Evaluation of Potential Pain Biomarkers in Saliva and Pain Perception After Corneal Advanced Surface Ablation Surgery

Purpose: To evaluate the evolution of a set of proposed pain biomarkers in the saliva of subjects following Advanced Surface Ablation (ASA), in order to determine their validity as objective pain measures. Methods: A multicenter, prospective, and descriptive study was carried out to assess the variations between biomarkers and perceived pain. The Inclusion criteria were healthy subjects who underwent a bilateral, alcohol-assisted surface ablation with epithelial removal (ASA). Pain intensity before and after surgery was assessed by Visual Analog Scale (VAS) and the Numeric Pain Rating Scale (NPRS). Cortisol, sAA, sIgA, testosterone, and sTNF alpha RII were assayed at four-time points (V0, baseline; V1, pre-surgery; V2, 1 hr post-surgery, and V3, 72 hrs post-surgery). Comorbidities and Hospital Anxiety and Depression (HADS) questionnaires were administrated before and at 6 hrs after the surgery. All patients were treated with cold patches, topical steroids, topical cold antibiotics, and benzodiazepines after ASA surgery. A descriptive analysis of biomarkers and pain intensity evolution and the agreement between biomarkers and pain was performed. Results: Concentration of sIgA and sTNF alpha RII post-surgery was significantly higher at each visit compared to baseline (p-value: 0.053, p-value: < 0.001, respectively). Relations between VAS scale score and putative biomarker variations were not statistically significant except for the sIgA but only at visit 0 (p-value: 0.024). The HADS questionnaire showed anxiety scores between 0 and 7 in all patients before and at 6 hrs after surgery. Conclusion: In this study, sIgA and sTNF alpha RII are the two potential biomarkers that present correlation with the VAS and these salivary substances showed acceptable levels of reproducibility in healthy subjects

Efficacy of extended infusion of beta-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE)

Background: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal beta-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. Methods: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. Discussion: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes

Multicenter study of plastic vs. self-expanding metal stents in endoscopic ultrasound-guided drainage of walled-off pancreatic necrosis - PROMETHEUS: a randomized controlled trial protocol.

Background: It seems that lumen-apposing metal stents (LAMS) are displacing plastic stents in the therapy of pancreatic-fluid collection in walled-off necrosis (WON). To date, there is no quality of evidence to recommend LAMS as the standard treatment in the management of WON. The theoretical benefit of LAMS over plastic stents needs to be proven. Methods/design: This is a randomized controlled, multicenter, prospective clinical trial with two parallel groups, without masking. One-hundred and fourteen patients with WON will undergo endoscopic ultrasound (EUS)-guided transmural draining in nine tertiary hospitals in Spain and will be randomized to the LAMS or plastic-stent group. The primary endpoint is the short-term (4 weeks) clinical success determined by the reduction of the collection (to < 50% or < 5 cm in size), along with clinical improvement. Secondary endpoints: long-term (4 months) clinical success (total resolution or 5 cm), procedure duration, level of difficulty, safety, and recurrences. Discussion: The PROMETHEUS trial has been designed to determine whether LAMS are superior to plastic stents in EUS-guided transmural drainage of WON

Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when = 50 years and symptomatic for <= 7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with <= 5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution

Intravital imaging of cardiac function at the single-cell level

Photograph used for a story in the Daily Oklahoman newspaper. Caption: "Wolverine fullback Jesse Cross finds the going tough as he gets smacked from both sides by an 'Ike' defensive duo.

Determination and risk assessment of naturally occurring genotoxic and carcinogenic alkenylbenzenes in basil-containing sauce of pesto

A risk assessment of basil-based pesto sauces containing methyleugenol and related alkenylbenzenes was performed based on their levels detected in a series of pesto sauces available on the Dutch market. The estimated daily intake (EDI) values of alkenylbenzenes as a result of consumption of the different pesto sauces amounted to 1.2–44.3 μg/kg bw for individual alkenylbenzenes, 14.3–43.5 μg/kg bw when adding up the alkenylbenzene levels assuming equal potency, and 17.3–62.9 μg/kg bw when expressed in methyleugenol equivalents using alkenylbenzenes defined toxic equivalency factors (TEF). The margin of exposure approach (MOE), used to evaluate the potential risks, resulted in MOE values that were generally lower than 10000 indicating a priority for risk management when assuming daily consumption. The levels of methyleugenol detected in the pesto sauces would allow consumption of 1.1–29.8, 7.5–208, 15.1–416.5, and 32.4–892.5 g of pesto sauce on a daily basis, once a week, once every two weeks, and once a month, respectively, to achieve MOE values above the 10000 limit indicating low priority for risk management. It is concluded that consumption of pesto sauces would only be of concern if consumed on a daily basis over longer periods of time.</p

Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRβ, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates

Assessing self-reported adherence to HIV therapy by questionnaire: the SERAD (Self-Reported Adherence) Study.

Contains fulltext : 52621.pdf (publisher's version ) (Open Access)The relationship between adherence to highly active antiretroviral therapy (HAART) and RNA-HIV viral load outcomes has been extensively shown. Although there are different procedures for assessing treatment adherence, there is no ideal method. We present the SERAD (Self-Reported Adherence) questionnaire, a qualitative and quantitative self-reported instrument designed to provide an easier adherence measurement. We also compared the questionnaire to three other methods to evaluate adherence to HAART regimens in HIV-infected patients. Two prospective, observational, longitudinal studies were developed: a single-center pilot study followed by a multicenter study. A total of 530 HIV-infected outpatients was prospectively included, 66 in the pilot study and 464 in the multicenter study. Four methods were used to study adherence to HAART regimens: the SERAD questionnaire, pill count, electronic monitoring, and plasma drug monitoring. Pearson's correlations and Bland and Altman's method were developed. The SERAD questionnaire showed good feasibility and significant validity. Adequate levels of agreement between methods were observed, particularly when adherence was high. Differences increased as adherence fell. Moreover, the questionnaire was completed correctly, the interviewers did not report uncovered aspects, and the information was collected easily. Our results suggest that the SERAD questionnaire is a feasible and useful instrument for assessing adherence to HAART regimens in HIV-infected patients, and makes it possible to obtain reliable qualitative and quantitative information related to treatment adherence

Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRβ, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates