Home exercise, branched-chain amino acids, and probiotics improve frailty in cirrhosis: A randomized clinical trial.

BACKGROUND: Frailty is a predictive factor of hospitalization, falls, and mortality in patients with cirrhosis, regardless of the degree of liver failure. The aim was to analyze whether a multifactorial intervention consisting of home-based exercise, branched-chain amino acids, and a multistrain probiotic can improve frailty in these patients. METHODS: Outpatients with cirrhosis were classified according to the Liver Frailty Index (LFI). Prefrail and frail patients were randomized into 2 groups. The intervention group was assigned to a multifactorial intervention consisting of exercise at home, branched-chain amino acid supplements, and a multistrain probiotic for 12 months. The control group received standard care. All patients were prospectively followed up every 3 months for 1 year to determine LFI, incidence of falls, emergency room visits, hospitalizations, and mortality. RESULTS: Thirty-two patients were included: 17 patients were assigned to the intervention group and 15 to the control group. In the intervention group, the baseline LFI decreased at 3, 6, 9, and 12 months (p = 0.019 for overall change with respect to the control group). The change in LFI (ΔLFI) at 12 months was -0.71 ± 0.24 in the intervention group and -0.09 ± 0.32 in the control group (p<0.001). During follow-up, patients in the intervention group had a lower 1-year probability of falls (6% vs. 47%, p = 0.03) and emergency room visits (10% vs. 44%, p = 0.04) than patients in the control group. CONCLUSIONS: A long-term multifactorial intervention that included exercise at home, branched-chain amino acids, and a multistrain probiotic improved frailty in outpatients with cirrhosis and was associated with a decrease in the incidence of clinical events such as falls and emergency room visits.

Impact of urban farming on health: a systematic review.

BACKGROUND: Urban farms are spaces designated for the cultivation of plants for food security, medicinal and curative purposes. Since the turn of the century, they have become more widespread and health benefits have been claimed; however, no consensus exists regarding this information. Hence, this study aims to provide information about the health effects of urban farming. METHODS: Protocol register number CRD42023448001. We followed the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Studies addressing urban farming interventions in any population group were included without age limitation of publication from PubMed, DOAJ, CAB Abstracts and NIH. Risk of bias was assessed using the Risk of Bias In Non-randomized Studies - of Interventions tool, and data were narratively synthesized. RESULTS: The search retrieved 2578 manuscripts, reduced to seven after screening. Urban farming's impact on health has been reflected in the physical domain by increasing self-reported health levels, physical activity, perceived general health, healthy eating and decreasing drug use. Parasites' presence has also been reported. In the mental aspect, urban farming is associated with relaxation and stress reduction. From a social perspective, urban farms provide a sense of belonging, personal growth and happiness. CONCLUSIONS: The benefits of urban farming outweigh the disadvantages. Further research should be conducted to clarify the potential benefits of this practice.

Pharmacodynamic changes in tumor and immune cells drive iberdomide's clinical mechanisms of activity in relapsed and refractory multiple myeloma.

Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9 months) and duration of response (DOR) (9.5 months) to those without CRBN dysregulation (11.2 month PFS, 9.4 month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity.

Economic Evaluation of a Web Application Implemented in Primary Care for the Treatment of Depression in Patients With Type 2 Diabetes Mellitus: Multicenter Randomized Controlled Trial.

BACKGROUND: Depressive disorder and type 2 diabetes mellitus (T2DM) are prevalent in primary care (PC). Pharmacological treatment, despite controversy, is commonly chosen due to resource limitations and difficulties in accessing face-to-face interventions. Depression significantly impacts various aspects of a person's life, affecting adherence to medical prescriptions and glycemic control and leading to future complications and increased health care costs. To address these challenges, information and communication technologies (eg, eHealth) have been introduced, showing promise in improving treatment continuity and accessibility. However, while eHealth programs have demonstrated effectiveness in alleviating depressive symptoms, evidence regarding glycemic control remains inconclusive. This randomized controlled trial aimed to test the efficacy of a low-intensity psychological intervention via a web app for mild-moderate depressive symptoms in individuals with T2DM compared with treatment as usual (TAU) in PC. OBJECTIVE: This study aimed to analyze the cost-effectiveness and cost-utility of a web-based psychological intervention to treat depressive symptomatology in people with T2DM compared with TAU in a PC setting. METHODS: A multicenter randomized controlled trial was conducted with 49 patients with T2DM, depressive symptoms of moderate severity, and glycosylated hemoglobin (HbA1c) of 7.47% in PC settings. Patients were randomized to TAU (n=27) or a web-based psychological treatment group (n=22). This web-based treatment consisted of cognitive behavioral therapy, improvement of diabetes self-care behaviors, and mindfulness. Cost-effectiveness analysis for the improvement of depressive symptomatology was conducted based on reductions in 3, 5, or 50 points on the Patient Health Questionnaire-9 (PHQ-9). The efficacy of diabetes control was estimated based on a 0.5% reduction in HbA1c levels. Follow-up was performed at 3 and 6 months. The cost-utility analysis was performed based on quality-adjusted life years. RESULTS: Efficacy analysis showed that the web-based treatment program was more effective in improving depressive symptoms than TAU but showed only a slight improvement in HbA1c. Incremental cost-effectiveness ratios of 186.76 for a 3-point reduction in PHQ-9 and 206.31 for reductions of 5 and 50 percentage points were obtained. In contrast, the incremental cost-effectiveness ratio for improving HbA1c levels amounted to €1510.90 (€1=US $1.18 in 2018) per participant. The incremental cost-utility ratio resulted in €4119.33 per quality-adjusted life year gained. CONCLUSIONS: The intervention, using web-based modules incorporating cognitive behavioral therapy tools, diabetes self-care promotion, and mindfulness, effectively reduced depressive symptoms and enhanced glycemic control in patients with T2DM. Notably, it demonstrated clinical efficacy and economic efficiency. This supports the idea that eHealth interventions not only benefit patients clinically but also offer cost-effectiveness for health care systems. The study emphasizes the importance of including specific modules to enhance diabetes self-care behaviors in future web-based psychological interventions, emphasizing personalization and adaptation for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03426709; https://clinicaltrials.gov/study/NCT03426709. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/S12888-019-2037-3.

Risk indicators for the severity of erosive wear in deciduous dentition of Mexican schoolchildren aged 5 to 7 years.

The objective of this work was to estimate the prevalence and severity of erosive tooth wear (ETW), and to identify risk indicators of deciduous dentition of a group of schoolchildren from public schools in Tlalnepantla de Baz, State of Mexico. A cross-sectional study was carried out in 352 schoolchildren from 5 to 7 years old. The severity of the ETW was evaluated using the Basic Erosive Wear Examination (BEWE). Risk indicators were evaluated through a survey which included food and beverage consumption, consumption habits, vitamin C consumption, gastroesophageal reflux, heartburn, belching, xerostomia, vomiting and teeth grinding. Multinomial logistic regression models were fitted. The prevalence of ETW was 99.7% (n = 351). Regarding severity, 46.6% were at a null/mild level, 27.3% moderate, and 26.1% severe. Males were more likely to present severe ETW (odds ratio (OR) = 2.23, 95% confidence interval (CI), 1.27-3.93; p = 0.005). The risk indicators for the severity of ETW were the frequent consumption of citrus fruits (OR = 2.09, 95% CI, 1.12-3.89; p = 0.021), fruit juice (OR = 1.99, 95% CI, 1.06-3.75; p = 0.033), processed beverages (OR = 2.15, 95% CI, 1.23-3.78; p = 0.008) and hot sauce (OR = 1.82, 95% CI, 1.03-3.20; p = 0.036). The prevalence of ETW in the deciduous dentition was very high (99.7%) and ~1/3 for severe ETW. The dietary factors associated with severe ETW are part of the regular consumption of Mexican school-age children, which impact their oral health condition. It is important to establish intervention strategies from the infant stage, focused on both children and their caregivers.

Metabolic control in type 2 diabetic patients treated with empagliflozin: A case series. / Control metabólico de pacientes diabéticos tipo 2 tratados con empagliflozina: serie de casos.

