Nationwide genetic analysis of more than 600 families with inherited eye diseases in Argentina.

This study corresponds to the first large-scale genetic analysis of inherited eye diseases (IED) in Argentina and describes the comprehensive genetic profile of a large cohort of patients. Medical records of 22 ophthalmology and genetics services throughout 13 Argentinian provinces were analyzed retrospectively. Patients with a clinical diagnosis of an ophthalmic genetic disease and a history of genetic testing were included. Medical, ophthalmological and family history was collected. A total of 773 patients from 637 families were included, with 98% having inherited retinal disease. The most common phenotype was retinitis pigmentosa (RP, 62%). Causative variants were detected in 379 (59%) patients. USH2A, RPGR, and ABCA4 were the most common disease-associated genes. USH2A was the most frequent gene associated with RP, RDH12 early-onset severe retinal dystrophy, ABCA4 Stargardt disease, PROM1 cone-rod dystrophy, and BEST1 macular dystrophy. The most frequent variants were RPGR c.1345 C > T, p.(Arg449*) and USH2A c.15089 C > A, p.(Ser5030*). The study revealed 156/448 (35%) previously unreported pathogenic/likely pathogenic variants and 8 possible founder mutations. We present the genetic landscape of IED in Argentina and the largest cohort in South America. This data will serve as a reference for future genetic studies, aid diagnosis, inform counseling, and assist in addressing the largely unmet need for clinical trials to be conducted in the region.

Clinical Outcomes and Predictors of Thirty-Day Readmissions of Hypertriglyceridemia-Induced Acute Pancreatitis.

Background: Hypertriglyceridemia (HTG) is a well-established cause of acute pancreatitis often leading to significant morbidity, mortality, and healthcare burden. This study aimed to describe the rate, reasons, and predictors of HTG-induced acute pancreatitis (HTG-AP) in the USA. Methods: This retrospective study analyzed the Nationwide Readmissions Database (NRD) for 2018 to determine all adults (≥ 18 years) readmitted within 30 days of an index hospitalization of HTG-AP. Hospitalization characteristics and adverse outcomes for 30-day readmissions were highlighted and compared with index admissions of HTG-AP. Furthermore, independent predictors for 30-day readmissions of HTG-AP were also identified. P values ≤ 0.05 were considered statistically significant. Results: In 2018, the rate of 30-day readmission of HTG-AP was noted to be 13.5%. At the time of readmission, AP (45.2%) was identified as the most common principal diagnosis, followed by chronic pancreatitis (6.3%) and unspecified sepsis (4.8%). Compared to index admissions, 30-day readmissions of HTG-AP had a higher proportion of patients with Charlson Comorbidity Index (CCI) scores ≥ 3 (48.5% vs. 33.8%, P < 0.001). Furthermore, we noted higher rates of inpatient mortality (1.7% vs. 0.7%, odds ratio (OR): 2.55, 95% confidence interval (CI): 1.83 - 3.57, P < 0.001), mean length of stay (LOS) (5.6 vs. 4.1 days, OR: 1.5, 95% CI: 1.2 - 1.7, P < 0.001), and mean total healthcare charge (THC) ($56,799 vs. $36,078, OR: 18,702, 95% CI: 15,136 - 22,267, P < 0.001) for 30-day readmissions of HTG-AP compared to index admissions. Independent predictors for 30-day all-cause readmissions of HTG-AP included hypertension, protein energy malnutrition (PEM), CCI scores ≥ 3, chronic kidney disease and discharge against medical advice. Conclusions: AP was the principal diagnosis on presentation in only 45.2% patients for 30-day readmissions of HTG-AP. Compared to index admissions, 30-day readmissions of HTG-AP had a higher comorbidity burden, inpatient mortality, mean LOS and mean THC.

Thirty-Day Hospital Readmissions for Acute Gout in the United States: Analysis of the Nationwide Readmission Database.

