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Baricitinib and imatinib are considered therapies for coronavirus disease 2019 (COVID-19), but their ultimate clinical impact remains to be elucidated, so our objective is to determine whether these kinase inhibitors provide benefit when added to standard care in hospitalized COVID-19 patients. Phase-2, open-label, randomized trial with a pick-the-winner design conducted from September 2020 to June 2021 in a single Spanish center. Hospitalized adults with COVID-19 pneumonia and a symptom duration ≤10 days were assigned to 3 arms: imatinib (400 mg qd, 7 days) plus standard-care, baricitinib (4 mg qd, 7 days) plus standard-care, or standard-care alone. Primary outcome was time to clinical improvement (discharge alive or a reduction of 2 points in an ordinal scale of clinical status) compared on a day-by-day basis to identify differences ≥15% between the most and least favorable groups. Secondary outcomes included oxygenation and ventilatory support requirements, additional therapies administered, all-cause mortality, and safety. One hundred and sixty-five patients analyzed. Predefined criteria for selection of the most advantageous arm were met for baricitinib, but not for imatinib. However, no statistically significant differences were observed in formal analysis, but a trend toward better results in patients receiving baricitinib was found compared to standard care alone (hazard ratio [HR] for clinical improvement: 1.41, 95% confidence intervals [CI]: 0.96-2.06; HR for discontinuing oxygen: 1.46, 95% CI: 0.94-2.28). No differences were found regarding additional therapies administered or safety. Baricitinib plus standard care showed better results for hospitalized COVID-19 patients, being the most advantageous therapeutic strategy among those proposed in this exploratory clinical trial.
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COVID-19 , Adulto , Humanos , Mesilato de Imatinib , SARS-CoV-2 , Tratamento Farmacológico da COVID-19 , Resultado do TratamentoRESUMO
High temperatures during the summer season are a very important factor to be considered due to their possible influence on drug stability and effectiveness. This is especially important in those patients included in clinical trials, polymedicated or with long-term pharmacological therapies.
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Infections caused by ceftolozane-tazobactam and ceftazidime-avibactam-resistant P. aeruginosa infections are an emerging concern. We aimed to analyze the underlying ceftolozane-tazobactam and ceftazidime-avibactam resistance mechanisms in all multidrug-resistant or extensively drug-resistant (MDR/XDR) P. aeruginosa isolates recovered during 1 year (2020) from patients with a documented P. aeruginosa infection. Fifteen isolates showing ceftolozane-tazobactam and ceftazidime-avibactam resistance were evaluated. Clinical conditions, previous positive cultures, and ß-lactams received in the previous month were reviewed for each patient. MICs were determined by broth microdilution. Multilocus sequence types (MLSTs) and resistance mechanisms were determined using short- and long-read whole-genome sequencing (WGS). The impact of Pseudomonas-derived cephalosporinases (PDCs) on ß-lactam resistance was demonstrated by cloning into an ampC-deficient PAO1 derivative (PAOΔC) and construction of 3D models. Genetic support of acquired ß-lactamases was determined in silico from high-quality hybrid assemblies. In most cases, the isolates were recovered after treatment with ceftolozane-tazobactam or ceftazidime-avibactam. Seven isolates from different sequence types (STs) owed their ß-lactam resistance to chromosomal mutations and all displayed specific substitutions in PDC: Phe121Leu and Gly222Ser, Pro154Leu, Ala201Thr, Gly214Arg, ΔGly203-Glu219, and Glu219Lys. In the other eight isolates, the ST175 clone was overrepresented (6 isolates) and associated with IMP-28 and IMP-13, whereas two ST1284 isolates produced VIM-2. The cloned PDCs conferred enhanced cephalosporin resistance. The 3D PDC models revealed rearrangements affecting residues involved in cephalosporin hydrolysis. Carbapenemases were chromosomal (VIM-2) or plasmid-borne (IMP-28, IMP-13) and associated with class-1 integrons located in Tn402-like transposition modules. Our findings highlighted that cephalosporin/ß-lactamase inhibitors are potential selectors of MDR/XDR P. aeruginosa strains producing PDC variants or metallo-ß-lactamases. Judicious use of these agents is encouraged.
