Correction: Balleza Alejandri et al. Empagliflozin and Dapagliflozin Improve Endothelial Function in Mexican Patients with Type 2 Diabetes Mellitus: A Double-Blind Clinical Trial. J. Cardiovasc. Dev. Dis. 2024, 11, 182.

In the original publication [...].

A comprehensive assessment of care competence and maternal experience of first antenatal care visits in Mexico: Insights from the baseline survey of an observational cohort study.

BACKGROUND: Comprehensive antenatal care (ANC) must prioritize competent, evidence-based medical attention to ensure a positive experience and value for its users. Unfortunately, there is scarce evidence of implementing this holistic approach to ANC in low- and middle-income countries, leading to gaps in quality and accountability. This study assessed care competence, women's experiences during the first ANC visit, and the factors associated with these care attributes. METHODS AND FINDINGS: The study analyzed cross-sectional baseline data from the maternal eCohort study conducted in Mexico from August to December 2023. The study adapted the Quality Evidence for Health System Transformation (QuEST) network questionnaires to the Mexican context and validated them through expert group and cognitive interviews with women. Pregnant women aged 18 to 49 who had their first ANC visit with a family physician were enrolled in 48 primary clinics of the Instituto Mexicano del Seguro Social across 8 states. Care competence and women's experiences with care were the primary outcomes. The statistical analysis comprised descriptive statistics, multivariable linear and Poisson regressions. A total of 1,390 pregnant women were included in the study. During their first ANC visit, women received only 67.7% of necessary clinical actions on average, and 52% rated their ANC experience as fair or poor. Women with previous pregnancies (adjusted regression coefficient [aCoef.] -3.55; (95% confidence intervals [95% CIs]): -4.88, -2.22, p < 0.001), at risk of depression (aCoef. -3.02; 95% CIs: -5.61, -0.43, p = 0.023), those with warning signs (aCoef. -2.84; 95% CIs: -4.65, -1.03, p = 0.003), common pregnancy discomforts (aCoef. -1.91; 95% CIs: -3.81, -0.02, p = 0.048), or those who had a visit duration of less than 20 minutes (<15 minutes: aCoef. -7.58; 95% CIs: -10.21, -4.95, p < 0.001 and 15 to 19 minutes: aCoef. -2.73; 95% CIs: -4.79, -0.67, p = 0.010) and received ANC in the West and Southeast regions (aCoef. -5.15; 95% CIs: -7.64, -2.66, p < 0.001 and aCoef. -5.33; 95% CIs: -7.85, -2.82, p < 0.001, respectively) had a higher probability of experiencing poorer care competence. Higher care competence (adjusted prevalence ratio [aPR] 1.004; 95% CIs:1.002, 1.005, p < 0.001) and receiving care in a small clinic (aPR 1.19; 95% CIs: 1.06, 1.34, p = 0.003) compared to a medium-sized clinic were associated with a better first ANC visit experience, while common pregnancy discomforts (aPR 0.94; 95% CIs: 0.89, 0.98, p = 0.005) and shorter visit length (aPR 0.94; 95% CIs: 0.88, 0.99, p = 0.039) were associated with lower women's experience. The primary limitation of the study is that participants' responses may be influenced by social desirability bias, leading them to provide socially acceptable responses. CONCLUSIONS: We found important gaps in adherence to ANC standards and that care competence during the first ANC visit is an important predictor of positive user experience. To inform quality improvement efforts, IMSS should institutionalize the routine monitoring of ANC competencies and ANC user experience. This will help identify poorly performing facilities and providers and address gaps in the provision of evidence-based and women-centered care.

Acute and Preventive Treatment of COVID-19-Related Headache: A Series of 100 Patients.

