Performances, feasibility and acceptability of nasopharyngeal swab, saliva and oral-self sampling swab for the detection of severe acute respiratory syndrome coronavirus 2.

Molecular diagnosis on nasopharyngeal swabs (NPS) is the current standard for COVID-19 diagnosis, but saliva may be an alternative specimen to facilitate access to diagnosis. We compared analytic performances, feasibility and acceptability of NPS, saliva, and oral-self sampling swab for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A prospective, multicenter study was conducted in military hospitals in France among adult outpatients attending COVID-19 diagnosis centers or hospitalized patients. For each patient, all samples were obtained and analyzed simultaneously with RT-PCR or transcription-mediated amplification method. Clinical signs, feasibility, and acceptability for each type of sample were collected. A total of 1220 patients were included, corresponding to 1205 NPS and saliva and 771 OS. Compared to NPS, the sensitivity, specificity, and kappa coefficient for tests performed on saliva were 87.8% (95% CI 83.3-92.3), 97.1% (95% CI 96.1-98.1), and 0.84 (95% CI 0.80-0.88). Analytical performances were better in symptomatic patients. Ct values were significantly lower in NPS than saliva. For OS, sensitivity was estimated to be 61.1% (95% CI 52.7-69.4) and Kappa coefficient to be 0.69 (95% CI 0.62-0.76). OS was the technique preferred by the patients (44.3%) before saliva (42.4%) and NPS (13.4%). Instructions were perceived as simple by patients (> 90%) for saliva and OS. Finally, the painful nature was estimated to be 0.9 for OS, on a scale from 0 to 10, and to be 5.3 for NPS. Performances of OS are not sufficient. Saliva is an acceptable alternative to NPS for symptomatic patient but the process required additional steps to fluidize the sample.

Recognition of sulfonylurea receptor (ABCC8/9) ligands by the multidrug resistance transporter P-glycoprotein (ABCB1): functional similarities based on common structural features between two multispecific ABC proteins.

ATP-sensitive K(+) (K(ATP)) channels are the target of a number of pharmacological agents, blockers like hypoglycemic sulfonylureas and openers like the hypotensive cromakalim and diazoxide. These agents act on the channel regulatory subunit, the sulfonylurea receptor (SUR), which is an ABC protein with homologies to P-glycoprotein (P-gp). P-gp is a multidrug transporter expressed in tumor cells and in some healthy tissues. Because these two ABC proteins both exhibit multispecific recognition properties, we have tested whether SUR ligands could be substrates of P-gp. Interaction with P-gp was assayed by monitoring ATPase activity of P-gp-enriched vesicles. The blockers glibenclamide, tolbutamide, and meglitinide increased ATPase activity, with a rank order of potencies that correlated with their capacity to block K(ATP) channels. P-gp ATPase activity was also increased by the openers SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide. Thus, these molecules bind to P-gp (although with lower affinities than for SUR) and are possibly transported by P-gp. Competition experiments among these molecules as well as with typical P-gp substrates revealed a structural similarity between drug binding domains in the two proteins. To rationalize the observed data, we addressed the molecular features of these proteins and compared structural models, computerized by homology from the recently solved structures of murine P-gp and bacterial ABC transporters MsbA and Sav1866. Considering the various residues experimentally assigned to be involved in drug binding, we uncovered several hot spots, which organized spatially in two main binding domains, selective for SR47063 and for glibenclamide, in matching regions of both P-gp and SUR.

Acceptance Mindfulness-Trait as a Protective Factor for Post-Natal Depression: A Preliminary Research.

(1) Background: the prevalence of postnatal depression (PND) reaches up to 20%. PND could be based on the interaction between a psychological vulnerability and chronic stress that pregnancy would activate. Vulnerability factors reflect a psychological profile mirroring mindfulness-trait (MT). A high level of MT is associated with an efficient regulation of both physiological and psychological stress, especially negative moods. Interestingly, mindfulness level can be improved by program based on mindfulness meditation. We hypothesize that MT is a protective factor for PND. We also postulate that negative moods increase during the pregnancy for women who develop a PND after delivery (2) Methods: we conducted a multicentric prospective longitudinal study including 85 women during their first trimester of their pregnancy and 72 from the childbirth to the baby's first birthday". At the inclusion, presence and acceptance of MT and various variables of personality and of psychological functioning were assessed. Mood evolution was monitored each month during the pregnancy and a delivery trauma risk was evaluated after delivery. PND detection was carried out at 48 h, 2, 6 and 12 months after the delivery with the Edinburgh Postnatal Depression Scale with a screening cut-off >11. (3) Results: high-acceptance MT is a protective factor for PND (OR: 0.79). Women without PND displayed less negative mood during pregnancy (p < 0.05 for Anxiety, Confusion and Anger). (4) Conclusions: these results suggest the value of deploying programs to enhance the level of mindfulness, especially in its acceptance dimension, before, during and after pregnancy, to reduce the risk of PND.

Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship.

P-glycoprotein (P-gp) is involved in the ATP-dependant cellular efflux of a large number of drugs including ivermectin, a macrocyclic lactone (ML) endectocide, widely used in livestock and human antiparasitic therapy. The interactions of P-gp with ivermectin and other MLs were studied. In a first approach, the ability of ivermectin (IVM), eprinomectin (EPR), abamectin (ABA), doramectin (DOR), selamectin (SEL), or moxidectin (MOX) to inhibit the rhodamine123 efflux was measured in recombinant cells overexpressing P-gp. Then, the influence of these compounds on the P-gp ATPase activity was tested on membrane vesicles prepared from fibroblasts overexpressing P-gp. All the MLs tested increased the intracellular rhodamine123. However, the potency of MOX to inhibit P-gp function was 10 times lower than the other MLs. They all inhibited the basal and decreased the verapamil-stimulated P-gp ATPase activity. But SEL and MOX were less potent than the other MLs when competing with verapamil. According to the structural specificity of SEL and MOX, we conclude that the integrity of the sugar moiety is determinant to achieve the optimal interaction of macrocyclic lactones with P-gp. The structure-affinity relationship for interaction with P-gp is important information for improving ML bioavailability and reversal of multidrug resistance (MDR).

Very long-term follow-up after percutaneous closure of patent foramen ovale.

AIMS: To evaluate the very long-term risk of recurrent thromboembolic events in patients treated by percutaneous PFO closure. METHODS AND RESULTS: Between 1998 and 2008, a total of 232 consecutive patients with PFO and a high suspicion of paradoxical embolism were treated by percutaneous closure. The following major events were observed during hospitalisation: implantation failure (one patient) and appearance of an acute left-sided device thrombus requiring surgery (one patient). The primary endpoint of the study was a recurrent embolic event beyond at least five years' follow-up. During a mean follow-up of 7.6±2.4 years, this event occurred in five patients, representing a 0.28% annual/patient risk. Other major complications during follow-up were the following: late thrombus formation on the device (two patients) and transient atrial fibrillation (15 patients). Three patients died during follow-up from cardiovascular causes considered not related to the index procedure. The PFO was judged closed on follow-up echocardiography in 92.3% of patients. CONCLUSIONS: Long-term follow-up following percutaneous PFO closure for presumed paradoxical embolism reveals very low recurrence rates. This observation should be put in perspective with recent published randomised trials comparing percutaneous closure and medical therapy.

ATP binding cassette multidrug transporters limit the anti-HIV activity of zidovudine and indinavir in infected human macrophages.

OBJECTIVES: To investigate whether P-glycoprotein (P-gp) and multidrug resistance proteins (MRPs), which limit the bioavailability of HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), modulate the anti-HIV activity of NRTIs, non-NRTIs and PIs in vitro. DESIGN: We used primary cultures of major HIV target cells: human monocyte-derived macrophages (MDMs) and lymphocytes. METHODS: P-gp and MRP expression in response to long-term zidovudine (3'-azido-3'-deoxythymidine; AZT) or indinavir treatment was quantified by RT-PCR. MDM and lymphocytes were infected in vitro with HIV-1/Ba-L and HIV-1-LAI, respectively, and treated with antiretroviral drugs. We evaluated the activity of these drugs in combination with PSC833, a P-gp inhibitor, and/or probenecid, an MRP1 inhibitor. Intracellular AZT triphosphate derivative (AZT-TP) was quantified by HPLC-MSMS. P-gp ATPase activity was measured with inside-out native membrane vesicles enriched in P-gp. RESULTS: Levels of MDR1, mrp4 and mrp5 mRNA were high following AZT treatment. In infected MDM, PSC833 and probenecid increased the anti-HIV activity of AZT and indinavir. AZT (5 nM) decreased HIV replication by 34% alone and by 72% in combination with P-gp/MRP inhibitors. Indinavir (10 nM) gave 14% inhibition alone and 81% in combination. The increase in anti-HIV activity of AZT was correlated with an increase in intracellular AZT-TP concentration. However, unlike PIs, neither AZT nor its metabolites interacted with P-gp. CONCLUSION: AZT increases the expression of multidrug transporters, thereby decreasing its pharmacological activity. The cellular efflux of AZT probably involves MRP4 or MRP5. In contrast, increases in indinavir anti-HIV activity require the inhibition of both P-gp and MRP1.