Population-specific variations in KCNH2 predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy.

Dihydroartemisinin-piperaquine is efficacious for the treatment of uncomplicated malaria and its use is increasing globally. Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the KCNH2 gene) by piperaquine has raised concerns about cardiac safety. Whether genetic factors could modulate the risk of piperaquine-mediated QT prolongations remained unclear. Here, we first profiled the genetic landscape of KCNH2 variability using data from 141,614 individuals. Overall, we found 1,007 exonic variants distributed over the entire gene body, 555 of which were missense. By optimizing the gene-specific parametrization of 16 partly orthogonal computational algorithms, we developed a KCNH2-specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of KCNH2 variability, we then sequenced 293 Malian patients with uncomplicated malaria and identified 13 variations within the voltage sensing and pore domains of Kv11.1 that directly interact with channel blockers. Cross-referencing of genetic and electrocardiographic data before and after piperaquine exposure revealed that carriers of two common variants, rs1805121 and rs41314375, experienced significantly higher QT prolongations (ΔQTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc >30 ms. Furthermore, we identified three carriers of rare population-specific variations who experienced clinically relevant delayed ventricular repolarization. Combined, our results map population-scale genetic variability of KCNH2 and identify genetic biomarkers for piperaquine-induced QT prolongation that could help to flag at-risk patients and optimize efficacy and adherence to antimalarial therapy.

Short physical performance battery is not associated with falls and injurious falls in older persons: longitudinal data of the SCOPE project.

INTRODUCTION: Falls and fall-related injuries in older persons are a major public health problem. Our objective was to study the predictive value of the Short Physical Performance Battery (SPPB) in the cohort of the SCOPE project on falls, injurious falls, and possible difference of prediction between indoors and outdoors falls. METHODS: For this sub-study of the SCOPE project participants reporting no falls at baseline, and survey data on falls at the 12-month and 24-month follow-up were included. Participant´s characteristics were assessed during the baseline interview and medical examinations. Falls as well as injurious falls and fall circumstances were obtained self-reported. SPPB and its association with fallers vs. no fallers at 12 and at 24 months were studied with logistic regression models. RESULTS: The 1198 participants had a median age of 79 years (77-82), and a median SPPB of 10 (8-11), with a 52.5% of female. A total of 227 and 277 falls (12- and 24- month visits, respectively) were reported. In the crude model, the SPPB sum scores (p < 0.001) as well as most single item scores were significant different between fallers and non-fallers over time. However, the association was attenuated in models adjusted for age, sex, marital status, number of medications, quality of life, handgrip strength, and muscle mass [e.g., 12 months; OR 0.94 (0.87-1.02)]. While SPPB fails to differentiate between injurious and non-injurious falls (p = 0.48), a lower SPPB score was associated with falls at home (p < 0.01) after 24 months. CONCLUSION: SBPP was not able to significantly predict the risk of falling as well as experiencing an injurious fall. TRIAL REGISTRATION: This study was registered prospectively on 25th February 2016 at clinicaltrials.gov (NCT02691546).

Triangle Tip-Jet Knife used as “probe mode” can reduce the risk of mucosal damage during incision and tunneling phase of peroral endoscopic myotomy (POEM) procedures

Peroral endoscopic myotomy (POEM) is a minimally invasive endoscopic technique for the treatment of achalasia and its use has been widely spread in recent years. The Triangle Tip-Jet (TTJ) (Olympus Triangle TipKnife-J, KD645L) has become very popular in this field and currently one of the most used knives for POEM procedures. It has the capability of knife dissection along with submucosal injection and its triangle tip shape is especially useful for pulling tissue during the myotomy phase. However, its length may be too long in situations such as tight esophagogastric junction (EGJ), narrow submucosa due to fibrosis, trimming after mucosal incision and/or less experienced endoscopists3 in which preserving the integrity of the mucosa is vitally important. Distal attachment conical caps like ST Hood (DH28GR,29CR; Fujifilm, Tokyo, Japan) are commonly used for POEM, resting the distal end of the TTJ on the cap, with only the triangular tip protruding. By using straight caps, you can get a wider view and greater maneuverability, however is more difficult to calculate the distance between the triangle tip and the distal attachment end due to its straight shape. The T-shape of the distal TTJ tip was designed for its use in an open position. In this way, while using straight caps and/or less experiences endoscopists during challenging procedures (tight EGJ, submucosal fibrosis) can make them feel unsafe during incision and/or tunneling phase. Herein, we suggest the use of the TTJ knife in “probe mode”4 to reduce the distal knife length from 4.5 mm to 0.3 mm, thus allowing a greater control of the knife tip. In addition, the TTJ probe mode can be safely used with both contact and non-contact currents, which are becoming increasingly popular in recent years. (AU)

Triangle Tip-Jet Knife used as "probe mode" can reduce the risk of mucosal damage during incision and tunneling phase of POEM procedures.