Background: Type 2 diabetes mellitus is a highly prevalent disease and is associated with increased morbidity and mortality. Due to the low percentage of adequate glycemic control, new strategies for the treatment of type 2 diabetes mellitus have been sought, including sodium-glucose cotransporter type 2 inhibitorss. Objective: To describe the evolution of patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital. The primary objective was to evaluate the efficacy of the medication regarding glycosylated hemoglobin A1c (HbA1c). The secondary objectives were: 1) achievement of HbA1c equal to or less than 7.5% according to survival analysis. 2) Change in glomerular filtration rate and urinary albumin excretion post treatment. Methods: Review of clinical records of all patients treated with empagliflozin from November 2019 to June 2023. Average follow-up of 19 (16.3 to 40) months. To compare HbA1c values according to follow-up ranges, the paired T test or Wilcoxon test was used. Results: We included 58 patients, 15 men and 43 women (74.1%), with an average age of 58.5 ± 9.2 years, ranging from 35 to 75 years. Baseline HbA1c of 10.3 ± 1.6% and 8.98% ± 2.2 in a follow-up of 18 to 24 months post-treatment, resulted in a decrease of 1.27% (p = 0.002; confidence interval 95%: 0.5 to 2.03). The most common adverse effect was urinary tract infection. Conclusions: Patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital achieved better glycemic control with few adverse effects.

Introducción: La diabetes mellitus tipo 2 es una enfermedad de alta prevalencia y está asociada a mayor morbimortalidad. Debido al bajo porcentaje de compensación, se han buscado nuevas estrategias de tratamiento farmacológico, como los inhibidores del cotransportador sodio-glucosa tipo 2. Objetivo: Describir la evolución de pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor, ubicado en el sector poniente de la Región Metropolitana, Chile. El objetivo primario fue evaluar la eficacia del medicamento respecto a hemoglobina glicosilada A1c. Los objetivos secundarios fueron registrar el logro de hemoglobina glicosilada A1c igual o menor a 7,5% según análisis de supervivencia. Luego, consignar el cambio en la velocidad de filtración glomerular y en la excreción urinaria de albúmina post tratamiento. Métodos: Revisión de ficha clínica de todos los pacientes tratados con empagliflozina desde noviembre de 2019 a junio de 2023. Media de seguimiento de 19 (de 16,3 a 40) meses. Para comparación entre valores de hemoglobina glicosilada A1c según rangos de seguimiento, se utilizó prueba T de Student de términos pareados o prueba de Wilcoxon. Resultados: Se estudió a 58 pacientes, 15 hombres y 43 mujeres (74,1%). Edad 58,5 ± 9,2 años, rango de 35 a 75 años. Hemoglobina glicosilada A1c basal de 10,3 ± 1,6% y 8,98% ± 2,2 en un rango de seguimiento de 18 a 24 meses post tratamiento, resultando en un descenso de 1,27% (p = 0,002; intervalo de confianza 95%: 0,5 a 2,03). El efecto adverso más frecuente fue infección del tracto urinario. Conclusiones: Los pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor lograron un mejor control glicémico con pocos efectos adversos.

Gamma Knife radiosurgery for the management of glomus jugulare tumors: A systematic review and report of the experience of a radioneurosurgery unit in Latin America.

Background: Glomus jugulare tumors (GJTs) are rare and mainly affect women between the 5th and 6th decades of life. Its localization and anatomic relationships make conventional surgical treatment difficult and with a considerable risk of complications. This manuscript aims to describe the results of Gamma Knife radiosurgery (GKR) in patients with GJT treated in a single center in Latin America, as well as to systematically review the literature to determine the clinical and radiological effectiveness of this technique. Methods: A search of information from January 1995 to June 2023 was performed. Twenty-two articles reporting 721 GJT patients treated with GKR were included in the study. Variables such as symptomatic control, control of tumor size, and complications were evaluated. These variables were described using measures of central tendency and proportions. For the institutional experience, 77 patients with GJT tumors were included in the study. Pre-treatment clinical variables and follow-up data were collected from medical charts and phone interviews. The Short Form-36 scale was applied to assess the quality of life. The data were analyzed using the statistical program STATA17.0. Results: A total of 721 patients were considered. The median of patients included in these studies was 18.5. The mean age was 58.4 years. The median of symptom control was 89%, and the median of imaging control was 95.7%. In our institution, 77 patients were included in the study. The mean age was 53.2 years. The median hospital stay was 4.92 hours. For the clinical follow-up, information on 47 patients was obtained. An improvement in pre-treatment symptoms was described in 58%, with general symptomatic control of 97%. The tumor-control rate was 95%, and there were statistically significant differences in six of the nine Short Form-36 scale domains. Conclusion: GKR is an effective, safe, and cost-effective technique that offers a high degree of symptomatic and tumor size control in patients with GJT.

Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice.

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.

Exploring the Associations of Inflammatory and Oxidative Stress Biomarkers with Pancreatic Diseases: An Observational and Mendelian Randomisation Study.

Identifying biomarkers linked to pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP) is crucial for early detection, treatment, and prevention. Methods: Association analyses of 10 serological biomarkers involved in cell signalling (IFN-γ, IL-6, IL-8, IL-10), oxidative stress (superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities, total glutathione (GSH), malondialdehyde (MDA) levels), and intestinal permeability proteins (zonulin, I-FABP2) were conducted across PDAC (n = 12), CP (n = 21) and control subjects (n = 23). A Mendelian randomisation (MR) approach was used to assess causality of the identified significant associations in two large genetic cohorts (FinnGen and UK Biobank). Results: Observational results showed a downregulation of SOD and GPx antioxidant enzyme activities in PDAC and CP patients, respectively, and higher MDA levels in CP patients. Logistic regression models revealed significant associations between CP and SOD activity (OR = 0.21, 95% CI [0.05, 0.89], per SD), GPx activity (OR = 0.28, 95% CI [0.10, 0.79], per SD), and MDA levels (OR = 2.05, 95% CI [1.36, 3.08], per SD). MR analyses, however, did not support causality. Conclusions: These findings would not support oxidative stress-related biomarkers as potential targets for pancreatic diseases prevention. Yet, further research is encouraged to assess their viability as non-invasive tools for early diagnosis, particularly in pre-diagnostic CP populations.

Cognitive Impairment Related to Chronic Kidney Disease Is Associated with a Decreased Abundance of Membrane-Bound Klotho in the Cerebral Cortex.

Cognitive impairment (CI) is a complication of chronic kidney disease (CKD) that is frequently observed among patients. The aim of this study was to evaluate the potential crosstalk between changes in cognitive function and the levels of Klotho in the brain cortex in an experimental model of CKD. To induce renal damage, Wistar rats received a diet containing 0.25% adenine for six weeks, while the control group was fed a standard diet. The animals underwent different tests for the assessment of cognitive function. At sacrifice, changes in the parameters of mineral metabolism and the expression of Klotho in the kidney and frontal cortex were evaluated. The animals with CKD exhibited impaired behavior in the cognitive tests in comparison with the rats with normal renal function. At sacrifice, CKD-associated mineral disorder was confirmed by the presence of the expected disturbances in the plasma phosphorus, PTH, and both intact and c-terminal FGF23, along with a reduced abundance of renal Klotho. Interestingly, a marked and significant decrease in Klotho was observed in the cerebral cortex of the animals with renal dysfunction. In sum, the loss in cerebral Klotho observed in experimental CKD may contribute to the cognitive dysfunction frequently observed among patients. Although further studies are required, Klotho might have a relevant role in the development of CKD-associated CI and represent a potential target in the management of this complication.

Association of microbiological factors with mortality in Escherichia coli bacteraemia presenting with sepsis/septic shock: a prospective cohort study.

OBJECTIVES: This study aimed to determine the association of Escherichia coli microbiological factors with 30-day mortality in patients with bloodstream infection (BSI) presenting with a dysregulated response to infection (i.e. sepsis or septic shock). METHODS: Whole-genome sequencing was performed on 224 E coli isolates of patients with sepsis/septic shock, from 22 Spanish hospitals. Phylogroup, sequence type, virulence, antibiotic resistance, and pathogenicity islands were assessed. A multivariable model for 30-day mortality including clinical and epidemiological variables was built, to which microbiological variables were hierarchically added. The predictive capacity of the models was estimated by the area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals (CI). RESULTS: Mortality at day 30 was 31% (69 patients). The clinical model for mortality included (adjusted OR; 95% CI) age (1.04; 1.02-1.07), Charlson index ≥3 (1.78; 0.95-3.32), urinary BSI source (0.30; 0.16-0.57), and active empirical treatment (0.36; 0.11-1.14) with an AUROC of 0.73 (95% CI, 0.67-0.80). Addition of microbiological factors selected clone ST95 (3.64; 0.94-14.04), eilA gene (2.62; 1.14-6.02), and astA gene (2.39; 0.87-6.59) as associated with mortality, with an AUROC of 0.76 (0.69-0.82). DISCUSSION: Despite having a modest overall contribution, some microbiological factors were associated with increased odds of death and deserve to be studied as potential therapeutic or preventive targets.