BACKGROUND/OBJECTIVE: The aims of this study were to describe the rates and characteristics of nonelective 30-day readmission among adult patients hospitalized for acute gout and to assess predictors of readmission. METHODS: We analyzed the 2017 Nationwide Readmission Database. Gout hospitalizations were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification code. Hospitalizations for adult patients were included. We excluded planned or elective readmissions. We utilized χ2 tests to compare baseline characteristics between readmissions and index hospitalizations. We used multivariate Cox regression to identify independent predictors of readmissions. RESULTS: A total of 11,727 index adult hospitalizations with acute gout listed as the principal diagnosis were discharged alive and included. One thousand five hundred ninety-four (13.6%) readmissions occurred within 30 days. Acute gout was the most common reason for readmission. Readmissions had higher inpatient mortality (2.4% vs 0.1%, p < 0.0001), greater mean age (68.1 vs 67.0 years, p = 0.021), and longer hospital length of stay (5.9 vs 3.8 days, p < 0.0001) compared with index hospitalizations. Charlson Comorbidity Index scores of ≥2 (score 2: adjusted hazards ratio [AHR], 1.67; p = 0.001; score ≥3: AHR, 2.08; p < 0.0001), APR-DRG (All Patients Refined Diagnosis Related Groups) severity levels ≥2 (level 2: AHR, 1.43; p = 0.044; level 3: AHR, 1.83; p = 0.002; level 4: AHR, 2.38; p = 0.002), admission to metropolitan hospital (AHR, 1.83; p = 0.012), atrial fibrillation (AHR, 1.31; p = 0.004), and anemia (AHR, 1.30; p = 0.001) were significantly associated with 30-day readmissions. CONCLUSIONS: Acute gout readmissions were associated with worse outcomes compared with index hospitalizations. Charlson Comorbidity Index scores ≥2, APR-DRG severity levels ≥2, admission to metropolitan hospital, atrial fibrillation, and anemia were significant predictors of readmission.

Rate and Predictors of 30-day Readmission Following Diabetic Ketoacidosis in Type 1 Diabetes Mellitus: A US Analysis.

CONTEXT: Diabetic ketoacidosis (DKA) is a serious endocrine emergency, associated with morbidity and mortality. Readmissions play a significant but sometimes preventable role in healthcare cost burden on the US. OBJECTIVE: This study aimed to describe rates and characteristics of nonelective 30-day readmission among adult patients with diabetes mellitus type 1 (T1DM) hospitalized for DKA and also identify predictors of readmission. METHODS: The study analyzed the 2018 Nationwide Readmission Database. DKA hospitalizations in patients with T1DM were classified using International Classification of Diseases, Tenth Revision, Clinical Modification codes. We utilized chi-squared tests to compare baseline characteristics between readmissions and index hospitalizations. Multivariable Cox regression was employed to identify independent predictors of readmission. Following this, we developed a 30-day readmission risk scoring system based on independent predictors. RESULTS: The 30-day all-cause readmission rate for DKA was 19.4%. A majority of patients (64.8%) had DKA as the principal diagnosis on readmission. Readmitted patients had a significantly higher mean age (35.3 vs 34.9 years, P = .018) and a higher proportion of females (52.8 vs 49.6%, P < .001) than the index admission. Readmission following DKA was associated with higher odds of inpatient mortality (0.69 vs 0.24%, OR 2.84, 95% CI 1.99-4.06, P < .001). Independent predictors of 30-day all-cause readmission included female sex, index hospitalizations with Charlson Comorbidity Index (CCI) score of 3 or greater, and being discharged against medical advice (AMA). CONCLUSION: The readmission rate for DKA in T1DM patients is high, and most patients have DKA as the principal diagnosis on readmission. A CCI equal to or greater than 3, hypertension, female sex, and being discharged AMA were significant predictors of readmission.

De novo design approaches targeting an envelope protein pocket to identify small molecules against dengue virus.

Dengue fever is a mosquito-borne viral disease that has become a major public health concern worldwide. This disease presents with a wide range of clinical manifestations, from a mild cold-like illness to the more serious hemorrhagic dengue fever and dengue shock syndrome. Currently, neither an approved drug nor an effective vaccine for the treatment are available to fight the disease. The envelope protein (E) is a major component of the virion surface. This protein plays a key role during the viral entry process, constituting an attractive target for the development of antiviral drugs. The crystal structure of the E protein reveals the existence of a hydrophobic pocket occupied by the detergent n-octyl-ß-d-glucoside (ß-OG). This pocket lies at the hinge region between domains I and II and is important for the low pH-triggered conformational rearrangement required for the fusion of the virion with the host's cell. Aiming at the design of novel molecules which bind to E and act as virus entry inhibitors, we undertook a de novo design approach by "growing" molecules inside the hydrophobic site (ß-OG). From more than 240000 small-molecules generated, the 2,4 pyrimidine scaffold was selected as the best candidate, from which one synthesized compound displayed micromolar activity. Molecular dynamics-based optimization was performed on this hit, and thirty derivatives were designed in silico, synthesized and evaluated on their capacity to inhibit dengue virus entry into the host cell. Four compounds were found to be potent antiviral compounds in the low-micromolar range. The assessment of drug-like physicochemical and in vitro pharmacokinetic properties revealed that compounds 3e and 3h presented acceptable solubility values and were stable in mouse plasma, simulated gastric fluid, simulated intestinal fluid, and phosphate buffered saline solution.