Peroral endoscopic myotomy (POEM) is a minimally invasive endoscopic technique for the treatment of achalasia and its use has been widely spread in recent years1,2. The Triangle Tip-Jet (TTJ) (Olympus Triangle TipKnife-J, KD645L) has become very popular in this field and currently one of the most used knives for POEM procedures. It has the capability of knife dissection along with submucosal injection and its triangle tip shape is especially useful for pulling tissue during the myotomy phase. However, its length may be too long in situations such as tight esophagogastric junction (EGJ), narrow submucosa due to fibrosis, trimming after mucosal incision and/or less experienced endoscopists3 in which preserving the integrity of the mucosa is vitally important. Distal attachment conical caps like ST Hood (DH28GR,29CR; Fujifilm, Tokyo, Japan) are commonly used for POEM, resting the distal end of the TTJ on the cap, with only the triangular tip protruding. By using straight caps, you can get a wider view and greater maneuverability, however is more difficult to calculate the distance between the triangle tip and the distal attachment end due to its straight shape. The T-shape of the distal TTJ tip was designed for its use in an open position. In this way, while using straight caps and/or less experiences endoscopists during challenging procedures (tight EGJ, submucosal fibrosis) can make them feel unsafe during incision and/or tunneling phase. Herein, we suggest the use of the TTJ knife in "probe mode"4 to reduce the distal knife length from 4.5 mm to 0.3 mm, thus allowing a greater control of the knife tip (Fig 2). In addition, the TTJ probe mode can be safely used with both contact and non-contact currents, which are becoming increasingly popular in recent years.

Increased sLRP1 and decreased atrial natriuretic peptide plasma levels in newly diagnosed T2DM patients are normalized after optimization of glycemic control.

Background: Low-density lipoprotein receptor-related protein 1 (LRP1) negatively modulates circulating atrial natriuretic peptide (ANP) levels. Both molecules are involved in the regulation of cardiometabolism. Objectives: To evaluate soluble LRP1 (sLRP1) and ANP levels in people with newly diagnosed type 2 diabetes mellitus (T2DM) and determine the effects of metabolic optimization. Methods: This single-center longitudinal observational study recruited patients with newly diagnosed T2DM (n = 29, HbA1c > 8.5%), and 12 healthy control, age- and sex-matched volunteers. sLRP1 and ANP levels were measured by immunoassays at T2DM onset and at one year after optimization of glycemic control (HbA1c ≤ 6.5%). Results: T2DM had higher sLRP1 levels than the control group (p = 0.014) and lower ANP levels (p =0.002). At 12 months, 23 T2DM patients reached the target of HbA1c ≤ 6.5%. These patients significantly reduced sLRP1 and increased ANP levels. Patients who did not achieve HbA1c < 6.5% failed to normalize sLRP1 and ANP levels. There was an inverse correlation in the changes in sLRP1 and ANP (p = 0.031). The extent of sLRP1 changes over 12 months of metabolic control positively correlated with those of total cholesterol, LDL cholesterol, TG, TG/HDLc, and apolipoprotein B. Conclusions: Newly diagnosed T2DM patients have an increased sLRP1/ANP ratio, and increased sLRP1 and decreased ANP levels are normalized in the T2DM patients that reached an strict glycemic and metabolic control. sLRP1/ANP ratio could be a reliable marker of cardiometabolic function.

Gonococcal Infection: Case Report of Bacteremia and Brief Review of a Series of Cases.