To describe the need and effectiveness of acute and preventive medications in a series of 100 consecutive patients referred due to COVID-19-related headaches. Patients were aged 48.0 (standard deviation (SD): 12.4), 84% were female, and 56% had a prior history of headache. The most common headache phenotype was holocranial (63%), frontal (48%), pressing (75%), of moderate intensity (7 out of 10), and accompanied by photophobia (58%). Acute medication was required by 93%, with paracetamol (46%) being the most frequently used drug, followed by ibuprofen (44%). The drugs with the highest proportion of a 2 h pain-freedom response were dexketoprofen (58.8%), triptans (57.7%), and ibuprofen (54.3%). Preventive treatment was required by 75% of patients. The most frequently used drugs were amitriptyline (66%), anesthetic blockades (18%), and onabotulinumtoxinA (11%). The drugs with the highest 50% responder rate were amitriptyline (45.5%), mirtazapine (50%), and anesthetic blockades (38.9%). The highest 75% responder rate was experienced following onabotulinumtoxinA (18.2%). In conclusion, most patients required acute medication, with triptans and non-steroidal anti-inflammatory drugs achieving the best responses. Three-quarters of patients required preventive medication. The most frequently used drug was amitriptyline, which obtained the best results. In some treatment-resistant patients, anesthetic blockades and onabotulinumtoxinA were also beneficial.

Exploring the lutein therapeutic potential in steatotic liver disease: mechanistic insights and future directions.

The global prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is increasing, now affecting 25%-30% of the population worldwide. MASLD, characterized by hepatic steatosis, results from an imbalance in lipid metabolism, leading to oxidative stress, lipoperoxidation, and inflammation. The activation of autophagy, particularly lipophagy, alleviates hepatic steatosis by regulating intracellular lipid levels. Lutein, a carotenoid with antioxidant and anti-inflammatory properties, protects against liver damage, and individuals who consume high amounts of lutein have a lower risk of developing MASLD. Evidence suggests that lutein could modulate autophagy-related signaling pathways, such as the transcription factor EB (TFEB). TFEB plays a crucial role in regulating lipid homeostasis by linking autophagy to energy metabolism at the transcriptional level, making TFEB a potential target against MASLD. STARD3, a transmembrane protein that binds and transports cholesterol and sphingosine from lysosomes to the endoplasmic reticulum and mitochondria, has been shown to transport and bind lutein with high affinity. This protein may play a crucial role in the uptake and transport of lutein in the liver, contributing to the decrease in hepatic steatosis and the regulation of oxidative stress and inflammation. This review summarizes current knowledge on the role of lutein in lipophagy, the pathways it is involved in, its relationship with STARD3, and its potential as a pharmacological strategy to treat hepatic steatosis.

Empagliflozin and Dapagliflozin Improve Endothelial Function in Mexican Patients with Type 2 Diabetes Mellitus: A Double-Blind Clinical Trial.

AIM: To assess the acute effect of empagliflozin versus dapagliflozin administration on flow-mediated vasodilation in patients with type 2 diabetes mellitus. DESIGN: A double-blind clinical trial, at the Experimental and Clinical Therapeutics Institute, University Health Sciences Center, at the Universidad de Guadalajara, in inpatients with T2D according to the 2023 ADA criteria. METHODS: Thirty patients (15 males and 15 females), aged between 35 and 65 years, were included in this study, according to the 2023 ADA criteria. The eligible patients were randomly assigned to three groups: empagliflozin 25 mg once daily, dapagliflozin 10 mg once daily, or placebo once daily. Anthropometric parameters were taken using validated techniques. FMD was measured using a high-resolution semiautomatic ultrasound UNEX-EF 38G (UNEX Co., Ltd., Nagoya, Japan). Arterial tension was determined with the OMRON electronic digital sphygmomanometer (HEM 907 XL, Kyoto, Japan). RESULTS: The group of patients who received empagliflozin had a significantly lower baseline flow-mediated dilation (FMD) compared to the group receiving dapagliflozin (p = 0.017); at the end of this study, the empagliflozin group achieved a comparable FMD to the dapagliflozin group (p = 0.88). CONCLUSION: After the treatment period, the empagliflozin and dapagliflozin groups achieved similar FMD, suggesting a class effect.

HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents.

