tecovirimat and antibiotic therapy. Ten days later, the patient was readmitted for the second time due to worsening symptoms and blockage of the nasal airway from progressing lesions. At this point, there were concerns for tecovirimat resistance, and after discussion with CDC, tecovirimat was reinitiated for the third time, with the addition of Cidofovir and Vaccinia, and showed an improvement in his symptoms. He received three doses of cidofovir and two doses of Vaccinia, and the patient was then discharged to complete 30 days of tecovirimat. Outpatient follow-up showed favorable outcomes and near resolution. Conclusion: We reported a challenging case of worsening mpox after Tecovirimat treatment in the setting of new HIV and ART initiation concerning IRIS vs. Tecovirimat resistance. Clinicians should consider the risk of IRIS and weigh the pros and cons of initiating or delaying ART. In patients not responding to first-line treatment with tecovirimat, resistance testing should be performed, and alternative options should be considered. Future research is needed to establish guidance on the role of Cidofovir and Vaccinia immune globulin and the continuation of tecovirimat for refractory mpox.

Introduction More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI.Methods and analysis EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI.Ethics and dissemination EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials.Trial registration number NCT04165369.

Objective Determine the sensitivity and specificity of neonatal jaundice visual estimation by primary healthcare workers (PHWs) and physicians as predictors of hyperbilirubinaemia.Design Multicentre observational cohort study.Setting Hospitals in Chandigarh and Delhi, India; Dhaka, Bangladesh; Durban, South Africa; Kumasi, Ghana; La Paz, Bolivia.Participants Neonates aged 1–20 days (n=2642) who presented to hospitals for evaluation of acute illness. Infants referred for any reason from another health facility or those needing immediate cardiopulmonary resuscitation were excluded.Outcome measures Infants were evaluated for distribution (head, trunk, distal extremities) and degree (mild, moderate, severe) of jaundice by PHWs and physicians. Serum bilirubin level was determined for infants with jaundice, and analyses of sensitivity and specificity of visual estimations of jaundice used bilirubin thresholds of >260 µmol/L (need for phototherapy) and >340 µmol/L (need for emergency intervention in at-risk and preterm babies).Results 1241 (47.0%) neonates had jaundice. High sensitivity for detecting neonates with serum bilirubin >340 µmol/L was found for ‘any jaundice of the distal extremities (palms or soles) OR deep jaundice of the trunk or head’ for both PHWs (89%–100%) and physicians (81%–100%) across study sites; specificity was more variable. ‘Any jaundice of the distal extremities’ identified by PHWs and physicians had sensitivity of 71%–100% and specificity of 55%–95%, excluding La Paz. For the bilirubin threshold >260 µmol/L, ‘any jaundice of the distal extremities OR deep jaundice of the trunk or head’ had the highest sensitivity across sites (PHWs: 58%–93%, physicians: 55%–98%).Conclusions In settings where serum bilirubin cannot be measured, neonates with any jaundice on the distal extremities should be referred to a hospital for evaluation and management, where delays in serum bilirubin measurement and appropriate treatment are anticipated following referral, the higher sensitivity sign, any jaundice on the distal extremities or deep jaundice of the trunk or head, may be preferred.

Introducción: La Enfermedad de Erdheim-Chester (ECD) es una rara forma de histiocitosis, caracterizada por la infiltración xantogranulomatosa de múltiples órganos por histiocitos cargados de lípidos. Se la considera un trastorno clonal inflamatorio mieloide que afecta principalmente a hombres con una edad media de 55 años. Métodos: Presentamos el caso de un hombre de 65 años que consultó a nuestro Servicio de Endocrinología por poliuria y polidipsia de 4 meses de evolución diagnosticándose diabetes insípida central asociada a infiltración hipofisaria. El paciente presentaba lesiones cutáneas pápulo-nodulares en tórax y xantelasma-símiles en cuello y cara de varios años de evolución, con biopsia compatible con histiocitosis no-Langerhans. El estudio genético de la biopsia cutánea detectó la mutación MAP2K1 confirmando la ECD. Resultados: El paciente inició tratamiento con interferón alfa con respuesta incompleta y mala tolerancia por lo que cambiamos el tratamiento a un inhibidor potente y selectivo de MEK, el cobimetinib. Tras 8 meses de tratamiento presenta desaparición de lesiones cutáneas y de la infiltración hipofisaria con notable mejoría de su calidad de vida. Conclusión: Presentamos el caso de un paciente adulto con una forma rara de histiocitosis (ECD) que a su vez presentó una forma atípica de ECD y, donde el estudio genético nos permitió confirmar el diagnóstico e introducir una terapia dirigida con cobimetinib con excelentes resultados.