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Ceftazidima , Infecções por Pseudomonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Proteínas de Bactérias , Ceftazidima/farmacologia , Ceftazidima/uso terapêutico , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Combinação de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Tazobactam/farmacologia , Tazobactam/uso terapêutico , beta-Lactamases/genética , beta-Lactamases/uso terapêuticoRESUMO
Coronavirus disease 2019 (COVID-19) infection in elderly patients is more aggressive and treatments have shown limited efficacy. Our objective is to describe the clinical course and to analyze the prognostic factors associated with a higher risk of mortality of a cohort of patients older than 80 years. In addition, we assess the efficacy of immunosuppressive treatments in this population. We analyzed the data from 163 patients older than 80 years admitted to our institution for COVID-19, during March and April 2020. A Lasso regression model and subsequent multivariate Cox regression were performed to select variables predictive of death. We evaluated the efficacy of immunomodulatory therapy in three cohorts using adjusted survival analysis. The mortality rate was 43%. The mean age was 85.2 years. The disease was considered severe in 76.1% of the cases. Lasso regression and multivariate Cox regression indicated that factors correlated with hospital mortality were: age (hazard ratio [HR] 1.12, 95% confidence interval [CI]: 1.03-1.22), alcohol consumption (HR 3.15, 95% CI: 1.27-7.84), CRP > 10 mg/dL (HR 2.67, 95% CI: 1.36-5.24), and oxygen support with Venturi Mask (HR 6.37, 95% CI: 2.18-18.62) or reservoir (HR 7.87, 95% CI: 3.37-18.38). Previous treatment with antiplatelets was the only protective factor (HR 0.47, 95% CI: 0.23-0.96). In the adjusted treatment efficacy analysis, we found benefit in the combined use of tocilizumab (TCZ) and corticosteroids (CS) (HR 0.09, 95% CI: 0.01-0.74) compared to standard treatment, with no benefit of CS alone (HR 0.95, 95% CI: 0.53-1.71). Hospitalized elderly patients suffer from a severe and often fatal form of COVID-19 disease. In this regard, several parameters might identify high-risk patients upon admission. Combined use of TCZ and CS could improve survival.
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Corticosteroides/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Tratamento Farmacológico da COVID-19 , COVID-19/mortalidade , Idoso de 80 Anos ou mais , COVID-19/virologia , Comorbidade , Quimioterapia Combinada , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Espanha/epidemiologia , Análise de SobrevidaRESUMO
BACKGROUND AND OBJECTIVE: Successful preventive treatment in chronic migraine (CM) remains an unmet need in some cases, and new therapeutic strategies are emerging. We aimed to test the effect of noninvasive, transcutaneous supraorbital nerve stimulation (tSNS) in a group of patients with CM. PATIENTS AND METHODS: This was an open label, quasi-experimental design. Twenty-five CM patients were recruited from two hospital headache clinics. After a one-month baseline period, monthly visits were scheduled during three months. Headache occurrence, its intensity, and symptomatic medication intake were recorded through a diary kept by each patient. Both a per-protocol analysis and an intention-to-treat analysis were performed for the main outcome measures. RESULTS: Twenty-one and 24 patients were included in the per-protocol and the intention-to-treat analyses, respectively. In the per-protocol analysis, a significant four-day decrease in the mean monthly days with moderate or severe headache was observed from baseline to the end of the study (t test, P = 0.0163), and there was a nonsignificant reduction of 2.95 in the mean monthly total headache days. In the intention-to-treat analysis, a nonsignificant 3.37 reduction in the mean monthly days with moderate or severe headache was observed for the same period, and there was a significant 2.75 reduction in the mean monthly days with any headache (t test, P = 0.016). CONCLUSIONS: tSNS could hold preventive properties in the treatment of CM, but the effect may be either mild or controversial. Double blind, sham-controlled studies are essential to confirm these findings and to outline their clinical relevance in the CM therapeutic scenario.
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Transtornos de Enxaqueca/prevenção & controle , Manejo da Dor/métodos , Estimulação Elétrica Nervosa Transcutânea/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Escherichia coli (E. coli) is responsible for the majority of community urinary tract infections. The objective of the study is to know the sensitivity spectrum of E. coli in urinary tract infections to be able to recommend the appropriate empirical antibiotic treatment. DESIGN: Cross-sectional, multicentric, retrospective study. LOCATION: Galician 8 public hospitals, practically the entire population of Galicia (Spain). PARTICIPANTS: 43,137 outpatients with urinary tract infection due to E. coli isolated in urine in 2016/2017. MAIN MEASUREMENTS: Analyzed variables: demographic, minimum inhibitory concentration and interpretation of sensitivity according to CLSI criteria and resistance mechanisms. The antibiotics studied were: ampicillin, amoxicillin-clavulanic acid, ciprofloxacin, cefotaxime, cefepime, gentamicin, nitrofurantoin, fosfomycin, cotrimoxazole, imipenem and ertapenem. The identification and sensitivity were made mainly by automated methods. RESULTS: The percentages of non-sensitivity of E. coli isolates were: ampicillin 49.2%, amoxicillin-clavulanic acid 17.8%, cefotaxime 6.7%, cefepime 5.7%, ertapenem 0.04%, imipenem 0.05%, gentamicin 9,1%, ciprofloxacin 26.2%, fosfomycin 3.3%, nitrofurantoin 2.4% and cotrimoxazole 23.9%. The non-sensitivities were higher in men and as age increases. Six percent of E. coli were producers of extended-spectrum beta-lactamases. CONCLUSIONS: The empirical treatment in Galicia for uncomplicated cystitis produced by E. coli in women continues to be nitrofurantoin and fosfomycin. In men under 15 years of age, fosfomycin is indicated and in men older than 15 years, treatment in our environment should include culture and administer a 3rd generation oral cephalosporin empirically. Cotrimoxazole and ciprofloxacin are not recommended as empirical treatment because of their high resistance rates.