A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 ≤ 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 µM). Compound 4d potently inhibited multiple kinase targets of interest for anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.

Association between ventilatory ratio and mortality in patients with acute respiratory distress syndrome and COVID 19: A multicenter, retrospective cohort study.

BACKGROUND: Mortality rates in patients with COVID-19 undergoing mechanical ventilation in the intensive care unit are high. The causes of this mortality have been rigorously investigated. The aim of the present study is to establish mortality risk factors related to lung mechanics measured at days 1 and 5 in patients with covid-19 ARDS managed with invasive mechanical ventilation in the intensive care unit. METHODS: A retrospective observational multicenter study including consecutive patients with a confirmed diagnosis of COVID-19-induced ARDS, admitted to three institutions and seven intensive care units in the city of Bogota between May 20, 2020 and May 30, 2022 who required mechanical ventilation for at least five days. Data were collected from the medical records of patients who met the inclusion criteria on day 1 and day 5 of mechanical ventilation. The primary outcome assessed was mortality at day 30. RESULTS: A total of 533 consecutive patients admitted with ARDS with COVID-19 were included. Ventilatory ratio, plateau pressure and driving pressure measured on day 5 were significantly higher in non-survivors (p < 0.05). Overall, 30-day follow-up mortality was 48.8%. The increases between day 1 and day 5 in the ventilatory ratio (OR 1.42, 95%CI 1.03-2.01, p = 0.04), driving pressure (OR 1.56, 95%CI 1.10-2.22, p = 0.01); and finally plateau pressure (OR 1.9, 95%CI 1.34-2.69, p = 0.001) were associated with an increased risk of death. There was no association between deterioration of PaO2/FIO2 index and mortality (OR 1.34, 95%CI 0.96-1.56, p = 0.053). CONCLUSIONS: Ventilatory ratio, plateau pressure, driving pressure, and age were identified as independent risk factors for 30-day mortality in patients with ARDS due to COVID-19 on day 5 of invasive mechanical ventilation.

1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors.

We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a-d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.

Structure-Activity Relationship and Biological Investigation of a REV-ERBα-Selective Agonist SR-29065 (34) for Autoimmune Disorders.

Autoimmune diseases affect 50 million Americans, predominantly women, and are thought to be one of the top 10 leading causes of death among women in age groups up to 65 years. A central role for TH17 cells has been highlighted by genome-wide association studies (GWAS) linking genes preferentially expressed in TH17 cells to several human autoimmune diseases. We and others have reported that the nuclear receptors REV-ERBα and ß are cell-intrinsic repressors of TH17 cell development and pathogenicity and might therefore be therapeutic targets for intervention. Herein, we describe detailed SAR studies of a novel REV-ERBα-selective scaffold. Metabolic stability of the ligands was optimized allowing for in vivo interrogation of the receptor in a mouse model of multiple sclerosis (EAE) with a ligand (34). Reduction in frequency and number of T-cells in the CNS as well as key REV-ERB target genes is a measure of target engagement in vivo.

In support of 2D:4D: More data exploring its conflicting results on handedness, sexual orientation and sex differences.

In the last few years, several studies have questioned the value of the second-to-fourth digit ratio (2D:4D) as a measure of exposure to sex hormones before birth. Controversy has also extended to the 2D:4D association with individual features previously related to this exposure such as handedness and sexual orientation. Given that it has been argued that sex differences in 2D:4D could be a consequence of body-size differences, we have tested in a large sample the allometric relationship between finger lengths and body size. Our results show that the association is either allometric or isometric, depending on the analyses performed. In any case, the deviation from isometry is not large enough to explain the typically observed sex difference in this trait. We have also tested the association between sexual orientation and 2D:4D, finding a relationship between 2D:4D and sexual orientation in men but not in women. We attribute this discordance with previously published meta-analysis to differences in genetic background, a variable that has gained relevance in recent years in studies involving 2D:4D. Finally, we did not find any relationship between 2D:4D and handedness, evaluated through self-reported preference and hand performance. Our main conclusion is that 2D:4D shows differences between sexes beyond their disparity in body size. In our opinion, 2D:4D can be used cautiously as an indicator of intrauterine exposure to sex hormones taking into account some considerations, such as analysing a very large sample and taking careful measurements of the ethnicity of the sample.

