Semaglutide in type 2 diabetes with chronic kidney disease at high risk progression—real-world clinical practice

Albuminuria; Obesity; SemaglutideAlbuminúria; Obesitat; SemaglutidaAlbuminuria; Obesidad; SemaglutidaBackground Semaglutide [glucagon-like peptide-1 receptor-agonist (GLP-1RA)] has shown nephroprotective effects in previous cardiovascular studies. However, its efficacy and safety in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) have been rarely studied. Methods This is a multicenter, retrospective, observational study in patients with T2D and CKD with glycosylated hemoglobin A1c (HbA1c) of 7.5–9.5% treated with subcutaneous semaglutide for 12 months in real-world clinical practice. The main objectives were glycemic control as HbA1c 5%. Results We studied a total of 122 patients, ages 65.50 ± 11 years, 62% men, duration of T2D 12 years, baseline HbA1c 7.57% ± 1.36% and an estimated glomerular filtration rate (eGFR) 50.32 ± 19.21 mL/min/1.73 m2; 54% had a urinary albumin:creatinine ratio (UACR) of 30–300 mg/g and 20% had a UACR >300 mg/g. After 12 months of follow-up, HbA1c declined −0.73% ± 1.09% (P 5% of their body weight. Systolic and diastolic blood pressure decreased −9.85 mmHg and −5.92 mmHg, respectively (P 300 mg/g). The mean eGFR (by the Chronic Kidney Disease Epidemiology Collaboration) remained stable. The need for basal insulin decreased 20% (P < .005). Only 7% of patients on insulin had mild hypoglycemic episodes. Semaglutide was stopped in 5.7% of patients for digestive intolerance. Conclusions In this real-world study, patients with T2D and CKD treated with subcutaneous semaglutide for 12 months significantly improved glycemic control and decreased weight. Albuminuria decreased by >50% in patients with macroalbuminuria. The administration of GLP-1RA in patients with T2D and CKD was safe and well tolerated

Influence of Demographic and Lifestyle Variables on Plasma Magnesium Concentrations and Their Associations with Cardiovascular Risk Factors in a Mediterranean Population

Several studies have shown that a low magnesium (Mg) intake in the diet is associated with greater cardiovascular risk and greater risk of diabetes. However, the results are not consistent in all populations. To minimize the biases derived from diet measurement, more objective biomarkers of magnesium status have been proposed. Although there is still no ideal biomarker for Mg, several studies have shown that plasma Mg concentrations could be a relatively acceptable biomarker for cardiovascular risk assessment. However, further studies are required to better characterize this marker in different populations. Our aim was to analyze the association between plasma Mg concentrations (measured through inductively coupled plasma mass spectrometry (ICP-MS)) methods, and cardiovascular risk factors in individuals from a general Mediterranean population (aged 18–80 years). The influence of demographic and lifestyle variables, including adherence to the Mediterranean diet, on plasma Mg concentrations was analyzed. The mean Mg level of the population studied was 0.77 ± 0.08 mmol/L, the prevalence of hypomagnesemia (<0.70 mmol/L) being 18.6%. We did not find any statistically significant differences between plasma Mg concentrations and sex, age, tobacco smoking and total adherence to the Mediterranean diet (p > 0.05). We found a statistically significant association between plasma Mg concentrations and the prevalence of type-2 diabetes (0.77 ± 0.08 mmol/L in non-diabetics versus 0.73 ± 0.13 mmol/L in diabetics; p = 0.009). Despite the low prevalence of type-2 diabetes in this population (11.24% in subjects with hypomagnesemia versus 3.91%, in normomagnesemia; p = 0.005), hypomagnesemia was associated with greater odds of being diabetic in comparison with normomagnesemia (OR = 3.36; p = 0.016, even after adjustment for sex, age, obesity, and medications). On the other hand, no statistically significant association of plasma Mg concentrations with obesity, hypertension, fasting triglycerides, HDL-cholesterol or uric acid was found. However, in contrast to what was initially expected, a statistically significant association was found between plasma Mg concentrations (basically in the highest quartile) and greater total cholesterol (p < 0.05) and LDL-cholesterol concentrations (p < 0.05). In conclusion, our results contribute to increasing the evidence gathered by numerous studies on the inverse association between hypomagnesemia and type-2 diabetes, as well as to the observation, previously reported in some studies, of a direct association with hypercholesterolemia. This paradoxical link should be deeply investigated in further studies.This study was partially funded, by the Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER) (grants CIBER 06/03, SAF2016–80532-R); the Junta de Andalucía (AGR145 research group); the University Jaume I (grant P1–1B2013–54); the Fundació La Marató de TV3 (grant 538/U/2016) and the Generalitat Valenciana (grants PROMETEO2017/017, and APOSTD/2019/136)

