Cdc50 (cell-cycle control protein 50) is a family of conserved eukaryotic proteins that interact with P4-ATPases (phospholipid translocases). Cdc50 association is essential for the endoplasmic reticulum export of P4-ATPases and proper translocase activity. In the present study, we analysed the role of Leishmania infantum LiRos3, the Cdc50 subunit of the P4-ATPase MLF (miltefosine) transporter [LiMT (L. infantum MLF transporter)], on trafficking and complex functionality using site-directed mutagenesis and domain substitution. We identified 22 invariant residues in the Cdc50 proteins from L. infantum, human and yeast. Seven of these residues are found in the extracellular domain of LiRos3, the conservation of which is critical for ensuring that LiMT arrives at the plasma membrane. The substitution of other invariant residues affects complex trafficking to a lesser extent. Furthermore, invariant residues located in the N-terminal cytosolic domain play a role in the transport activity. Partial N-glycosylation of LiRos3 reduces MLF transport and total N-deglycosylation completely inhibits LiMT trafficking to the plasma membrane. One of the N-glycosylation residues is invariant along the Cdc50 family. The transmembrane and exoplasmic domains are not interchangeable with the other two L. infantum Cdc50 proteins to maintain LiMT interaction. Taken together, these findings indicate that both invariant and N-glycosylated residues of LiRos3 are implicated in LiMT trafficking and transport activity.

Background : We report the long-term outcomes, changes in laboratory parameters, the incidence of secondary nosocomial infections and treatment cost of a Spanish cohort of patients with severe COVID-19 that received tocilizumab (TCZ). Methods : Retrospective cohort of PCR confirmed adult patients who received TCZ from March 1 to 24, 2020 in a tertiary hospital was analyzed. Patients were followed up until 10 May 2020. Results : We included 162 patients (median age 64 years; 70.4% male). At time of TCZ administration, 48.1% of patients were on invasive mechanical ventilation (IMV). Over a median follow-up of 53 days, 46.9% of patients were discharge in good conditions and 19.8% were still hospitalized. The overall mortality was 33.3%, being higher in patients on IMV than those who did not (46.2% vs 26.7%, P < 0.001). A significant improvement in the lymphocyte count, C-reactive protein, lactate dehydrogenase, and D-dimer was observed. Overall, 43.2% patients presented nosocomial infections, causing death in 8%. Infections were more prevalent in ICU units (63.0% vs 17.1%, P < 0.001). The total cost of TCZ was €371,784. Conclusions : Among the patients who used TCZ, one third died, regardless the improvement in some inflammatory biomarkers. The incidence of secondary nosocomial infections was high.

BackgroundOncology clinical trials can lead to relevant financial savings in drug acquisition for healthcare providers. Considerable methodological heterogeneity is observed among previous studies estimating these savings.MethodsWe developed a methodology to estimate the economic benefit obtained from the enrollment of patients into clinical trials through the analysis of drug cost avoidance. We designed a decision algorithm to determine if a clinical trial is associated with drug cost avoidance. This algorithm is based on five scenarios according to the availability or not of standard treatment, the presence or absence of a control arm (placebo or active treatment), and the provider of the medication. We considered as reference the cost of the standard treatment that the patient would have received in routine clinical practice. We standardized drug doses and treatment durations according to the literature. Costs were considered from a National Health System perspective. We applied this methodology at a single, research-active University Hospital in 2019. A cost avoidance analysis per trial and patient was carried out on cancer patients.ResultsWe analyzed 140 trials in which 198 patients were recruited. Drug cost avoidance was found in 120 trials (85.7%). The estimated total drug cost avoidance amounted to over €3,200,000. Melanoma and genitourinary tumors were the tumor types associated with the highest cost avoidance. The average drug cost avoidance per patient was €16,245.ConclusionWe describe a standardized method to estimate drug cost avoidance in clinical trials. We have applied it to all ongoing oncology clinical trials in our center. This methodology could be valuable for other centers to analyze the potential saving of clinical trials.

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Background Drug-referencing apps are among the most frequently used by emergency health professionals. To date, no study has analyzed the quantity and quality of apps that provide information on emergency drugs. Objective This study aimed to identify apps designed to assist emergency professionals in managing drugs and to describe and analyze their characteristics. Methods We performed an observational, cross-sectional, descriptive study of apps that provide information on drugs for adult emergency care. The iOS and Android platforms were searched in February 2021. The apps were independently evaluated by 2 hospital clinical pharmacists. We analyzed developer affiliation, cost, updates, user ratings, and number of downloads. We also evaluated the main topic (emergency drugs or emergency medicine), the number of drugs described, the inclusion of bibliographic references, and the presence of the following drug information: commercial presentations, usual dosage, dose adjustment for renal failure, mechanism of action, therapeutic indications, contraindications, interactions with other medicinal products, use in pregnancy and breastfeeding, adverse reactions, method of preparation and administration, stability data, incompatibilities, identification of high-alert medications, positioning in treatment algorithms, information about medication reconciliation, and cost. Results Overall, 49 apps were identified. Of these 49 apps, 32 (65%) were found on both digital platforms; 11 (22%) were available only for Android, and 6 (12%) were available only for iOS. In total, 41% (20/49) of the apps required payment (ranging from €0.59 [US $0.64] to €179.99 [US $196.10]) and 22% (11/49) of the apps were developed by non–health care professionals. The mean weighted user rating was 4.023 of 5 (SD 0.71). Overall, 45% (22/49) of the apps focused on emergency drugs, and 55% (27/49) focused on emergency medicine. More than half (29/47, 62%) did not include bibliographic references or had not been updated for more than a year (29/49, 59%). The median number of drugs was 66 (range 4 to >5000). Contraindications (26/47, 55%) and adverse reactions (24/47, 51%) were found in only half of the apps. Less than half of the apps addressed dose adjustment for renal failure (15/47, 32%), interactions (10/47, 21%), and use during pregnancy and breastfeeding (15/47, 32%). Only 6% (3/47) identified high-alert medications, and 2% (1/47) included information about medication reconciliation. Health-related developer, main topic, and greater amount of drug information were not statistically associated with higher user ratings (P=.99, P=.09, and P=.31, respectively). Conclusions We provide a comprehensive review of apps with information on emergency drugs for adults. Information on authorship, drug characteristics, and bibliographic references is frequently scarce; therefore, we propose recommendations to consider when developing an app of these characteristics. Future efforts should be made to increase the regulation of drug-referencing apps and to conduct a more frequent and documented review of their clinical content.