Neisseria (N) gonorrhoeae is the microorganism responsible for the second-most reported sexually transmitted disease in the world, commonly infecting mucosal surfaces such as the endocervix, urethra, and pharynx. Gonococcal disease is generally non-symptomatic or pauci-symptomatic, but if untreated, it can progress to a more serious disease with joint, cardiac, or nervous system involvement. Disseminated gonococcal infection occurs in 0.5 to 3% of patients with gonorrhea and can present with purulent arthritis or a combination of dermatitis, tenosynovitis, and migratory polyarthralgia. This article presents the case of a 45-year-old woman examined in the emergency room for fever and acute pain in her right shoulder and knee. A few days later, the patient developed petechiae and vesiculopustular lesions on her right hand. Blood analysis showed elevated inflammation markers, and cultures yielded gram-negative diplococcus identified as N. gonorrhoeae. The patient was successfully treated with ceftriaxone, with complete remission of signs and symptoms of infection. The article then examines a series of 42 cases of gonococcal disease diagnosed in a tertiary hospital, their microbiologic susceptibilities, and the antibiotics chosen to treat them.

Alzheimer's disease: a continuum with visual involvements.

Introduction: Alzheimer's disease (AD) is the most common form of dementia affecting the central nervous system, and alteration of several visual structures has been reported. Structural retinal changes are usually accompanied by changes in visual function in this disease. The aim of this study was to analyse the differences in visual function at different stages of the pathology (family history group (FH+), mild cognitive impairment (MCI), mild AD and moderate AD) in comparison with a control group of subjects with no cognitive decline and no family history of AD. Methods: We included 53 controls, 13 subjects with FH+, 23 patients with MCI, 25 patients with mild AD and, 21 patients with moderate AD. All were ophthalmologically healthy. Visual acuity (VA), contrast sensitivity (CS), colour perception, visual integration, and fundus examination were performed. Results: The analysis showed a statistically significant decrease in VA, CS and visual integration score between the MCI, mild AD and moderate AD groups compared to the control group. In the CS higher frequencies and in the colour perception test (total errors number), statistically significant differences were also observed in the MCI, mild AD and moderate AD groups with respect to the FH+ group and also between the control and AD groups. The FH+ group showed no statistically significant difference in visual functions compared to the control group. All the test correlated with the Mini Mental State Examination score and showed good predictive value when memory decline was present, with better values when AD was at a more advanced stage. Conclusion: Alterations in visual function appear in subjects with MCI and evolve when AD is established, being stable in the initial stages of the disease (mild AD and moderate AD). Therefore, visual psychophysical tests are a useful, simple and complementary tool to neuropsychological tests to facilitate diagnosis in the preclinical and early stages of AD.

Exploratory Longitudinal Study of Ocular Structural and Visual Functional Changes in Subjects at High Genetic Risk of Developing Alzheimer's Disease.

This study aimed to analyze the evolution of visual changes in cognitively healthy individuals at risk for Alzheimer's disease (AD). Participants with a first-degree family history of AD (FH+) and carrying the Ε4+ allele for the ApoE gene (ApoE ε4+) underwent retinal thickness analysis using optical coherence tomography (OCT) and visual function assessments, including visual acuity (VA), contrast sensitivity (CS), color perception, perception digital tests, and visual field analysis. Structural analysis divided participants into FH+ ApoE ε4+ and FH- ApoE ε4- groups, while functional analysis further categorized them by age (40-60 years and over 60 years). Over the 27-month follow-up, the FH+ ApoE ε4+ group exhibited thickness changes in all inner retinal layers. Comparing this group to the FH- ApoE ε4- group at 27 months revealed progressing changes in the inner nuclear layer. In the FH+ ApoE ε4+ 40-60 years group, no progression of visual function changes was observed, but an increase in VA and CS was maintained at 3 and 12 cycles per degree, respectively, compared to the group without AD risk at 27 months. In conclusion, cognitively healthy individuals at risk for AD demonstrated progressive retinal structural changes over the 27-month follow-up, while functional changes remained stable.

Quality of Life and Kidney Function in Older Adults: Prospective Data of the SCOPE Study.

A longitudinal alteration in health-related quality of life (HRQoL) over a two-year period and its association with early-stage chronic kidney disease (CKD) progression was investigated among 1748 older adults (>75 years). HRQoL was measured by the Euro-Quality of Life Visual Analog Scale (EQ-VAS) at baseline and at one and two years after recruitment. A full comprehensive geriatric assessment was performed, including sociodemographic and clinical characteristics, the Geriatric Depression Scale-Short Form (GDS-SF), Short Physical Performance Battery (SPPB), and estimated glomerular filtration rate (eGFR). The association between EQ-VAS decline and covariates was investigated by multivariable analyses. A total of 41% of the participants showed EQ-VAS decline, and 16.3% showed kidney function decline over the two-year follow-up period. Participants with EQ-VAS decline showed an increase in GDS-SF scores and a greater decline in SPPB scores. The logistic regression analyses showed no contribution of a decrease in kidney function on EQ-VAS decline in the early stages of CKD. However, older adults with a greater GDS-SF score were more likely to present EQ-VAS decline over time, whereas an increase in the SPPB scores was associated with less EQ-VAS decline. This finding should be considered in clinical practice and when HRQoL is used to evaluate health interventions among older adults.