GPNMB Biomarker Levels in GBA1 Carriers with Lewy Body Disorders.

BACKGROUND: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease. OBJECTIVE: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype. METHODS: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status. RESULTS: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status. CONCLUSIONS: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Control metabólico de pacientes diabéticos tipo 2 tratados con empagliflozina: serie de casos / Metabolic control in type 2 diabetic patients treated with empagliflozin: A case series

Introducción La diabetes mellitus tipo 2 es una enfermedad de alta prevalencia y está asociada a mayor morbimortalidad. Debido al bajo porcentaje de compensación, se han buscado nuevas estrategias de tratamiento farmacológico, como los inhibidores del cotransportador sodio-glucosa tipo 2. Objetivo Describir la evolución de pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor, ubicado en el sector poniente de la Región Metropolitana, Chile. El objetivo primario fue evaluar la eficacia del medicamento respecto a hemoglobina glicosilada A1c. Los objetivos secundarios fueron registrar el logro de hemoglobina glicosilada A1c igual o menor a 7,5% según análisis de supervivencia. Luego, consignar el cambio en la velocidad de filtración glomerular y en la excreción urinaria de albúmina post tratamiento. Métodos Revisión de ficha clínica de todos los pacientes tratados con empagliflozina desde noviembre de 2019 a junio de 2023. Media de seguimiento de 19 (de 16,3 a 40) meses. Para comparación entre valores de hemoglobina glicosilada A1c según rangos de seguimiento, se utilizó prueba T de Student de términos pareados o prueba de Wilcoxon. Resultados Se estudió a 58 pacientes, 15 hombres y 43 mujeres (74,1%). Edad 58,5 ± 9,2 años, rango de 35 a 75 años. Hemoglobina glicosilada A1c basal de 10,3 ± 1,6% y 8,98% ± 2,2 en un rango de seguimiento de 18 a 24 meses post tratamiento, resultando en un descenso de 1,27% (p = 0,002; intervalo de confianza 95%: 0,5 a 2,03). El efecto adverso más frecuente fue infección del tracto urinario. Conclusiones Los pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor lograron un mejor control glicémico con pocos efectos adversos.

Background Type 2 diabetes mellitus is a highly prevalent disease and is associated with increased morbidity and mortality. Due to the low percentage of adequate glycemic control, new strategies for the treatment of type 2 diabetes mellitus have been sought, including sodium-glucose cotransporter type 2 inhibitorss. Objective To describe the evolution of patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital. The primary objective was to evaluate the efficacy of the medication regarding glycosylated hemoglobin A1c (HbA1c). The secondary objectives were: 1) achievement of HbA1c equal to or less than 7.5% according to survival analysis. 2) Change in glomerular filtration rate and urinary albumin excretion post treatment. Methods Review of clinical records of all patients treated with empagliflozin from November 2019 to June 2023. Average follow-up of 19 (16.3 to 40) months. To compare HbA1c values according to follow-up ranges, the paired T test or Wilcoxon test was used. Results We included 58 patients, 15 men and 43 women (74.1%), with an average age of 58.5 ± 9.2 years, ranging from 35 to 75 years. Baseline HbA1c of 10.3 ± 1.6% and 8.98% ± 2.2 in a follow-up of 18 to 24 months post-treatment, resulted in a decrease of 1.27% (p = 0.002; confidence interval 95%: 0.5 to 2.03). The most common adverse effect was urinary tract infection. Conclusions Patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital achieved better glycemic control with few adverse effects.

New pyridine-based chalcones and pyrazolines with anticancer, antibacterial, and antiplasmodial activities.