Introducción: el propósito del tratamiento del paciente alcohólico es la rehabilitación mediante actividades de reeducación, readaptación y la reinserción social, siendo la abstinencia absoluta de alcohol la condición para lograrlo, además con la dispensarización se establecen procedimientos para desarrollar acciones de seguimiento y control.Objetivo: determinar la evolución de los pacientes alcohólicos egresados del Servicio de Deshabituación al alcohol y otras drogas del Hospital psiquiátrico de la provincia Mayabeque. Métodos: se realizó un estudio descriptivo, transversal, en el Hospital Psiquiátrico Provincial “Crisanto Betancourt Hernández”, municipio Güines, provincia Mayabeque, durante los años 2014 y 2015. Después de aplicar, los criterios de inclusión y exclusión, al universo de 87 pacientes, se seleccionaron 50 por un muestreo probabilístico simple aleatorio. Se estudiaron las variables de tiempo de abstinencia, recaídas, recursos terapéuticos utilizados y dispensarización en el primero y segundo nivel de atención. La información se obtuvo por la observación, entrevistas y revisión documental de los archivos estadísticos.Resultados: el 34 % de los pacientes se mantuvo en abstinencia entre uno a tres meses, el 46% con recaídas evaluadas de regular; el acamprosato fue el fármaco más utilizado (28 %) y el 100 % fueron dispensarizados en el segundo nivel de atención.Conclusiones: el tiempo de abstinencia que predomina es de uno a tres meses, la recaída fue evaluada de regular, como recursos terapéuticos el acamprosato es el fármaco más utilizado y efectivo. Todos los pacientes fueron dispensarizados en la atención secundaria de salud.

Candida auris is an emerging multidrug-resistant fungus that causes hospital-associated outbreaks of invasive infections with high death rates. During 2015–2016, health authorities in Colombia detected an outbreak of C. auris. We conducted an investigation to characterize the epidemiology, transmission mechanisms, and reservoirs of this organism. We investigated 4 hospitals with confirmed cases of C. auris candidemia in 3 cities in Colombia. We abstracted medical records and collected swabs from contemporaneously hospitalized patients to assess for skin colonization. We identified 40 cases; median patient age was 23 years (IQR 4 months–56 years). Twelve (30%) patients were

Objetivo: Evaluar el riesgo de enfermedad cardiovascular a cinco y a diez años en pacientes con infección por VIH en terapia antirretroviral, por medio de las escalas Framingham y Data collection on Adverse Effects of Anti-HIV Drugs Study. Materiales y métodos: Estudio observacional de corte transversal y prospectivo. Se incluyeron pacientes con infección por el VIH en tratamiento antirretroviral de un centro de referencia para pacientes con VIH, entre el 1 de enero y el 30 de abril de 2019. Se realizó evaluación del riesgo cardiovascular a cinco y a diez años a través de los modelos de predicción de Framingham y la escala Data collection on Adverse Effects of Anti-HIV Drugs Study (DAD), y una comparación entre ellos a través de modelos estadísticos. Resultados: Se incluyeron 159 pacientes, con un promedio de edad de 48,90 años ± 9,90. La media de valoración del riesgo cardiovascular por escala de Framingham a 5 años fue de 2,70 % ± 2,80; Framingham a 10 años fue 6,10 % ± 5,70; DAD a 5 años, 3,50 % ± 4,10; DAD a 10 años, de 6,90 % ± 7,70; y el riesgo escala de Framingham a 10 años recalculado para Colombia (multiplicado por 0,75) fue de 4,50 ± 4,20. A través de un modelo de regresión logística, se determinó que la puntuación con mayor número de variables significativamente relacionadas con el resultado de riesgo cardiovascular alto es el modelo DAD a 10 años. Conclusiones: El estudio evidenció una diferencia significativa, con mayor riesgo estimado de enfermedad cardiovascular al utilizar el modelo DAD en comparación con el Framingham, tanto para la estimación a cinco años como a diez.