Functional visual tests to evaluate the effect of small astigmatism correction with toric contact lenses.

The prescription of daily contact lenses does not often include a full astigmatic correction. We question here whether this full astigmatic correction (for low to moderate astigmatism) provides a substantial improvement in the overall visual performance compared to a more conservative approach based only on the prescription of spherical contact lenses. The visual performance of 56 contact lens neophytes divided in two contact lens fitting groups (toric versus spherical lens fit) was assessed using standard visual acuity and contrast sensitivity tests. A new set of functional tests simulating everyday tasks was also used. Results showed that subjects with toric lenses had significantly better visual acuity and contrast sensitivity than those with spherical lenses. Functional tests did not render significant differences between groups, which was explained by several factors like i) the visual demand of the functional tests, ii) the dynamic blur due to misalignments and iii) small misfits between the available and measured axis of the astigmatic contact lens.

Evolution of antibody titers after two doses of mRNA Pfizer-BioNTech vaccine and effect of the third dose in nursing home residents.

OBJECTIVES: We evaluated the IgG antibody titer against SARS-CoV-2 in 196 residents of a Spanish nursing home after the second dose of the BNT162b2 vaccine and the evolution of this titer over time. The role of the third dose of the vaccine on immune-response is also analysed in 115 of participants. METHODS: Vaccine response was evaluated 1, 3 and 6 months after second dose of Pfizer-BioNTech COVID-19 Vaccine and 30 days after booster vaccination. Total anti-RBD (receptor binding domain) IgG immunoglobulins were measured to assess response. Six month after the second dose of vaccine and previously to the booster, T-cell response was also measured in 24 resident with different antibody levels. T-spot Discovery SARS-CoV-2 kit was used to identify cellular immunogenicity. RESULTS: As high as 99% of residents demonstrated a positive serological response after second dose. Only two patients showed no serologic response, two men without records of previous SARS-CoV-2 infection. A higher immune response was associated with prior SARS-CoV-2 infection regardless of the gender or age. The anti-S IgG titers decreased significantly in almost all the participants (98.5%) after six months of vaccination whatever previous COVID-infection. The third dose of vaccine increased antibody titers in all patients, although initial vaccination values were not restored in the majority of cases. CONCLUSION: The main conclusion of the study is that vaccine resulted in good immunogenicity in this vulnerable population. Nevertheless more data are needed on the long-term maintenance of antibody response after booster vaccination.

The effects of white matter hyperintensities on MEG power spectra in population with mild cognitive impairment.

Cerebrovascular disease is responsible for up to 20% of cases of dementia worldwide, but also it is a major comorbid contributor to the progression of other neurodegenerative diseases, like Alzheimer's disease. White matter hyperintensities (WMH) are the most prevalent imaging marker in cerebrovascular disease. The presence and progression of WMH in the brain have been associated with general cognitive impairment and the risk to develop all types of dementia. The aim of this piece of work is the assessment of brain functional differences in an MCI population based on the WMH volume. One-hundred and twenty-nine individuals with mild cognitive impairment (MCI) underwent a neuropsychological evaluation, MRI assessment (T1 and Flair), and MEG recordings (5 min of eyes closed resting state). Those participants were further classified into vascular MCI (vMCI; n = 61, mean age 75 ± 4 years, 35 females) or non-vascular MCI (nvMCI; n = 56, mean age 72 ± 5 years, 36 females) according to their WMH total volume, assessed with an automatic detection toolbox, LST (SPM12). We used a completely data-driven approach to evaluate the differences in the power spectra between the groups. Interestingly, three clusters emerged: One cluster with widespread larger theta power and two clusters located in both temporal regions with smaller beta power for vMCI compared to nvMCI. Those power signatures were also associated with cognitive performance and hippocampal volume. Early identification and classification of dementia pathogenesis is a crucially important goal for the search for more effective management approaches. These findings could help to understand and try to palliate the contribution of WMH to particular symptoms in mixed dementia progress.