Magnetic Nanoclusters Increase the Sensitivity of Lateral Flow Immunoassays for Protein Detection: Application to Pneumolysin as a Biomarker for Streptococcus pneumoniae

Lateral flow immunoassays for detecting biomarkers in body fluids are simple, quick, inexpensive point-of-care tests widely used in disease surveillance, such as during the coronavirus disease 2019 (COVID-19) pandemic. Improvements in sensitivity would increase their utility in healthcare, food safety, and environmental control. Recently, biofunctional magnetic nanoclusters have been used to selectively label target proteins, which allows their detection and quantification with a magneto-inductive sensor. This type of detector is easily integrated with the lateral flow immunoassay format. Pneumolysin is a cholesterol-dependent cytolysin and one of the most important protein virulence factors of pneumonia produced by Streptococcus pneumoniae. It is recognized as an important biomarker for diagnosis in urine samples. Pneumonia is the infectious disease that causes the most deaths globally, especially among children under five years and adults over 65 years, most of them in low- and middle-income countries. There especially, a rapid diagnostic urine test for pneumococcal pneumonia with high sensitivity and specificity would be helpful in primary care. In this work, a lateral flow immunoassay with magnetic nanoclusters conjugated to anti-pneumolysin antibodies was combined with two strategies to increase the technique's performance. First, magnetic concentration of the protein before the immunoassay was followed by quantification by means of a mobile telephone camera, and the inductive sensor resulted in detection limits as low as 0.57 ng (telephone camera) and 0.24 ng (inductive sensor) of pneumolysin per milliliter. Second, magnetic relocation of the particles within the test strip after the immunoassay was completed increased the detected signal by 20%. Such results obtained with portable devices are promising when compared to non-portable conventional pneumolysin detection techniques such as enzyme-linked immunosorbent assays. The combination and optimization of these approaches would have excellent application in point-of-care biodetection to reduce antibiotic misuse, hospitalizations, and deaths from community-acquired pneumonia

Mitogen-Activated Protein Kinase 14 Promotes AKI

An improved understanding of pathogenic pathways may identify novel acute kidney injury (AKI) therapeutic approaches. Unbiased LC-MS/MS protein expression profiling combined with focused data mining identified MAP3K14 and non-canonical NFκB activation at the crossroads of the enriched pathways MAPK, ubiquitin-mediated proteolysis, chemokines, NFκB and apoptosis in the kidney cortex of experimental toxic AKI. In AKI the upstream kinase MAP3K14, the NFκB DNA binding heterodimer RelB/NFκB2, and proteins involved in NFκB2 p100 ubiquitination and proteasomal processing to p52, such as Ube2m and cullin1 were up-regulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in experimental and human AKI. In vivo evidence of MAP3K14 activation in experimental folic acid-induced AKI consisted of NFκB2 p100 processing to p52, nuclear location and DNA binding of RelB and NFκB2. MAP3K14 activity-deficient aly/aly mice were protected from kidney dysfunction, inflammation and apoptosis in AKI induced by folic acid and from lethality in cisplatin-induced AKI. MAP3K14 siRNA targeting in cultured tubular cells decreased inflammation and cell death. Bone marrow transplantation experiments where consistent with a protective effect of renal cell MAP3K14 targeting. Cell culture and in vivo studies identified chemokines MCP-1, RANTES and CXCL10 as MAP3K14 targets in tubular cells, thus identifying potential mediators of the deleterious effect of MAP3K14 in kidney injury. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target

Chemical and Physical Defense Traits in Two Sexual Forms of Opuntia robusta in Central Eastern Mexico