Introduction: Gitelman syndrome is a rare hereditary primary renal tubular disorder, with a prevalence of approximately 1 to 10 cases per 40 000 people. It does not have specific symptoms, so its diagnosis depends on high clinical suspicion by the treating physical and a sequential approach to hypokalemia, especially in young patients. Thus, a diagnostic algorithm is proposed at the end of this report. Case presentation: A 23-year-old woman with a history of hospitalization due to hypokalemia presented to the emergency service with intermittent cramping in her lower limbs, which was exacerbated by gastrointestinal symptoms. Laboratory tests reported the following findings: metabolic alkalosis, elevated levels of potassium, magnesium, chloride and sodium in urine, and reduced levels of calcium in urine. Thus, potassium supplementation and eplerenone administration were started, obtaining the complete resolution of symptoms. At her last follow-up appointment, the patient was asymptomatic, and her serum electrolyte levels were normal. In addition, during her hospital stay and due to the high suspicion of Gitelman syndrome, a genetic study was performed, which reported a mutation of the SCL12A3 gene, confirming the diagnosis. Conclusion: The sequential approach to a patient with recurrent hypokalemia is very important to reach an accurate diagnosis among a wide range of differential diagnoses.

Hispanics are the majority ethnic population in Puerto Rico where we reviewed charts of 109 hospitalized COVID-19 patients to better understand demographic and clinical characteristics of COVID-19 and determine risk factors for poor outcomes. Eligible medical records of hospitalized patients with confirmed COVID-19 illnesses were reviewed at four participating hospitals in population centers across Puerto Rico and data were abstracted that described the clinical course, interventions, and outcomes. We found hospitalized patients had a median of 3 underlying conditions with obesity and diabetes as the most frequently reported conditions. Intensive care unit (ICU) admission occurred among 28% of patients and 18% of patients died during the hospitalization. Patients 65 or older or with immune deficiencies had a higher risk for death. Common symptoms included cough, dyspnea, and fatigue; less than half of patients in the study reported fever which was less frequent than reported elsewhere in the literature. It is important for interventions within Hispanic communities to protect high-risk groups.

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A–4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66–0.68) for GOLD 2015 and 0.65 (95% CI 0.63–0.66) for GOLD 2019. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system.

ABSTRACT: Background: We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA population sequencing. Methods: Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/μL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224. Findings: 41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71·4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92·7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation. Interpretation: In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results. Funding: Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III PI16/00837-PI16/00678.

BackgroundDengue, chikungunya, and Zika viruses are increasingly important public health problems. Burning vegetation, leaves, and other plant products have been shown to be effective mosquito repellents for their vector, Aedes spp., but there has been scant research on whether firewood cooking smoke in households influences mosquito populations or mosquito-borne diseases. About 2.9 billion people worldwide use biomass fuel for household cooking and heating, resulting in an estimated 1.6 million deaths annually from household air pollution (HAP)-related diseases. Global health agencies now encourage households to transition from biomass to clean fuels, but it is unclear whether such interventions may actually increase risk for mosquito-borne diseases. This retrospective case-control study evaluated associations between arboviral infections and cooking with firewood in Santa Rosa, Guatemala.MethodVigilancia Integrada Comunitaria (VICo) was a prospective public health surveillance system for bacterial, parasitic, and viral causes of diarrheal, neurological, respiratory, and febrile illnesses in hospitals and clinics in the department of Santa Rosa, Guatemala. Enrolled VICo in-patients and out-patients during 2011-2018 were interviewed using standardized questionnaires on demographics and household characteristics. Blood and stool specimens were collected and tested to identify the etiologies presenting symptoms. Cases were defined as laboratory-positive for dengue, chikungunya, or Zika virus infections. Controls were laboratory-positive for bacterial and viral diarrheal illnesses (e.g., Salmonella, Shigella, Campylobacter, Escherichia coli, rotavirus, norovirus, sapovirus, or astrovirus). Cooking with firewood, kitchen location, stove type, and firewood cooking frequency were the independent exposure variables. Logistic regression models were used to analyze unadjusted and adjusted associations between arboviral infections and exposures of interest.ResultThere were 311 arboviral cases and 1,239 diarrheal controls. Arboviral infections were inversely associated with cooking with firewood in the main house (AOR: 0.22; 95% CI: 0.08-0.57), cooking with firewood on an open hearth (AOR: 0.50; 95% CI: 0.33-0.78), and cooking with firewood ≥5 times per week (AOR: 0.54; 95% CI: 0.36-0.81), adjusting for age, sex, ethnicity, socioeconomic status index, number of people per household, community population density, community elevation, recruitment location, season, and admission year.ConclusionSeveral primary determinants of HAP exposure were inversely associated with arboviral infections. Additional studies are needed to understand whether interventions to reduce HAP might actually increase risk for mosquito-borne infectious diseases, which would warrant improved education and mosquito control efforts in conjunction with fuel interventions.

