The analysis of asthma control using Markov models: MOSAR study (Multicenter Observational Study of Asthma in Rabat-Morocco).

BACKGROUND: This study aimed to analyze the probabilities of transitioning between controlled, uncontrolled, and partially controlled states of asthma patients and investigate the influence of age, smoking, dust allergy, and obesity on these probabilities. METHODS: This study aimed to analyze the probabilities of transitioning between controlled, uncontrolled, and partially controlled states of asthma patients and investigate the influence of age, smoking, dust allergy, and obesity on these probabilities. RESULTS: Results showed that controlled patients were more likely to remain in that state, with approximately 79 out of 100 patients expected to stay in optimal control in the long term. A discrete nonhomogeneous time Markov Model with the stationarity criterion was used to examine the factors affecting patient states and transitions. Patients seen during the spring and summer seasons were more likely to move into a controlled state compared with those seen in the fall and winter seasons. Patients with dust allergies and obesity significantly impacted asthma exacerbation, with overweight patients more likely to transition into a controlled state. The study estimated the transition intensities matrix under certain conditions, assuming the regularity of patients. In the long term, the probability of an asthmatic patient being in a controlled state was approximately 0.8. CONCLUSION: This study provided insights into the probabilities and factors influencing asthma progression in Morocco. Dust allergy and obesity were identified as significant contributors to asthma exacerbation, emphasizing the need for effective management strategies.

Ancient Loss of Catalytic Selenocysteine Spurred Convergent Adaptation in a Mammalian Oxidoreductase.

Selenocysteine, the 21st amino acid specified by the genetic code, is a rare selenium-containing residue found in the catalytic site of selenoprotein oxidoreductases. Selenocysteine is analogous to the common cysteine amino acid, but its selenium atom offers physical-chemical properties not provided by the corresponding sulfur atom in cysteine. Catalytic sites with selenocysteine in selenoproteins of vertebrates are under strong purifying selection, but one enzyme, glutathione peroxidase 6 (GPX6), independently exchanged selenocysteine for cysteine <100 million years ago in several mammalian lineages. We reconstructed and assayed these ancient enzymes before and after selenocysteine was lost and up to today and found them to have lost their classic ability to reduce hydroperoxides using glutathione. This loss of function, however, was accompanied by additional amino acid changes in the catalytic domain, with protein sites concertedly changing under positive selection across distant lineages abandoning selenocysteine in glutathione peroxidase 6. This demonstrates a narrow evolutionary range in maintaining fitness when sulfur in cysteine impairs the catalytic activity of this protein, with pleiotropy and epistasis likely driving the observed convergent evolution. We propose that the mutations shared across distinct lineages may trigger enzymatic properties beyond those in classic glutathione peroxidases, rather than simply recovering catalytic rate. These findings are an unusual example of adaptive convergence across mammalian selenoproteins, with the evolutionary signatures possibly representing the evolution of novel oxidoreductase functions.

Quantification of cyclin D1 and D2 proteins in multiple myeloma identifies different expression patterns from those revealed by gene expression profiling.

Upregulation of a cyclin D gene determined by expression microarrays is an almost universal event in multiple myeloma (MM), but this finding has not been properly confirmed at the protein level. For this reason, we carried out a quantitative analysis of cyclin D proteins using a capillary electrophoresis nanoimmunoassay in newly diagnosed MM patients. Exclusive expression of cyclin D1 and D2 proteins was detected in 54 of 165 (33%) and 30 of 165 (18%) of the MM patients, respectively. Of note, cyclin D1 or D2 proteins were undetectable in 41% of the samples. High levels of cyclin D1 protein were strongly associated with the presence of t(11;14) or 11q gains. Cyclin D2 protein was detected in all the cases bearing t(14;16), but in only 24% of patients with t(4;14). The presence of cyclin D2 was associated with shorter overall survival (hazard ratio =2.14; P=0.017), although patients expressing cyclin D2 protein, but without 1q gains, had a favorable prognosis. In conclusion, although one of the cyclins D is overexpressed at the mRNA level in almost all MM patients, in approximately half of the patients this does not translate into detectable protein. This suggests that cyclins D could not play an oncogenic role in a proportion of patients with MM (clinicaltrials gov. identifier: NCT01916252).