Laparoscopic bile duct exploration during pregnancy: a multi-center case series and literature review.

BACKGROUND: The physiological changes of pregnancy increase the risk of gallstone formation and choledocholithiasis. Traditionally, endoscopic retrograde cholangiopancreatography (ERCP) has been the main approach for managing choledocholithiasis during pregnancy, but recent progress in laparoscopic bile duct exploration (LBDE) has demonstrated this technique as a safe and effective alternative option. METHODS: A retrospective multicenter study of all patients who underwent LBDE during pregnancy from five centers with proven experience in LBDE between January 2010 and June 2020 was performed. The primary endpoint was to analyze the role of LBDE during pregnancy and to further characterize its position as a safe and effective alternative for the management of choledocholithiasis. A systematic review of the published literature relating to LBDE during pregnancy until February 2022 was also performed. RESULTS: Five institutions reported performing LBDE during pregnancy in 8 patients. Median surgical time was 75 min (range: 60-140 min). The bile duct was cleared successfully in all patients, and the median hospital stay was 2 days (range: 1-3 days). The literature review identified a total of 7 patients with a successful CBD clearance rate of 86%. There were no major maternal, fetal, or pregnancy-related complications in any of the total 15 patients included. The symptomatic common bile duct lithiasis with deranged liver function tests was the most frequent indication (n=7). CONCLUSION: LBDE during pregnancy appears to be safe and effective. More evidence reporting outcomes of LBDE during pregnancy is needed before any strong recommendations can be made.

Early visual alterations in individuals at-risk of Alzheimer's disease: a multidisciplinary approach.

BACKGROUND: The earliest pathological features of Alzheimer's disease (AD) appear decades before the clinical symptoms. The pathology affects the brain and the eye, leading to retinal structural changes and functional visual alterations. Healthy individuals at high risk of developing AD present alterations in these ophthalmological measures, as well as in resting-state electrophysiological activity. However, it is unknown whether the ophthalmological alterations are related to the visual-related electrophysiological activity. Elucidating this relationship is paramount to understand the mechanisms underlying the early deterioration of the system and an important step in assessing the suitability of these measures as early biomarkers of disease. METHODS: In total, 144 healthy subjects: 105 with family history of AD and 39 without, underwent ophthalmologic analysis, magnetoencephalography recording, and genotyping. A subdivision was made to compare groups with less demographic and more risk differences: 28 high-risk subjects (relatives/APOEɛ4 +) and 16 low-risk (non-relatives/APOEɛ4 -). Differences in visual acuity, contrast sensitivity, and macular thickness were evaluated. Correlations between each variable and visual-related electrophysiological measures (M100 latency and time-frequency power) were calculated for each group. RESULTS: High-risk groups showed increased visual acuity. Visual acuity was also related to a lower M100 latency and a greater power time-frequency cluster in the high-risk group. Low-risk groups did not show this relationship. High-risk groups presented trends towards a greater contrast sensitivity that did not remain significant after correction for multiple comparisons. The highest-risk group showed trends towards the thinning of the inner plexiform and inner nuclear layers that did not remain significant after correction. The correlation between contrast sensitivity and macular thickness, and the electrophysiological measures were not significant after correction. The difference between the high- and low- risk groups correlations was no significant. CONCLUSIONS: To our knowledge, this paper is the first of its kind, assessing the relationship between ophthalmological and electrophysiological measures in healthy subjects at distinct levels of risk of AD. The results are novel and unexpected, showing an increase in visual acuity among high-risk subjects, who also exhibit a relationship between this measure and visual-related electrophysiological activity. These results have not been previously explored and could constitute a useful object of research as biomarkers for early detection and the evaluation of potential interventions' effectiveness.

Inflammaging and Blood Pressure Profiles in Late Life: The Screening for CKD among Older People across Europe (SCOPE) Study.