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Infecções por Escherichia coli , Infecções Urinárias , Adolescente , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Estudos Transversais , Escherichia coli , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/epidemiologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Espanha , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/epidemiologiaRESUMO
We have explored the simultaneous degradation of cyanides and thiocyanate present in wastewaters from a cokemaking factory using photoassisted methods under varied illumination conditions (from simulated solar light to UV light). Overall, the photochemical degradation of cyanides was more efficient than that of thiocyanates, regardless of the illumination conditions, the effect being more pronounced in the absence of a photocatalyst. This is due to their different degradation mechanism that in the case of thiocyanates is dominated by fast recombination reactions and/or charge transfer reactions to electron scavengers. In all cases, cyanate, ammonia, nitrates, and nitrites were formed at different amounts depending on the illumination conditions. The conversion yield under simulated solar light was almost complete for cyanides and quite high for thiocyanates after 6 h of illumination. Regarding toxicity, photochemical oxidation at 254 nm and under simulated solar light decreased significantly the toxicity of the pristine wastewater, showing a correlation with the intensity of the irradiation source. This indicate that simulated light can be effectively used to reduce the toxicity of industrial effluents, opening an interesting perspective for optimizing cyanide detoxification systems based on natural light.
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Cianetos/química , Tiocianatos/química , Purificação da Água/métodos , Resíduos Industriais/análise , Fotólise , Águas Residuárias/análiseAssuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Pulmão/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , COVID-19 , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Lopinavir/administração & dosagem , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ritonavir/administração & dosagem , SARS-CoV-2 , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
This study defines the optimal parameters that allow the use of waste mollusk shells (WS) to remove heavy metals from three mining and metallurgical leachates. First, the influence of parameters such as pH, contact time, initial metal concentration, adsorbent dose and the presence of co-ions in Cu2+, Cd2+, Zn2+ and Ni2+ adsorption was investigated in synthetic solutions. Metal uptake was found to be dependent on the initial pH of the solution, the removal rate increasing with the increase in pH, showing the highest affinity at pH 5-6. The removal efficiency at lower concentrations was greater than at higher values. The competitive adsorption results on bimetallic solutions showed that the adsorption capacity of the sorbent was restricted by the presence of other ions and suppressed the uptake of heavy metals compared to the single adsorption. Cu2+ was the metal that most inhibited the removal of Cd2+, Zn2+ and Ni2+. The Langmuir isotherm provided the best fit to the experimental data for Cu2+, Cd2+ and Zn2+ and the Freundlich isotherm, for Ni2+. The data showed that the maximum adsorption capacity amax for Zn2+, Cd2+ and Cu2+, was 526.32 mg g-1, 555.56 mg g-1 and 769.23 mg g-1, respectively. Sorption kinetics data best fit the pseudo-second-order kinetic model. The results obtained in the tests with three mining and metallurgical leachates showed that WS were effective in simultaneously removing several heavy metals ions such as Cu, Ni, Zn, Cd, Ni, As and Se.
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OBJECTIVE: To describe an atypical case of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. RESULTS: A patient in his 60s presented with 6 months of progressive ataxia, proximal myoclonus and bulbar symptomatology. Cerebrospinal fluid (CSF) analysis showed monocytic pleocytosis, elevated protein level and elevated adenosine deaminase (ADA) level. CSF microbiological studies were negative and brain and cervical MRI showed no significant findings. We tested for nuclear, cytoplasmatic and synaptic neural autoantibodies as well as anti-GFAP antibodies. While awaiting these results, the patient was commenced on methylprednisolone boluses (1 g/day for 5 days), noting rapid neurological improvement. Eventually, CSF tests were positive for anti-GFAP antibodies. CONCLUSION: We report atypical manifestations of GFAP astrocytopathy. Further research is needed to fully understand the spectrum of neurological manifestations of this autoimmune disease and facilitate timely diagnosis.