Validación de la escala de gravedad percibida de la violencia de pareja contra la mujer en población ecuatoriana

Introducción: La violencia de pareja contra la mujer (VPM) es un problema de salud pública a nivel global cuya prevalencia en Ecuador es de las más elevadas de Latinoamérica. La gravedad percibida de la VPM influye en las actitudes públicas hacia la VPM, como la aceptabilidad, el sentido de responsabilidad personal o la disposición a intervenir en casos de VPM. Método: En este estudio se presenta la adaptación de la escala española de gravedad percibida de la VPM (PS-IPVAW) al contexto cultural ecuatoriano, en una muestra de 652 participantes. Resultados: Los resultados mostraron que la escala PS-IPVAW tiene una buena consistencia interna, que sus ítems tienen una baja carga de deseabilidad social, que es invariante entre géneros y que se relaciona con la culpabilidad a la víctima, la aceptabilidad de la VPM y el sexismo hostil. Discusión: La escala PS-IPVAW es un instrumento con suficientes evidencias de fiabilidad y validez para evaluar la gravedad percibida de la VPM en Ecuador y representa un importante aporte para mejorar las estrategias de prevención, intervención y erradicación de este tipo de violencia en el contexto ecuatoriano.

Introduction: Intimate partner violence against women (IPVAW) is a global public health problem whose prevalence in Ecuador is among the highest in Latin America. The perceived severity of IPV influences public attitudes toward IPVAW, such as acceptability, sense of personal responsibility, or willingness to intervene in cases of IPV. Method: This study presents the adaptation of the Spanish scale of perceived severity of IPVAW (PS-IPVAW) to the Ecuadorian cultural context, in a sample of 652 participants. Results: Our results showed that the PS-IPVAW scale has good internal consistency, its items presented low loadings of social desirability, that it is invariant across genders and that it is related to victim blaming, acceptability of IPV and hostile sexism. Discussion: The PS-IPVAW scale showed adequate evidence.

Medicinal (Radio)Chemistry: Building Radiopharmaceuticals for the Future.

Radiopharmaceuticals are increasingly playing a leading role in diagnosing, monitoring, and treating disease. In comparison with conventional pharmaceuticals, the development of radiopharmaceuticals does follow the principles of medicinal chemistry in the context of imaging-altered physiological processes. The design of a novel radiopharmaceutical has several steps similar to conventional drug discovery and some particularity. In the present work, we revisited the insights of medicinal chemistry in the current radiopharmaceutical development giving examples in oncology, neurology, and cardiology. In this regard, we overviewed the literature on radiopharmaceutical development to study overexpressed targets such as prostate-specific membrane antigen and fibroblast activation protein in cancer; ß-amyloid plaques and tau protein in brain disorders; and angiotensin II type 1 receptor in cardiac disease. The work addresses concepts in the field of radiopharmacy with a special focus on the potential use of radiopharmaceuticals for nuclear imaging and theranostics.

Panapophenanthrin, a Rare Oligocyclic Diterpene from Panus strigellus.

During the course of our search for biologically active secondary metabolites from fungal cultures, a new oligocyclic diterpenoidal derivative, panapophenanthrin (1), was isolated from Panus strigellus. In addition, two known metabolites, panepophenanthrin (2) and dihydrohypnophilin (3), were also obtained. The chemical structures of the isolated compounds were elucidated based on extensive 1D and 2D NMR spectral analyses together with high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The absolute configuration was determined through TDDFT-ECD calculations. All of the compounds were assessed for their antimicrobial and cytotoxic activities. Compounds 1 and 3 showed moderate to weak activities in the performed antimicrobial assays, while compound 1 exhibited potent cytotoxic activity against the mammalian cell lines mouse fibroblast (L929) and human endocervical adenocarcinoma (KB3.1).

A survey of the parasites of Ural saiga antelopes and Turkmenian kulans of Kazakhstan.

Saiga antelope and Turkmenian kulans are considered critically endangered and near threatened, respectively, by the International Union for Conservation of Nature (IUCN). Due to these species' fragile status, it is important to understand the pathogens infecting their remaining populations. A total of 496 faecal samples were collected from Ural saiga antelope in western Kazakhstan during June, September, and November of 2021 and May and August of 2022 and 149 faecal samples were collected from kulans in the Altyn-Emel nature reserve in south-eastern Kazakhstan from June to August of 2021. Additionally, endo- and ecto-parasites were collected from 17 saiga that were found deceased due to natural causes. Nine helminths (3 cestodes, 6 nematodes) and two protozoans were found in Ural saiga antelope. In addition to intestinal parasites, one case of cystic echinococcosis due to Echinococcus granulosus infection and one case of cerebral coenurosis due to Taenia multiceps infection was identified on necropsy. None of the collected ticks (all Hyalomma scupense) were found positive for Theileria annulate (enolase gene) or Babesia spp. (18 S ribosomal RNA gene) via PCR. Three intestinal parasites (Parascaris equorum, Strongylus sp., and Oxyuris equi) were found in kulans. All identified parasites, in both saiga and kulans, are also found in domesticated livestock, suggesting a need for better understanding of how parasites are maintained within and between regional wild and domestic ungulate populations.

De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues.

The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier-Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.

AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model.

Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants in AMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families. Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment. The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications. Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins.

Tumor Molecular Profiling in Hispanics: Moving Towards Precision Oncology and Health Equity.

BACKGROUND: Tumor molecular profiling techniques, such as next-generation sequencing (NGS) to identify somatic genetic alterations, allow physicians to have a better understanding of the affected carcinogenic pathways and guide targeted therapy. The objective of our study was to characterize common somatic alterations and carcinogenic pathways among Puerto Rican Hispanics with solid tumors. METHODS: We conducted a single-institution, retrospective study to characterize molecular tumor profiles using a 592-gene NGS platform. Actionable mutations with current or developing therapies targeting affected genes/pathways were highlighted. RESULTS: Tumors from 50 Hispanic patients were evaluated using CARIS Life Science© NGS testing. The median age of our study population was 55 (range 21-84); 54% (n = 27) were males. The primary tumor sites were colorectal (n = 24), gastric (n = 5), breast (n = 4), and lung (n = 3). The most common genetic mutations identified were in TP53 (44%), APC (38%), and KRAS (32%); followed by alterations in EGFR (4%), HER2 (6%), and homologous recombinant deficiency genes (BRCA2, 6%). Genetic alterations were found in multiple signaling pathways particularly in the cell cycle control pathway, MAPK and Wnt/ß-Catenin signaling pathways. Targetable biomarkers were identified in 27/50 (54.0%) of tumors. DISCUSSION: Molecular profiling techniques, such as next-generation sequencing, have substantially expanded access to alterations in the cancer genome. Our findings demonstrated important actionable mutations in most of the tumors evaluated and support the integration of somatic mutation profiling in the evaluation of Hispanic cancer patients with advanced cancer to help guide therapeutic options.

Pathogenic REST variant causing Jones syndrome and a review of the literature.

Jones syndrome is a rare dominantly inherited syndrome characterized by gingival fibromatosis and progressive sensorineural hearing loss becoming symptomatic in the second decade of life. Here, we report a father and his two daughters presenting with a typical Jones syndrome (OMIM %135550) phenotype. Exome sequencing identified a repressor element 1-silencing transcription factor (REST, OMIM *600571) (NM_005612.5) c.2670_2673del p.(Glu891Profs*6) heterozygous variant segregating with Jones syndrome in the family. We review the clinical data from all previously published patients with Jones syndrome and previously published patients with pathogenic REST variants associated with gingival fibromatosis or sensorineural hearing loss. This study suggests that pathogenic REST variants cause Jones syndrome.

Photocatalytic solid-phase degradation of polyethylene with fluoride-doped titania under low consumption ultraviolet radiation.

Photodegradation of plastic in solid-phase requires the polymer to be composited with an efficient photocatalyst. We report herein the successful synthesis and characterization of fluoride-doped-TiO2 and its applicability, for the first time, on solid-phase photodegradation of polyethylene films. Nearly half weight loss of polyethylene, containing only 2% of the photocatalyst, is eliminated after three weeks of ultraviolet A radiation using a low consumption light emitting diode lamp, defeating previously reported data. The half-life time of the plastic was around 3 weeks, highlighting the viability of this process for real applications. Results were compared to raw PE and PE composite with well-known TiO2, resulting in, respectively, 0 and 26% of weight loss. The degradation process was monitored by optical microscopy, scanning electron microscopy, X-ray diffraction, thermogravimetric analysis, Fourier transform infrared and X-ray photoelectron spectroscopy, which revealed the formation of plastic cracks, loss of polyethylene crystallinity and thus stability, the oxidation of C-H bonds and the oxidized state of the surface compounds during photodegradation. The obtained results open a path for the future production of cleaner and self-photodegradable plastics, where the photocatalyst would be introduced in all the manufactured plastics, making possible the quicker photodegradation of the plastics that end up on the environment and the plastics reaching wastewater treatment plants.

Soft-Tissue Changes in Unilateral Cleft Lip and Palate Patients after Non-surgical Maxillary Advancement with Face Mask Therapy - A Prospective Cohort Study.

Introduction: The aim of this study was to evaluate soft-tissue changes in Egyptian cleft lip/palate (CLP) patients after conservative non-surgical maxillary advancement using face mask therapy. Methods: This prospective cohort study included 20 Egyptian patients with unilateral CLP, six females and 14 males, ranging in age from 10 to 15 years and suffering from moderate maxillary deficiency. These patients had been chosen randomly from the Oro-dental Genetics Clinic at the National Research Centre, Egypt. For lateral cephalometry tracing and superimposition of pre-operative and post-treatment data, this study used Dolphin 11.0 software. Subnasal (Sn), pronasal (Pn), soft tissue pogonion (Pg), labial superior (Ls), stomion superioris (Ss), labiale inferior (Li), stomion inferioris (Si) and soft tissue Menton (Me) were the soft tissue points used in this analysis. Results: All of the cases were successful and demonstrated a positive response to the orthodontic traction. All post-operative linear measurements of the measured soft-tissue points showed statistically significant advancement (P = 0.05) except for pronasal linear measurements, which did not show a significant difference post-treatment (P = 0.84). Discussion: With the use of the face mask procedure, both upper and lower lip soft-tissue points improved significantly, but nasal points remained unchanged, requiring more management.

Incidence of perioperative delirium at the hospital nacional arzobispo loayza, october to December 2021, Lima Peru / Incidencia de delirium perioperatorio en el Hospital Nacional Arzobispo Loayza, octubre a diciembre 2021, Lima Perú

OBJETIVO: Determinar la incidencia de delirium perioperatorio (DPO) en el Hospital Nacional "Arzobispo Loayza", de octubre a diciembre del 2021. MÉTODOS: Estudio observacional cualicuantitativo y prospectivo, realizado en una población de 910 pacientes, en los que se aplicó: AMT Test Confussion Assessment Method (CAM) y el cuestionario de Pfeiffer (Short Portable Mental Status Questionnaire, SPMSQ). Utilizamos Chi2 para demostrar la existencia de asociación y las pruebas de V de Cramer y Phi para cuantificar la intensidad de dicha relación en caso existiera. RESULTADOS: Del total de pacientes (910) el 18,46% presentaron de delirium perioperatorio. El sexo y la religión no influye en esta. La edad si influye en la presentación del DPO puesto que el 50% (145) de los pacientes de 61 años o más la presentaron, a diferencia de los que tenían entre 36 -60 años solo el 5,31 % y los de 18 ­ 35 solo el 0,88 % presentaron DPO. Según el nivel de instrucción: el 100% sin instrucción presentaron DPO, el 73,1 con primaria presentaron DPO, el 18,5 con secundaria presentaron DPO y el 5,8 % con educación superior presentaron DPO. Según la técnica anestésica se encontró DPO en el 28,9% (60) del tipo raquídea con sedación, el 22,4% (11) del tipo epidural con sedación, el 16,7% (83) del tipo General TIVA TCI, el 12,9% (4) del tipo Bloqueo con sedación, el 9,5% (10) del tipo General balanceada; para los tipos de anestesia General TIVA manual, General Multimodal y Raquídea sin sedación no se presentaron casos de DPO. Según el tiempo operatorio: el 100% (9) de los pacientes con más de 6 horas de tiempo operatorio, el 27,1% (38) de los pacientes que tienen de 3 a 6 horas de tiempo operatorio y el 16,5% (121) de los pacientes que tienen de 1 a 3 horas de tiempo operatorio presentaron casos de DPO. Según el tiempo de hospitalización previo a la cirugía: el 48% (36) de los pacientes con tiempo de hospitalización de 16 a 30 días, el 20,5% (26) de los pacientes con tiempo de hospitalización de 8 a 15 días y el 16% (97) de los pacientes con tiempo de hospitalización de 3 a 7 días presentaron casos de DPO. Según la presencia de comorbilidades: el 51,6% (16) que tienen HTA y ER, el 41,7% (30) que tienen Diabetes y el 40,8% (20) que tienen HTA y DM2 presentan casos de DPO. Según presencia de demencia: el 100% (6) de los pacientes que tienen historia de demencia y el 17,9% (162) de los pacientes que no tienen historia de demencia presentaron DPO. según historia de antecedentes psiquiátricos, el 68,4% (13) de los que si tienen historia de trastorno psiquiátrico y el 17,4% (155) de los que no tienen historia de trastorno psiquiátrico presentaron DPO. Según historia de tratamiento psiquiátrico: el 100% (6) de los que si tienen historia de tratamiento y el 17,9% (162) de los que no tienen historia de tratamiento psiquiátrico presentaron DPO. Según cuestionario PFEIFFER pre-quirúrgico y post-quirúrgico: el 100% de los que tienen deterioro cognitivo leve, moderado o severo según el cuestionario PFEIFFER PRE QX presentaron DPO. Según diagnóstico de delirio pre-quirúrgico y post-quirúrgico: el 100% presentaron DPO. CONCLUSIONES: No existe una asociación entre el sexo y la religión y la presentación de DPO. Si existe una asociación entre la edad, grado de instrucción, tipo de anestesia, tiempo operatorio, tiempo de hospitalización previo a la cirugía, comorbilidades, historia de demencia, historia de trastorno psiquiátrico, historia de tratamiento psiquiátrico, cuestionario Pfeiffer pre, post quirúrgico, delirio pre quirúrgico y delirio post quirúrgico y la presentación de DPO,

OBJECTIVE: To determine the incidence of perioperative delirium (POD) at the Hospital nacioanl Arzobispo Loayza, from October to December 2021. METHODS: Qualitative and prospective observational study, carried out in a population of 910 patients, in which the AMT Test Confusion Assessment Method (CAM) and the Pfeiffer questionnaire (Short Portable Mental Status Questionnaire, SPMSQ) were applied. We used Chi2 to demonstrate the existence of association and Cramer's V and Phi tests to quantify the intensity of said relationship if it existed. RESULTS: Of the total of patients (910), 18.46% presented perioperative delirium. Sex and religion do not influence this. Age does influence the presentation of POD since 50% (145) of the patients 61 years of age or older presented it, unlike those between 36 -60 years of age only 5.31% and those of 18 - 35 only 0.88% presented POD. According to the level of education: 100% with no education, 73.1% with primary education, 18.5% with secondary education and 5.8% with higher education, presented DPO. According to the anesthetic technique, POD was found in 28.9% (60) of the spinal type with sedation, 22.4% (11) of the epidural type with sedation, 16.7% (83) of the General TIVA TCI type, 12.9% (4) of the Block type with sedation, 9.5% (10) of the General balanced type; for the types of general anesthesia manual TIVA, General Multimodal and Spinal anesthesia without sedation there were no cases of POD. According to the operative time: 100% (9) of the patients with more than 6 hours of operative time, 27.1% (38) of the patients who have 3 to 6 hours of operative time and 16.5% (121) of the patients who have 1 to 3 hours of operative time presented cases of POD. According to hospitalization time prior to surgery: 48% (36) of patients with hospitalization time of 16 to 30 days, 20.5% (26) of patients with hospitalization time of 8 to 15 days and 16% (97) of the patients with hospitalization time of 3 to 7 days presented POD. According to the presence of comorbidities: 51.6% (16) with AHT and RD, 41.7% (30) with Diabetes and 40.8% (20) with AHT and DM2 present POD. According to the presence of dementia: 100% (6) of the patients with a history of dementia and 17.9% (162) of the patients with no history of dementia presented POD. According to psychiatric history, 68.4% (13) of those who did have a history of psychiatric disorder and 17.4% (155) of those who did not have a history of psychiatric disorder presented POD. According to history of psychiatric treatment: 100% (6) of those who do have a history of treatment and 17.9% (162) of those who do not have a history of psychiatric treatment presented POD. According to the pre-surgical and post-surgical PFEIFFER questionnaire: 100% of those with mild, moderate or severe cognitive impairment according to the PFEIFFER PRE QX questionnaire presented POD. According to diagnosis of pre-surgical and post-surgical delirium: 100% presented POD. CONCLUSIONS: There is no association between sex and religion and the presentation of POD. If there is an association between age, educational level, type of anesthesia, operative time, hospitalization time prior to surgery, comorbidities, history of dementia, history of psychiatric disorder, history of psychiatric treatment, pre-, post-surgical Pfeiffer questionnaire, pre-surgical delirium and post-surgical delirium and the presentation of POD,

Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection.

Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.

Genetic adaptations to SIV across chimpanzee populations.

Central and eastern chimpanzees are infected with Simian Immunodeficiency Virus (SIV) in the wild, typically without developing acute immunodeficiency. Yet the recent zoonotic transmission of chimpanzee SIV to humans, which were naïve to the virus, gave rise to the Human Immunodeficiency Virus (HIV), which causes AIDS and is responsible for one of the deadliest pandemics in human history. Chimpanzees have likely been infected with SIV for tens of thousands of years and have likely evolved to reduce its pathogenicity, becoming semi-natural hosts that largely tolerate the virus. In support of this view, central and eastern chimpanzees show evidence of positive selection in genes involved in SIV/HIV cell entry and immune response to SIV, respectively. We hypothesise that the population first infected by SIV would have experienced the strongest selective pressure to control the lethal potential of zoonotic SIV, and that population genetics will reveal those first critical adaptations. With that aim we used population genetics to investigate signatures of positive selection in the common ancestor of central-eastern chimpanzees. The genes with signatures of positive selection in the ancestral population are significantly enriched in SIV-related genes, especially those involved in the immune response to SIV and those encoding for host genes that physically interact with SIV/HIV (VIPs). This supports a scenario where SIV first infected the central-eastern ancestor and where this population was under strong pressure to adapt to zoonotic SIV. Interestingly, integrating these genes with candidates of positive selection in the two infected subspecies reveals novel patterns of adaptation to SIV. Specifically, we observe evidence of positive selection in numerous steps of the biological pathway responsible for T-helper cell differentiation, including CD4 and multiple genes that SIV/HIV use to infect and control host cells. This pathway is active only in CD4+ cells which SIV/HIV infects, and it plays a crucial role in shaping the immune response so it can efficiently control the virus. Our results confirm the importance of SIV as a selective factor, identify specific genetic changes that may have allowed our closest living relatives to reduce SIV's pathogenicity, and demonstrate the potential of population genomics to reveal the evolutionary mechanisms used by naïve hosts to reduce the pathogenicity of zoonotic pathogens.

Curcumin Plant for Colorectal Cancer Prediction and Prevention Using In Silico Molecular Analysis; HOT-MELT Extrusion.