The neutrophil-to-lymphocyte ratio (NLR) is a marker for systemic inflammation. Since inflammation plays a relevant role in vascular aging, the aim of this study was to investigate whether NLR is associated with blood pressure profiles in older adults. This study was performed within the framework of the SCOPE study including 2461 outpatients aged 75 years and over. Mean blood pressure values, namely systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were investigated across tertiles of NLR. Change in blood pressure levels in 2 years of follow-up were compared across categories of baseline NLR. Data of 2397 individuals were used, of which 1854 individuals had hypertension. Mean values of blood pressure did not differ across categories of baseline NLR in individuals without hypertension. Individuals with hypertension with a high-range NLR had lower SBP and PP when compared to those in low-range NLR (mean difference SBP -2.94 mmHg, p = 0.032 and PP -2.55 mmHg, p = 0.030). Mean change in blood pressure in 2 years did only slightly differ in non-clinically relevant ranges, when compared across tertiles of baseline NLR. NLR as a marker of inflammaging was not associated with unfavorable blood pressure profiles in older individuals with or without hypertension.

Invasive Streptococcus agalactiae Disease With Meningitis and Septic Arthritis in a Non-pregnant Patient.

Streptococcus agalactiae is a common constituent of the human flora. However, infection in immunocompetent adults is uncommon and the involvement of the central nervous system (CNS) or development of septic arthritis are exceedingly rare and by our knowledge, were only described simultaneously once in a retrospective study. We present the case of a 66-year-old woman with S. agalactiae bacteremia presenting meningitis and septic arthritis of the left shoulder. The patient presented to the emergency department with altered mental status and fever. Lumbar puncture revealed cerebral spine fluid (CSF) pleocytosis and elevated proteins. Blood and CSF cultures identified the presence of a susceptible strain of S. agalactiae. During hospitalization, the patient complained of left shoulder pain, enabling the identification of articular fluid collections, which were drained confirming their infectious origin. Colic ulcers were found to be the starting point of this infection with posterior involvement of the CNS and the development of septic arthritis by hematogenous dissemination.

Impact of SGLT2 inhibitors on renal function in elderly with type 2 diabetes in the firstyear of treatment / Impacto de los inhibidores de SGLT2 sobre la función renal en ancianos con diabetes tipo 2 durante el primer año de tratamiento

Objectives: This study aims to evaluate the effect of iSGLT2 on estimated glomerular filtration rate (eGFR) and albuminuria in elderly patients during the first year of treatment.Methods and Methodologies: Retrospective cohort study includingelderly patients (>65 years) with type 2 diabetes (T2D) treated withiSGLT2. Data were collected at the beginning of treatment, 3, 6, 9 and12 months after.Results: A total of 115 elderly patients were included, 48.7% male,mean age 72.4±5.2 years, median HbA1c 8.4±1.7% and medianT2D duration of 17±12 years. Dapagliflozin was initiated in 60.9%and empagliflozin in 39.1%. An eGFR of 30-60mL/min/1.73m2 wasobserved in 21.7%, with moderately increased albuminuria in 12.2%and severely increased albuminuria in 4.3%.Throughout the first year, there was a significant reduction in HbA1c(-0.32%±1,6%; p<0.038). Regarding eGFR, no significant differences at the beginning of treatment or after 1-year were observed,nonetheless, a non-significant reduction was observed in the firstsemester, followed by a significant increase in eGFR (71.4-84.9mL/min/1.73m2; p<0.006) in the second semester. As to the variation ofeGFR yearlong, there were no significant differences between dapagliflozin and empagliflozin, although in the first semester, empagliflozinpresented a greater variation in eGFR(p=0.021). There was no significant reduction in albuminuria(p=0,074).Conclusions: In our sample, iSGLT2 seems to preserve the glycemiceffects, without worsening renal function in an elderly population during the first-year treatment. It seems that the nephroprotective effectis also preserved in the elderly in real life. (AU)