New pyridine-based chalcones 4a-h and pyrazolines 5a-h (N-acetyl), 6a-h (N-phenyl), and 7a-h (N-4-chlorophenyl) were synthesized and evaluated by the National Cancer Institute (NCI) against 60 different human cancer cell lines. Pyrazolines 6a, 6c-h, and 7a-h satisfied the pre-determined threshold inhibition criteria, obtaining that compounds 6c and 6f exhibited high antiproliferative activity, reaching submicromolar GI50 values from 0.38 to 0.45 µM, respectively. Moreover, compound 7g (4-CH3) exhibited the highest cytostatic activity of these series against different cancer cell lines from leukemia, nonsmall cell lung, colon, ovarian, renal, and prostate cancer, with LC50 values ranging from 5.41 to 8.35 µM, showing better cytotoxic activity than doxorubicin. Furthermore, the compounds were tested for antibacterial and antiplasmodial activities. Chalcone 4c was the most active with minimal inhibitory concentration (MIC) = 2 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA), while the pyrazoline 6h showed a MIC = 8 µg/mL against Neisseria gonorrhoeae. For anti-Plasmodium falciparum activity, the chalcones display higher activity with EC50 values ranging from 10.26 to 10.94 µg/mL. Docking studies were conducted against relevant proteins from P. falciparum, exhibiting the minimum binding energy with plasmepsin II. In vivo toxicity assay in Galleria mellonella suggests that most compounds are low or nontoxic.

Pancreatic cancer biomarkers: A pathway to advance in personalized treatment selection.

Pancreatic cancer is one of the tumors with the worst prognosis, and unlike other cancers, few advances have been made in recent years. The only curative option is surgery, but only 15-20% of patients are candidates, with a high risk of relapse. In advanced pancreatic cancer there are few first-line treatment options and no validated biomarkers for better treatment selection. The development of targeted therapies in pancreatic cancer is increasingly feasible due to tumor-agnostic treatments, such as PARP inhibitors in patients with BRCA1, BRCA2 or PALB2 alterations or immunotherapies in patients with high microsatellite instability/tumor mutational burden. In addition, other therapeutic molecules have been developed for patients with KRAS G12C mutation or fusions in NTRK or NRG1. Consequently, there has been a growing interest in biomarkers that may help guide targeted therapy in pancreatic cancer. Therefore, this review aims to offer an updated perspective on biomarkers with therapeutic potential in pancreatic cancer.

Response to Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis with the N1303K mutation: Case report and review of the literature.

Cystic fibrosis (CF) is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Thousands of CFTR mutations have been identified, but only a fraction are known to cause CF, with the most common being the prototypical class II CFTR mutation F508del. Elexacaftor-Tezacaftor-Ivacaftor (ETI) is a CFTR modulator that significantly increases ppFEV1 and reduces exacerbation frequencies. It is indicated for people with CF (pwCF) 2 years or older with at least one copy of F508del or one copy of the other 177 CFTR mutations that are responsive to ETI based on clinical or in vitro data. N1303K is the second most common class II mutation in the U.S. but is not yet FDA-approved for CFTR modulator therapy. However, N1303K is very similar to the F508del mutation and reveals variable in vitro responses to ETI. Theratyping provides an opportunity to consider ETI therapy for pwCF with mutations currently not approved by the FDA. We describe the case of an adult CF patient with W1282X and N1303K CFTR mutations and advanced CF lung disease (ACFLD) and declining lung function in which ETI was started after theratyping of nasal cells showed a meaningful response to ETI (current enhanced to over 10% of WT CFTR). The patient experienced clinical improvement with a 5% improvement in ppFEV1 and 10% increase in weight. However, there was no change in sweat chloride and the increase in ppFEV1 was less than what has been described for ACFLD patients with more typical ETI-amenable mutations. However, the response was in line with a few other cases described in the literature. This suggests a partial functional CFTR rescue like first-generation modulators for F508del. Thus, pwCF with N1303K CFTR variant could be considered for ETI eligibility.

Nephrocalcinosis fortuitously discovered: the role of surreptitious self administration of diuretics.