In this study, we showed that the seed output is higher in hermaphrodites than in females of O. robusta but also has a higher variance. Furthermore, the hermaphrodite sexual form is on average spinier than the female form, and reproductive cladodes are spinier in hermaphrodites than in females. In addition, we showed that hermaphrodite empty cladodes contain a higher concentration of phenolic compounds than female empty cladodes and found a possible trade-off between the production of phenolic compounds in parental cladodes and their content in daughter cladodes. There also was a possible trade-off between the density of spines on areolae and average number of areolae per cladode, and a positive relationship between physical and chemical defense traits. With the current data, we cannot conclude that sexual polymorphism in the study population is herbivore mediated. In addition, we cannot make inferences about the possible evolution from gynodioecy to dioecy in O. robusta because of the need for accurate information concerning the costs of inbreeding, the entire costs of reproduction, the lifetime reproductive success, the estimation of vegetative growth traits, and possible competition for pollinators with other plant species.Sexually dimorphic plants provide an excellent opportunity for examining the differences in the extent of their defense against herbivores because they exhibit sex-related differences in reproductive investment. Such differences enable comparison of the sex with high reproduction expenses with the sex that expends less. The more costly sex is usually also better defended against herbivores. Generally, females are considered more valuable than hermaphrodites in terms of fitness; however, hermaphrodites are more valuable if they can produce seed by autonomous selfing, provided that the inbreeding depression is low and pollen is limited. We studied a gynodioecious population of Opuntia robusta from Central- Eastern Mexico, which has been reported to be trioecious, dioecious, or hermaphrodite, and addressed the following questions: 1) Is the hermaphrodite’s reproductive output higher than the female’s, and are hermaphrodites thus better defended? 2) Are plant tissues differentially defended? 3) Do trade-offs exist among different physical defense traits? and 4) among physical and chemical defense traits? We found that 1) hermaphrodites had a higher seed output and more spines per areola than females and that their spines contained less moisture. Non-reproductive hermaphrodite cladodes contained more total phenolic compounds (TPCs) than female ones. In addition, 2) hermaphrodite reproductive cladodes bore more spines than female cladodes, and 3) and 4) we found a negative relationship between spine number per areola and areola number per cladode and a positive relationship between spine number per areola per plant and TPC concentration per plant. Non-reproductive hermaphrodite cladodes contained a higher concentration of TPCs than female cladodes, and parental cladodes contained fewer TPCs than both reproductive and empty cladodes.UAEM project 2823/2009U CONACyT project 180694/201

Remdesivir in Very Old Patients (≥80 Years) Hospitalized with COVID-19: Real World Data from the SEMI-COVID-19 Registry

Background: Large cohort studies of patients with COVID-19 treated with remdesivir have reported improved clinical outcomes, but data on older patients are scarce. Objective: This work aims to assess the potential benefit of remdesivir in unvaccinated very old patients hospitalized with COVID-19; (2) Methods: This is a retrospective analysis of patients >= 80 years hospitalized in Spain between 15 July and 31 December 2020 (SEMI-COVID-19 Registry). Differences in 30-day all-cause mortality were adjusted using a multivariable regression analysis. (3) Results: Of the 4331 patients admitted, 1312 (30.3%) were >= 80 years. Very old patients treated with remdesivir (n: 140, 10.7%) had a lower mortality rate than those not treated with remdesivir (OR (95% CI): 0.45 (0.29-0.69)). After multivariable adjustment by age, sex, and variables associated with lower mortality (place of COVID-19 acquisition; degree of dependence; comorbidities; dementia; duration of symptoms; admission qSOFA; chest X-ray; D-dimer; and treatment with corticosteroids, tocilizumab, beta-lactams, macrolides, and high-flow nasal canula oxygen), the use of remdesivir remained associated with a lower 30-day all-cause mortality rate (adjusted OR (95% CI): 0.40 (0.22-0.61) (p < 0.001)). (4) Conclusions: Remdesivir may reduce mortality in very old patients hospitalized with COVID-19

Impact of Arterial Stiffness on All-Cause Mortality in Patients Hospitalized With COVID-19 in Spain

Older age and cardiovascular comorbidities are well-known risk factors for all-cause mortality in patients with coronavirus disease 2019 (COVID-19). Hypertension and age are the 2 principal determinants of arterial stiffness (AS). This study aimed to estimate AS in patients with COVID-19 requiring hospitalization and analyze its association with all-cause in-hospital mortality. This observational, retrospective, multicenter cohort study analyzed 12 170 patients admitted to 150 Spanish centers included in the SEMI-COVID-19 Network. We compared AS, defined as pulse pressure ≥60 mm Hg, and clinical characteristics between survivors and nonsurvivors. Mean age was 67.5 (±16.1) years and 42.5% were women. Overall, 2606 (21.4%) subjects died. Admission systolic blood pressure (BP) <120 and ≥140 mm Hg was a predictor of higher all-cause mortality (23.5% and 22.8%, respectively, P<0.001), compared with systolic BP between 120 and 140 mm Hg (18.6%). The 4379 patients with AS (36.0%) were older and had higher systolic and lower diastolic BP. Multivariate analysis showed that AS and systolic BP <120 mm Hg significantly and independently predicted all-cause in-hospital mortality (adjusted odds ratio [ORadj]: 1.27, P=0.0001; ORadj: 1.48, P=0.0001, respectively) after adjusting for sex (males, ORadj: 1.6, P=0.0001), age tertiles (second and third tertiles, ORadj: 2.0 and 4.7, P=0.0001), Charlson Comorbidity Index (second and third tertiles, ORadj: 4.8 and 8.6, P=0.0001), heart failure, and previous and in-hospital antihypertensive treatment. Our data show that AS and admission systolic BP <120 mm Hg had independent prognostic value for all-cause mortality in patients with COVID-19 requiring hospitalization