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BACKGROUND: In the United States, asthma prevalence is particularly high among urban children. Although the underlying immune mechanism contributing to asthma has not been identified, having impaired T regulatory (Treg) cells at birth may be a determining factor in urban children. The objective of this study was to compare Treg phenotype and function in cord blood (CB) of newborns to those in peripheral blood (PB) of a subset of participating mothers. METHODS: Treg numbers, expression, and suppressive function were quantified in subjects recruited prenatally from neighborhoods where >/= 20% of families have incomes below the poverty line. Proportion of Treg cells and expression of naïve (CD45RA) or activated (CD45RO, CD69, and HLA-DR) markers in CD4+T cells was measured by flow cytometry. Treg suppressive capacity was determined by quantifying PHA-stimulated lymphocyte proliferation in mononuclear cell samples with and without CD25 depletion. RESULTS: In an urban cohort of 119 newborns and 82 mothers, we found that newborns had similar number of cells expressing FOXP3 as compared to the mothers but had reduced numbers of CD4+CD25+bright cells that predominantly expressed the naïve (CD45RA) rather than the activated/memory (CD45RO) phenotype found in the mothers. Additionally, the newborns had reduced mononuclear cell TGF-beta production, and reduced Treg suppression of PHA-stimulated lymphocyte proliferation compared to the mothers. CONCLUSION: U.S. urban newborns have Treg cells that express FOXP3, albeit with an immature phenotype and function as compared to the mothers. Longitudinal follow-up is needed to delineate Treg cell maturation and subsequent risk for atopic diseases in this urban birth cohort.
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OBJECTIVE: To develop a relative value unit (RVU)-based tool for the measurement and reimbursement of pharmacy services for clinical trials. METHODS: A portfolio of activities was agreed by consensus in four tertiary hospitals. Related activities were pooled into several categories or intermediate products. We recorded the duration of each activity by multiple determinations. We then calculated the average time of all determinations. The reference activity was assigned a value of 1. All other activities were compared to the reference activity to obtain the RVU. To establish which items should be invoiced to third parties for the activities performed, we defined the final products (different types of clinical trials according to their complexity). RESULTS: Ten intermediate products and five final products were differentiated. Six intermediate products could be repeated over the course of a clinical trial and seven were performed whether or not the clinical trial had included patients. Each final product consisted of different categories. The total number of RVUs produced for a clinical trial was the sum of each constant category value plus the repetitive category values multiplied by the number of repetitions. CONCLUSION: The application of RVU methodology in investigational drug services allows a more precise quantification of services performed. After a prospective validation to confirm the applicability of this tool, it may contribute to more appropriate invoicing to third parties for these services.
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The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.
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Doença de Alzheimer/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Irmãos , EspanhaRESUMO
BACKGROUND AND AIMS: The aim of our study was to describe the characteristics and clinical outcomes of pulmonary hypertension (PH) patients who underwent their follow-up at a single centre. METHODS: We included patients who fulfilled the criteria for the diagnosis of PH by right heart catheterisation. A detailed clinical history and complete physical examination were recorded for each patient. Demographic data, laboratory testing, haemodynamic values and treatment records were also collected. A 6-min walk test was used to evaluate exercise capacity. Survival analysis was performed using the Kaplan-Meier method, and a log-rank test was used to compare survival curves among groups. A multivariate Cox's proportional hazards model was used in order to identify independent predictors of mortality in the overall PH population. RESULTS: A total of 93 patients (64 women and 29 men) were studied. The patients were distributed across the groups as follows: 50.5% in group 1, 20.4% in group 2, 9.7% in group 3, 14% in group 4 and 5.4% in group 5. The most common type of PH in our population was portopulmonary hypertension followed by PH associated with left heart disease, and idiopathic and chronic thromboembolic disease. Nineteen deaths, constituting 20.5% of the sample population, were reported. The Kaplan-Meier estimates of the 1-, 2- and 3-year survival rates were 91%, 89% and 85%, respectively. There were no statistically significant differences in survival among the groups (P = 0.18). A multivariate analysis revealed that the cardiac index (CI) was an independent predictor of death. CONCLUSIONS: The survival rates of PH patients are higher than previously reported. In our study, the largest number of deaths occurred in groups 1 and 2, and CI was found to be an independent predictor of mortality.