USO DE MICROHÁBITATS Y DIVERSIDAD DE PRESAS CONSUMIDAS POR Craugastor berkenbuschii (Anura: Craugastoridae) EN MÉXICO / Use of microhabitats and diversity of consumed preys by Craugastor berkenbuschii (Anura: Craugastoridae) in Mexico

RESUMEN Analizamos el uso de microhábitat para las diferentes clases etarias entre épocas climáticas y comparamos la diversidad de presas consumidas por los machos y hembras adultas de Craugastor berkenbuschii en un arroyo tropical del sureste de México. Los datos fueron colectados en diez transectos de 100 x 15 m, separados entre sí por 25 m de distancia entre ellos. Los muestreos diurnos y nocturnos se realizaron mensualmente entre septiembre 2017 y agosto 2018. A cada individuo observado le registramos el sexo, la clase etaria y el microhábitat utilizado al momento del avistamiento. Las presas consumidas fueron extraídas mediante lavados estomacales in situ. Registramos un total de 437 individuos; 165 fueron adultos, 162 juveniles y 110 crías. Los microhábitats utilizados fueron roca, hojarasca, suelo, tronco, rama, hojas y raíz, de los cuales roca fue el más utilizado independientemente de la época del año y clases etarias. Se identificaron 21 órdenes de presas, 19 órdenes en hembras y 11 en machos. El índice de diversidad verdadera (1D), mostró valores similares para machos y hembras, con 9,67 y 9,08 respectivamente. El índice de distintividad taxonómica promedio (A+) determinó que las hembras consumen una mayor diversidad de presas que los machos, con 5,12 y 4,25, respectivamente. Los resultados muestran que las diferentes clases etarias de C. berkenbuschii aprovechan una gran variedad de microhábitats entre épocas climáticas y que existen diferencias entre las presas consumidas entre machos y hembras adultas.

ABSTRACT We analyzed microhabitat use for different age classes between climatic seasons and compared the diversity of prey consumed by adult males and females of Craugastor berkenbuschii in a tropical stream in southeastern Mexico. The data was collected in ten transects of 100 x 15 m, separated from each other by 25 m of the distance between them. Day and night sampling was carried out monthly between September 2017 and august 2018. For each observed individual, we recorded the sex, age class, and microhabitat used at the time of the sighting. The consumed prey was extracted by means of in situ stomach washings. We registered a total of 437 individuals; 165 were adults, 162 were juveniles, and 110 were young. The microhabitats used were rock, litter, soil, trunk, branch, leaves, and root, of which rock was the most used regardless of the time of year and age classes. Twenty-one orders of prey were identified, 19 orders in females and 11 in males. The true diversity index (1D) showed similar values for males and females, with 9.67 and 9.08 respectively. The average taxonomic distinctness index (A+) determined that females consume a greater diversity of prey than males, with 5.12 and 4.25, respectively. The results show that the different age classes of C. berkenbuschii take advantage of a wide variety of microhabitats between climatic seasons and that there are differences between the prey consumed between adult males and females.

Structure-based design of bitopic ligands for the µ-opioid receptor.

Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose1. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site2 found in µOR3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp2.50 residue in the Na+ site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at Gi subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest Gz efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for Gi, Go and Gz subtypes and arrestins, thus modulating their in vivo pharmacology.