Quantum Chemical Approaches in Structure-Based Virtual Screening and Lead Optimization.

Today computational chemistry is a consolidated tool in drug lead discovery endeavors. Due to methodological developments and to the enormous advance in computer hardware, methods based on quantum mechanics (QM) have gained great attention in the last 10 years, and calculations on biomacromolecules are becoming increasingly explored, aiming to provide better accuracy in the description of protein-ligand interactions and the prediction of binding affinities. In principle, the QM formulation includes all contributions to the energy, accounting for terms usually missing in molecular mechanics force-fields, such as electronic polarization effects, metal coordination, and covalent binding; moreover, QM methods are systematically improvable, and provide a greater degree of transferability. In this mini-review we present recent applications of explicit QM-based methods in small-molecule docking and scoring, and in the calculation of binding free-energy in protein-ligand systems. Although the routine use of QM-based approaches in an industrial drug lead discovery setting remains a formidable challenging task, it is likely they will increasingly become active players within the drug discovery pipeline.

Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2.

Bovine viral diarrhea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses to the livestock industry each year. The global prevalence of persistent BVDV infection and the lack of a highly effective antiviral therapy have spurred intensive efforts to discover and develop novel anti-BVDV therapies in the pharmaceutical industry. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. We performed prospective small-molecule high-throughput docking to identify molecules that likely bind to the region delimited by domains I and II of the envelope protein E2 of BVDV. Several structurally different compounds were purchased or synthesized, and assayed for antiviral activity against BVDV. Five of the selected compounds were active displaying IC50 values in the low- to mid-micromolar range. For these compounds, their possible binding determinants were characterized by molecular dynamics simulations. A common pattern of interactions between active molecules and aminoacid residues in the binding site in E2 was observed. These findings could offer a better understanding of the interaction of BVDV E2 with these inhibitors, as well as benefit the discovery of novel and more potent BVDV antivirals.

Algunos aspectos fisiopatológicos, de prevención y tratamientos de la constipación en la infancia / Physiopathological aspects, prevention and treatment of constipation in childhood

Se revisa el tema constipación en el niño, incluyendo la definición de constipación, encopresis e incontinencia fecal. Se citan algunos aspectos fisiopatológicos, así como las causas más frecuentes, evaluación clínica, indicaciones de pruebas especiales y algunos aspectos de tratamientos con dietas, laxantes y adiestramiento. Se muestran los resultados clínico-epidemiológicos en 115 pacientes tratados ambulatoriamente por un grupo multidiciplinario en consulta especializada. Se concluye que la constipación es una enfermedad frecuente en la infancia, con alta prevalencia en el menor de 5 años, en la que predominan los malos hábitos en la defecación y alimentación. En el menor de un año se deben tener en cuenta las causas anatómicas que no sean neurológicas, por lo que el tacto rectal es imprescindible en el examen físico. Se demuestra que el manejo multidisciplinario, la interrelación con la atención primaria de salud y el algoritmo de diagnóstico y tratamiento disminuyen el tiempo de evolución de la enfermedad

Algunos aspectos fisiopatológicos, de prevención y tratamientos de la constipación en la infancia / Physiopathological aspects, prevention and treatment of constipation in childhood

Se revisa el tema constipación en el niño, incluyendo la definición de constipación, encopresis e incontinencia fecal. Se citan algunos aspectos fisiopatológicos, así como las causas más frecuentes, evaluación clínica, indicaciones de pruebas especiales y algunos aspectos de tratamientos con dietas, laxantes y adiestramiento. Se muestran los resultados clínico-epidemiológicos en 115 pacientes tratados ambulatoriamente por un grupo multidiciplinario en consulta especializada. Se concluye que la constipación es una enfermedad frecuente en la infancia, con alta prevalencia en el menor de 5 años, en la que predominan los malos hábitos en la defecación y alimentación. En el menor de un año se deben tener en cuenta las causas anatómicas que no sean neurológicas, por lo que el tacto rectal es imprescindible en el examen físico. Se demuestra que el manejo multidisciplinario, la interrelación con la atención primaria de salud y el algoritmo de diagnóstico y tratamiento disminuyen el tiempo de evolución de la enfermedad(AU)