Background: Furosemide is a drug widely used for several medical conditions and could be used without medical prescription. Furosemide-related nephrocalcinosis can occur regardless of age, although the risk is higher in premature infants. The defining characteristic of nephrocalcinosis is generalized calcium deposition in the kidney. The most useful imaging studies for evaluation are ultrasonography and computed tomography (more effective in detecting calcification). Case Presentation: A 32-year-old woman with a history of depressive syndrome was admitted for evaluation of fortuitously discovered nephrocalcinosis and hypokalemia. The studies performed revealed the presence of a metabolic alkalosis with discrete hyperreninism/hyperaldosteronism but normal ratio, normotension and urinary study showed elevated sodium, chloride, potassium and calcium fluctuating in different determinations. Surreptitious diuretic intake was suspected and urine analysis revealed doses equivalent to 80-120 mg. The patient was advised to discontinue all diuretic treatment; she was adequately supplemented with potassium and she was followed-up in outpatient clinics. During the follow-up, clinical and analytical improvement was noted, which led to the discontinuation of supplementation. Conclusion: Surreptitious diuretic intake is a clinical condition to rule out in patients with chronic hypokalemia, metabolic alkalosis with elevated urinary sodium and chloride. The relation between surreptitious diuretic intake and nephrocalcinosis has not been fully elucidated in adults.

Applicability of an unsupervised cluster model developed on first wave COVID-19 patients in second/third wave critically ill patients.

OBJECTIVE: To validate the unsupervised cluster model (USCM) developed during the first pandemic wave in a cohort of critically ill patients from the second and third pandemic waves. DESIGN: Observational, retrospective, multicentre study. SETTING: Intensive Care Unit (ICU). PATIENTS: Adult patients admitted with COVID-19 and respiratory failure during the second and third pandemic waves. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Collected data included demographic and clinical characteristics, comorbidities, laboratory tests and ICU outcomes. To validate our original USCM, we assigned a phenotype to each patient of the validation cohort. The performance of the classification was determined by Silhouette coefficient (SC) and general linear modelling. In a post-hoc analysis we developed and validated a USCM specific to the validation set. The model's performance was measured using accuracy test and area under curve (AUC) ROC. RESULTS: A total of 2330 patients (mean age 63 [53-82] years, 1643 (70.5%) male, median APACHE II score (12 [9-16]) and SOFA score (4 [3-6]) were included. The ICU mortality was 27.2%. The USCM classified patients into 3 clinical phenotypes: A (n = 1206 patients, 51.8%); B (n = 618 patients, 26.5%), and C (n = 506 patients, 21.7%). The characteristics of patients within each phenotype were significantly different from the original population. The SC was -0.007 and the inclusion of phenotype classification in a regression model did not improve the model performance (0.79 and 0.78 ROC for original and validation model). The post-hoc model performed better than the validation model (SC -0.08). CONCLUSION: Models developed using machine learning techniques during the first pandemic wave cannot be applied with adequate performance to patients admitted in subsequent waves without prior validation.

Comparison of inferior vena cava filter use and outcomes between cancer and non-cancer patients in a tertiary hospital.

BACKGROUND: While accepted indications for the use of inferior vena cava filter (IVCF) in patients with a venous thromboembolism (VTE) have remained stable, their use continues to be frequent. Retrieval rates are still low, being particularly notable in the population with cancer. This study aims to review the rate of adherence to guidelines recommendation and to compare retrieval rates and complications in both cancer and non-cancer patients. METHODS: A retrospective study was performed including 185 patients in whom an IVCF was placed in Hospital Clinic of Barcelona. Baseline characteristics, clinical outcomes, and IVCF-related outcomes were analyzed. A strongly recommended indication (SRI) was considered if it was included in all the revised clinical guidelines and non-strongly if it was included in only some. RESULTS: Overall, 47 % of the patients had a SRI, without differences between groups. IVCF placement after 29 days from the VTE event was more frequent in the cancer group (46.1 vs. 17.7 %). Patients with cancer (48.1 % of the cohort) were older, with higher co-morbidity and bleeding risk. Anticoagulation resumption (75.3 % vs. 92.7 %) and IVCF retrieval (50.6 % vs. 66.7 %) were significantly less frequent in cancer patients. No significant differences were found regarding IVCF-related complications, hemorrhagic events and VTE recurrence. CONCLUSIONS: SRI of IVCF placement was found in less than half of the patients. Cancer patients had higher rates of IVCF placement without indication and lower anticoagulation resumption and IVCF retrieval ratios, despite complications were similar in both groups.