Teratoma de ligamento redondo, reporte de caso y revisión de la bibliografía / Round ligament teratoma, case report and literature review

Resumen ANTECEDENTES: El teratoma es un tumor casi siempre benigno, con una amplia variabilidad en su localización, extremadamente rara, en el ligamento redondo. CASO CLÍNICO: Paciente de 30 años, con antecedente de un embarazo a término. En la revisión ecográfica se reportó una lesión quística paraovárica izquierda de 46 x 35 mm, sin componente sólido, graso ni calcificaciones. En el examen ginecológico se palpó una masa por encima del útero, orientada hacia el lado izquierdo, no dolorosa. El resto del examen físico trascurrió sin otras alteraciones. La impresión diagnóstica inicial fue de teratoma abdominopélvico sustentada en la ecografía transvaginal en la que los ovarios se observaron normales, con una masa de ecogenicidad mixta de 50 x 40 x 46 mm, con áreas ecolúcidas y ecogénicas de intensidad variable hacia la fosa iliaca izquierda superior, sin contacto con el ovario. El ligamento redondo se seccionó a ambos lados de la masa y se extrajo sin complicaciones; el reporte histopatológico fue de: teratoma quístico maduro. CONCLUSIONES: El ligamento redondo es una localización infrecuente de los quistes dermoides que debe considerarse en los diagnósticos diferenciales de las masas pélvicas; es susceptible de tratamiento quirúrgico por vía laparoscópica.

Abstract BACKGROUND: Teratoma is an almost always benign tumor, with a wide variability in its location; its location in the round ligament is extremely rare. CLINICAL CASE: 30-year-old patient, with a history of a full-term pregnancy. On routine ultrasound examination, a 46 x 35 mm left paraovarian cystic lesion was reported, with no solid, fatty component or calcifications. In the gynecological examination a mass was palpated above the uterus, oriented to the left side, non-painful. The rest of the physical examination passed without other alterations. The initial diagnostic impression was of abdomino-pelvic teratoma supported by transvaginal ultrasound in which the ovaries were normal, with a mass of mixed echogenicity of 50 x 40 x 46 mm, with echolucent and echogenic areas of variable intensity towards the left superior iliac fossa, without contact with the ovary. The round ligament was sectioned on both sides of the mass and removed without complications; the histopathologic report was: mature cystic teratoma. CONCLUSIONS: The round ligament is an infrequent location of dermoid cysts that should be considered in the differential diagnoses of pelvic masses; it is amenable to surgical treatment laparoscopically.

Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor.

Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn2+ binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC50 = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn2+ ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S1' loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 µM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.

Morphing Natural Product Platensimycin via Heck, Sonogashira, and One-Pot Sonogashira/Cycloaddition Reactions to Produce Antibiotics with In Vivo Activity.

Type II fatty acid synthases are promising drug targets against major bacterial pathogens. Platensimycin (PTM) is a potent inhibitor against ß-ketoacyl-[acyl carrier protein] synthase II (FabF) and ß-ketoacyl-[acyl carrier protein] synthase I (FabB), while the poor pharmacokinetics has prevented its further development. In this work, thirty-two PTM derivatives were rapidly prepared via Heck, Sonogashira, and one-pot Sonogashira/cycloaddition cascade reactions based on the Gram-scale synthesis of 6-iodo PTM (4). About half of the synthesized compounds were approximately equipotent to PTM against the tested Staphylococcus aureus strains. Among them, the representative compounds 4, A4, and B8 exhibited different plasma protein binding affinity or stability in the human hepatic microsome assay and showed improved in vivo efficacy over PTM in a mouse peritonitis model. In addition, A4 was also effective in an S. aureus-infected skin mouse model. Our study not only significantly expands the known PTM derivatives with improved antibacterial activities in vivo, but showcased that C-C cross-coupling reactions are useful tools to functionalize natural product drug leads.