Objetivos: Evaluar el efecto de iSGLT2 sobre la tasa de filtraciónglomerular estimada (TFGe) y la albuminuria en ancianos durante elprimer año de tratamiento.Métodos: Estudio coorte retrospectivo que incluyó a pacientes ancianos (>65 años) con diabetes tipo 2(DM2) tratados con iSGLT2.Los datos se recogieron al inicio del tratamiento, 3, 6, 9 y 12 mesesdespués.Resultados: Se incluyeron 115 ancianos, 48,7% varones, edad media 72,4±5,2 años, mediana de HbA1c 8,4±1,7% y de duración dela DM2 de 17±12 años. Se inició dapagliflozina en 60,9% y empagliflozina en 39,1%.Se observó una TFGe de 30-60 ml/min/1,73m2 en 21,7%, con unaumento moderado de la albuminuria en 12,2% y un aumento gravede la albuminuria en 4,3%.Durante el primer año, hubo una reducción significativa de la HbA1c(-0,32%±1,6%; p<0,038). En la TFGe no se observaron diferenciassignificativas al inicio del tratamiento ni al año, sin embargo, se observó una reducción no significativa en el primer semestre, seguida deun aumento significativo (71,4-84,9ml/min/1,73m2; p<0,006) en elsegundo semestre. La variación de la TFGe a lo largo del año no presentó diferencias significativas entre dapagliflozina y empagliflozina,aunque en el primer semestre la empagliflozina presentó una mayorvariación (p=0,021). No se ha demostrado una reducción significativade la albuminuria (p=0,074).Conclusiones: En nuestra muestra, iSGLT2 parece preservar losefectos glucémicos, sin empeorar la función renal en una poblaciónanciana durante el primer año de tratamiento. Por tanto, parece mantenerse el efecto nefroprotector en mayores de 65 años en vida real. (AU)

New insights into the antiviral activity of nordihydroguaiaretic acid: Inhibition of dengue virus serotype 1 replication.

BACKGROUND: Dengue virus (DENV) is considered one of the most important pathogens in the world causing 390 million infections each year. Currently, the development of vaccines against DENV presents some shortcomings and there is no antiviral therapy available for its infection. An important challenge is that both treatments and vaccines must be effective against all four DENV serotypes. Nordihydroguaiaretic acid (NDGA), isolated from Larrea divaricata Cav. (Zygophyllaceae) has shown a significant inhibitory effect on a broad spectrum of viruses, including DENV serotypes 2 and 4. PURPOSE: We evaluated the in vitro virucidal and antiviral activity of NDGA on DENV serotype 1 (DENV1), including the study of its mechanism of action, to provide more evidence on its antiviral activity. METHODS: The viability of viral particles was quantified by the plaque-forming unit reduction method. NDGA effects on DENV1 genome and viral proteins were evaluated by qPCR and immunofluorescence, respectively. Lysosomotropic activity was assayed using acridine orange and neutral red dyes. RESULTS: NDGA showed in vitro virucidal and antiviral activity against DENV1. The antiviral effect would be effective within the first 2 h after viral internalization, when the uncoating process takes place. In addition, we determined by qPCR that NDGA decreases the amount of intracellular RNA of DENV1 and, by immunofluorescence, the number of cells infected. These results indicate that the antiviral effect of NDGA would have an intracellular mechanism of action, which is consistent with its ability to be incorporated into host cells. Considering the inhibitory activity of NDGA on the cellular lipid metabolism, we compared the antiviral effect of two inhibitors acting on two different pathways of this type of metabolism: 1) resveratrol that inhibits the sterol regulatory element of binding proteins, and 2) caffeic acid that inhibits the 5-lipoxygenase (5-LOX) enzyme. Only caffeic acid produced an inhibitory effect on DENV1 infection. We studied the lysosomotropic activity of NDGA on host cells and found, for the first time, that this compound inhibited the acidification of cell vesicles which would prevent DENV1 uncoating process. CONCLUSION: The present work contributes to the knowledge of NDGA activity on DENV. We describe its activity on DENV1, a serotype different to those that have been already reported. Moreover, we provide evidence on which stage/s of the viral replication cycle NDGA exerts its effects. We suggest that the mechanism of action of NDGA on DENV1 is related to its lysosomotropic effect, which inhibits the viral uncoating process.

Members of Venezuelan Equine Encephalitis complex entry into host cells by clathrin-mediated endocytosis in a pH-dependent manner.

Pixuna virus (PIXV) and Río Negro virus (RNV) are mosquito-borne alphaviruses belonging to the Venezuelan Equine Encephalitis (VEE) complex, which includes pathogenic epizootic and enzootic subtypes responsible for life-threatening diseases in equines. Considering that the first steps in viral infection are crucial for the efficient production of new progeny, the aim of this study was to elucidate the early events of the replication cycle of these two viruses. To this end, we used chemical inhibitors and the expression of dominant-negative constructs to study the dependence of clathrin and endosomal pH on PIXV and RNV internalization mechanisms. We demonstrated that both viruses are internalized primarily via clathrin-mediated endocytosis, where the low pH in endosomes is crucial for viral replication. Contributing knowledge regarding the entry route of VEE complex members is important to understand the pathogenesis of these viruses and also to develop new antiviral strategies.