Clinical and Pathological Characterization of Lynch-Like Syndrome

Background & aims: Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. Methods: We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. Results: We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. Conclusions: Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC

Inappropriate antibiotic use in the COVID-19 era: Factors associated with inappropriate prescribing and secondary complications. Analysis of the registry SEMI-COVID

Background: Most patients with COVID-19 receive antibiotics despite the fact that bacterial co-infections are rare. This can lead to increased complications, including antibacterial resistance. We aim to analyze risk factors for inappropriate antibiotic prescription in these patients and describe possible complications arising from their use. Methods: The SEMI-COVID-19 Registry is a multicenter, retrospective patient cohort. Patients with antibiotic were divided into two groups according to appropriate or inappropriate prescription, depending on whether the patient fulfill any criteria for its use. Comparison was made by means of multilevel logistic regression analysis. Possible complications of antibiotic use were also identified. Results: Out of 13,932 patients, 3047 (21.6%) were prescribed no antibiotics, 6116 (43.9%) were appropriately prescribed antibiotics, and 4769 (34.2%) were inappropriately prescribed antibiotics. The following were independent factors of inappropriate prescription: February-March 2020 admission (OR 1.54, 95%CI 1.18-2.00), age (OR 0.98, 95%CI 0.97-0.99), absence of comorbidity (OR 1.43, 95%CI 1.05-1.94), dry cough (OR 2.51, 95%CI 1.94-3.26), fever (OR 1.33, 95%CI 1.13-1.56), dyspnea (OR 1.31, 95%CI 1.04-1.69), flu-like symptoms (OR 2.70, 95%CI 1.75-4.17), and elevated C-reactive protein levels (OR 1.01 for each mg/L increase, 95% CI 1.00-1.01). Adverse drug reactions were more frequent in patients who received ANTIBIOTIC (4.9% vs 2.7%, p < .001). Conclusion: The inappropriate use of antibiotics was very frequent in COVID-19 patients and entailed an increased risk of adverse reactions. It is crucial to define criteria for their use in these patients. Knowledge of the factors associated with inappropriate prescribing can be helpful

Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study

Background: Limited evidence exists on the role of glucose-lowering drugs in patients with COVID-19. Our main objective was to examine the association between in-hospital death and each routine at-home glucose-lowering drug both individually and in combination with metformin in patients with type 2 diabetes mellitus admitted for COVID-19. We also evaluated their association with the composite outcome of the need for ICU admission, invasive and non-invasive mechanical ventilation, or in-hospital death as well as on the development of in-hospital complications and a long-time hospital stay. Methods: We selected all patients with type 2 diabetes mellitus in the Spanish Society of Internal Medicine’s registry of COVID-19 patients (SEMI-COVID-19 Registry). It is an ongoing, observational, multicenter, nationwide cohort of patients admitted for COVID-19 in Spain from March 1, 2020. Each glucose-lowering drug user was matched with a user of other glucose-lowering drugs in a 1:1 manner by propensity scores. In order to assess the adequacy of propensity score matching, we used the standardized mean difference found in patient characteristics after matching. There was considered to be a significant imbalance in the group if a standardized mean difference > 10% was found. To evaluate the association between treatment and study outcomes, both conditional logit and mixed effect logistic regressions were used when the sample size was ≥ 100. Results: A total of 2666 patients were found in the SEMI-COVID-19 Registry, 1297 on glucose-lowering drugs in monotherapy and 465 in combination with metformin. After propensity matching, 249 patients on metformin, 105 on dipeptidyl peptidase-4 inhibitors, 129 on insulin, 127 on metformin/dipeptidyl peptidase-4 inhibitors, 34 on metformin/sodium-glucose cotransporter 2 inhibitor, and 67 on metformin/insulin were selected. No at-home glucose-lowering drugs showed a significant association with in-hospital death; the composite outcome of the need of intensive care unit admission, mechanical ventilation, or in-hospital death; in-hospital complications; or long-time hospital stays. Conclusions: In patients with type 2 diabetes mellitus admitted for COVID-19, at-home glucose-lowering drugs showed no significant association with mortality and adverse outcomes. Given the close relationship between diabetes and COVID-19 and the limited evidence on the role of glucose-lowering drugs, prospective studies are needed