The impact of a soluble complex (SC) of curcumin (CuR) synthesized using hot melt (HM) and hot-melt extrusion (HE) technologies on adenocarcinoma cells for the treatment of colorectal cancer by enhancing CuR solubility is investigated in this work. In silico molecular modelling, solubility, drug release, and physicochemical analysis were all part of the phase solubility (PS) study, which featured a novel dyeing test and a central composite design to optimize the best complex (CDD). The optimal HE-SC (1 : 5) enhances solubility (0.8521 ± 0.016 mg·mL-1) and dissolution (91.87 ± 0.208% at 30 min), and it has an ideal stability constant (309 and 377 M-1) at 25 and 37°C and an AL type of isotherm, implying 1 : 1 stoichiometry according to the findings. An intermolecular hydrogen bond that has not undergone any chemical change and has resulted in the complete conversion of the amorphous form aids in the creation of SC. In vitro cytotoxicity was measured at IC50 on the SW480 (72 M·mL-1) and Caco-2 (40 M·mL-1) cells. According to apoptotic studies, apoptosis was responsible for the vast majority of cell death, with necrosis accounting for a small proportion of the total. In vivo toxicity was established using a zebrafish model, and a western blot examination revealed apoptosis at the molecular level. It was argued that the novel formulations developed using HE technology are more significant and effective than existing pure CuR formulations.

Genomic, Proteomic, and Phenotypic Spectrum of Novel O-Sialoglycoprotein Endopeptidase Variant in Four Affected Individuals With Galloway-Mowat Syndrome.

Galloway-Mowat syndrome is a rare autosomal recessive disease characterized by a unique combination of renal and neurological manifestations, including early-onset steroid-resistant nephrotic syndrome, microcephaly, psychomotor delay, and gyral abnormalities of the brain. Most patients die during early childhood. Here, we identified a novel homozygous O-sialoglycoprotein endopeptidase (OSGEP) variant, NM_017807.3:c.973C>G (p.Arg325Gly), in four affected individuals in an extended consanguineous family from Saudi Arabia. We have described the detailed clinical characterization, brain imaging results, and muscle biopsy findings. The described phenotype varied from embryonic lethality to early pregnancy loss or death at the age of 9. Renal disease is often the cause of death. Protein modeling of this OSGEP variant confirmed its pathogenicity. In addition, proteomic analysis of the affected patients proposed a link between the KEOPS complex function and human pathology and suggested potential pathogenic mechanisms.

Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis.

Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.

Recurrent Plasmodium vivax Cases of Both Short and Long Latency Increased with Transmission Intensity and Were Distributed Year-Round in the Most Affected Municipalities of the RACCN, Nicaragua, 2013-2018.

The characteristics of P. vivax recurrent episodes were examined using a centralized secondary source of malaria records in Nicaragua and in the two most affected municipalities in the RACCN. The study of 36,787 malaria cases due to P. vivax or P. falciparum revealed that, nationwide, 3624 patients had at least one recurrent infection. This was achieved by matching names, gender, age, community/municipality, ethnicity, etc. P. vivax was responsible for 88% of recurrent infections of 25-450 days of latency (51.9% were women and 48.1% were men), and these were assumed to be relapse episodes. Of them, 88.2% and 4.4% occurred in the municipalities of Puerto Cabezas and Rosita, respectively. The proportion of P. vivax patients having presumed relapse episodes rose with elevated transmission rates in both municipalities, reaching 7% in Rosita (2017) and 14.5% in Puerto Cabezas (2018). In both areas, relapse episodes were evident over time and were characterized by the production of a continuous stippling pattern with a slope evolving from one transmission peak to the next. During the dry season, short-latency relapse episodes were more robust, while long-latency ones increased just before the P. vivax transmission season began, with a high proportion of long-latency relapses during this period. The abundance of recurrent P. vivax infections, the wide range of relapse latency lengths, and temporal distribution tended to favor year-round transmission. It is necessary to evaluate compliance with and the effectiveness of primaquine treatment and contemplate the use of an alternative drug, among other actions.