Efficacy of Transversus Abdominis Plane Block in the Reduction of Pain and Opioid Requirement in Laparoscopic and Robot-assisted Hysterectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the available evidence of TAP Block in efficacy in laparoscopic or robotic hysterectomy. DATA SOURCES: We searched databases and gray literature for randomized controlled trials in which transversus abdominis plane (TAP) block was compared with placebo or with no treatment in patients who underwent laparoscopic or robot-assisted hysterectomy. METHOD OF STUDY SELECTION: Two researchers independently evaluated the eligibility of the selected articles. TABULATION, INTEGRATION, AND RESULTS: Seven studies were selected, involving 518 patients. Early postoperative pain showed a difference in the mean mean difference (MD): - 1.17 (95% confidence interval [CI]: - 1.87-0.46) in pain scale scores (I2 = 68%), which was statistically significant in favor of using TAP block, but without clinical relevance; late postoperative pain: DM 0.001 (95%CI: - 0.43-0.44; I2 = 69%); opioid requirement: DM 0.36 (95%CI: - 0.94-1.68; I2 = 80%); and incidence of nausea and vomiting with a difference of 95%CI = - 0.11 (- 0.215-0.006) in favor of TAP. CONCLUSION: With moderate strength of evidence, due to the high heterogeneity and imbalance in baseline characteristics among studies, the results indicate that TAP block should not be considered as a clinically relevant analgesic technique to improve postoperative pain in laparoscopic or robotic hysterectomy, despite statistical significance in early postoperative pain scale scores. CLINICAL TRIAL NUMBER AND REGISTRY: PROSPERO ID - CRD42018103573.

OBJETIVO: Resumir as evidências disponíveis sobre a eficácia do bloqueio TAP em histerectomia laparoscópica ou robótica. FONTES DE DADOS: Pesquisamos bancos de dados e literatura cinza por ensaios clínicos randomizados nos quais o bloqueio do plano transverso do abdome (TAP na sigla em inglês) foi comparado com placebo ou com nenhum tratamento em pacientes que foram submetidos a histerectomia laparoscópica ou assistida por robô. MéTODOS DE SELEçãO DE ESTUDOS: Dois pesquisadores avaliaram independentemente a elegibilidade dos artigos selecionados. TABULAçãO, INTEGRAçãO E RESULTADOS: Sete estudos foram selecionados envolvendo 518 pacientes. A dor pós-operatória precoce apresentou diferença nas médias (DM) de: -1 17 (intervalo de confiança [IC] de 95%: - 1 87­0 46) nos escores da escala de dor (I2 = 68%) o que foi estatisticamente significativo a favor do uso do bloqueio TAP mas sem relevância clínica; dor pós-operatória tardia: DM 0001 (IC95%: - 043­044; I2 = 69%); necessidade de opioides: DM 0 36 (95%CI: - 0 94­168; I2 = 80%); e incidência de náuseas e vômitos com diferença de 95% CI = - 011 (- 0215­0006) a favor do TAP. CONCLUSãO: Com moderada força de evidência devido à alta heterogeneidade e ao desequilíbrio nas características basais entre os estudos os resultados indicam que o bloqueio do TAP não deve ser considerado como uma técnica analgésica clinicamente relevante para melhorar a dor pós-operatória em histerectomia laparoscópica ou robótica apesar da significância estatística nas pontuações da escala de dor pós-operatória inicial. NúMERO E REGISTRO DO ENSAIO CLíNICO:: PROSPERO ID - CRD42018103573.

Efficacy of Transversus Abdominis Plane Block in the Reduction of Pain and Opioid Requirement in Laparoscopic and Robot-assisted Hysterectomy: A Systematic Review and Meta-analysis / Eficácia do bloqueio transverso do plano abdominal na redução da dor e da necessidade de opioides em histerectomia laparoscópica e assistida por robô: Uma revisão sistemática e metanálise