Abstract Background External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. Methods We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. Results Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile–3rd quartile = 0.655–0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUCADO – AUCBODE = 0.015 [95% confidence interval (CI) = −0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUCBODE updated – AUCBODE = 0.008 [95% CI = −0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. Conclusions Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research.

Pancreatic cancer is the fourth cause of cancer deaths in the United States. Worldwide this type of cancer is responsible for 227,000 deaths per year. Pancreatic cancer is multifactorial, with smoking being the main risk factor. Endoscopic ultrasoundguided fine needle aspiration is a highly effective technique for the diagnosis of neoplastic lesions of the pancreas. Cytological diagnosis by this technique should be performed under the guidelines of the pancreatic-biliary system of the Papanicolaou Society of Cytopathology. These guidelines address indications, techniques, terminology and nomenclature, ancillary studies and post-procedure management, as well as cytological criteria for diagnosis. The specificity of a positive or malignant interpretation for the pancreatic fine needle aspiration corresponds to 90-95% in most studies.

Endocytosis of transmembrane proteins is orchestrated by the AP2 clathrin adaptor complex. AP2 dwells in a closed, inactive state in the cytosol, but adopts an open, active conformation on the plasma membrane. Membrane-activated complexes are also phosphorylated, but the significance of this mark is debated. We recently proposed that NECAP negatively regulates AP2 by binding open and phosphorylated complexes (Beacham et al., 2018). Here, we report high-resolution cryo-EM structures of NECAP bound to phosphorylated AP2. The site of AP2 phosphorylation is directly coordinated by residues of the NECAP PHear domain that are predicted from genetic screens in C. elegans. Using membrane mimetics to generate conformationally open AP2, we find that a second domain of NECAP binds these complexes and cryo-EM reveals both domains of NECAP engaging closed, inactive AP2. Assays in vitro and in vivo confirm these domains cooperate to inactivate AP2. We propose that phosphorylation marks adaptors for inactivation.

La endocarditis infecciosa es una entidad compleja, con cambios en la clínica y bacteriología en los últimos años. Pocos estudios existen sobre esta patología en la Argentina. Materiales y métodos: Estudio sobre los trabajos publicados en los congresos de la Sociedad Argentina de Medicina desde el año 1980 hasta el 2003 , se extrajeron datos demográficos, clínicos y microbiológicos en relación con esta enfermedad. Resultados: se publicaron 27 trabajos con 628 pacientes en total. La edad promedio fue de 50.7 años. Un tercio de los pacientes murieron. Fiebre, soplo y eritrosedimentación elevada fueron los datos clínicos más frecuentes. El stafilococcus spp fue el agente etiológico más aislado, seguido de streptococcus spp. El ecocardiograma fue diagnóstico en dos tercios de los pacientes. Conclusión: Los datos encontrados no se diferencian con los publicados en la literatura en su gran mayoría. Este trabajo representa un panorama de la endocarditis en nuestro país.

In obstructive cholestasis, there is an integral adaptive response aimed to diminish the bile flow and minimize the injury of bile ducts caused by increased intraluminal pressure and harmful levels of bile salts and bilirrubin. Canalicular bicarbonate secretion, driven by the anion exchanger 2 (AE2), is an influential determinant of the canalicular bile salt-independent bile flow. In this work, we ascertained whether AE2 expression and/or activity is reduced in hepatocytes from rats with common bile duct ligation (BDL), as part of the adaptive response to cholestasis. After 4 days of BDL, we found that neither AE2 mRNA expression (measured by quantitative real-time PCR) nor total levels of AE2 protein (assessed by western blot) were modified in freshly isolated hepatocytes. However, BDL led to a decrease in the expression of AE2 protein in plasma membrane fraction as compared with SHAM control. Additionally, AE2 activity (JOH-, mmol/L/min), measured in primary cultured hepatocytes from BDL and SHAM rats, was decreased in the BDL group versus the control group (1.9 ± 0.3 vs. 3.1 ± 0.2, p