Abstract Objective To summarize the available evidence of TAP Block in efficacy in laparoscopic or robotic hysterectomy. Data Sources We searched databases and gray literature for randomized controlled trials in which transversus abdominis plane (TAP) block was compared with placebo or with no treatment in patients who underwent laparoscopic or robot-assisted hysterectomy. Method of Study Selection Two researchers independently evaluated the eligibility of the selected articles. Tabulation, Integration, and Results Seven studies were selected, involving 518 patients. Early postoperative pain showed a difference in the mean mean difference (MD): - 1.17 (95% confidence interval [CI]: - 1.87-0.46) in pain scale scores (I2=68%), which was statistically significant in favor of using TAP block, but without clinical relevance; late postoperative pain: DM 0.001 (95%CI: - 0.43-0.44; I2=69%); opioid requirement: DM 0.36 (95%CI: - 0.94-1.68; I2=80%); and incidence of nausea and vomiting with a difference of 95%CI=- 0.11 (- 0.215-0.006) in favor of TAP. Conclusion With moderate strength of evidence, due to the high heterogeneity and imbalance in baseline characteristics among studies, the results indicate that TAP block should not be considered as a clinically relevant analgesic technique to improve postoperative pain in laparoscopic or robotic hysterectomy, despite statistical significance in early postoperative pain scale scores. Clinical Trial Number and Registry: PROSPERO ID - CRD42018103573.

Resumo Objetivo Resumir as evidências disponíveis sobre a eficácia do bloqueio TAP em histerectomia laparoscópica ou robótica. Fontes de Dados Pesquisamos bancos de dados e literatura cinza por ensaios clínicos randomizados nos quais o bloqueio do plano transverso do abdome (TAP na sigla em inglês) foi comparado com placebo ou com nenhum tratamento em pacientes que foram submetidos a histerectomia laparoscópica ou assistida por robô. Métodos de Seleção de Estudos Dois pesquisadores avaliaram independentemente a elegibilidade dos artigos selecionados. Tabulação, Integração e Resultados Sete estudos foram selecionados envolvendo 518 pacientes. A dor pós-operatória precoce apresentou diferença nasmédias (DM) de: -1 17 (intervalo de confiança [IC] de 95%: - 1 87-0 46) nos escores da escala de dor (I2=68%) o que foi estatisticamente significativo a favor do uso do bloqueio TAP mas sem relevância clínica; dor pós-operatória tardia: DM 0001 (IC95%: - 043-044; I2=69%); necessidade de opioides: DM0 36 (95%CI: - 0 94-168; I2=80%); e incidência de náuseas e vômitos com diferença de 95% CI=- 011 (- 0215-0006) a favor do TAP. Conclusão Com moderada força de evidência devido à alta heterogeneidade e ao desequilíbrio nas características basais entre os estudos os resultados indicam que o bloqueio do TAP não deve ser considerado como uma técnica analgésica clinicamente relevante para melhorar a dor pós-operatória em histerectomia laparoscópica ou robótica apesar da significância estatística nas pontuações da escala de dor pósoperatória inicial. Número e Registro do Ensaio Clínico: PROSPERO ID - CRD42018103573.

Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells.

Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.

Comparable Outcomes of Matched Sibling Donor and Matched Unrelated Donor Stem Cell Transplantation in Children With Acute Leukemia in Argentina.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective mode of consolidation therapy for children with high-risk acute leukemia. In high-income countries, match sibling donor (MSD) and match unrelated donor (MUD) HSCT have similar outcomes, but data are scarce in upper-middle-income countries. Our objective was to compare MSD and MUD HSCT outcomes for children with acute leukemia in Argentina. PATIENTS AND METHODS: This was a single-institution retrospective cohort study. We included children with acute leukemia who underwent HSCT with either MSD or MUD between 2014 and 2019. RESULTS: The study included 45 patients who received MSD (n=27) or MUD (n=18) for acute leukemia. Event-free survival was not significantly different between MSD (62.3±10.7%) versus MUD (54.2±15.0%; P=0.54) at 5 years. Similarly, there was no significant difference in 5-year overall survival between MSD (71.9±9.8%) versus MUD (65.1±13.5%; P=0.38). The cumulative incidence of treatment-related mortality (P=0.31), cumulative incidence of relapse (P=0.99), and proportion with acute-graft-versus-host disease (P=0.76) and chronic-graft-versus-host disease (P=0.68) were also not significantly different. CONCLUSIONS: In Argentina, we did not show significant differences in outcomes between MSD and MUD HSCT for children with high-risk leukemia. Future work should focus on strategies to reduce the relapse risk in children with high-risk leukemia in upper-middle-income countries.