A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients

Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating SARS-CoV-2 variability in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naive individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance is found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site mean & PLUSMN;Standard error: 18.7 x 10(-4) & PLUSMN; 2.1 x 10(-4) vs. 3.3 x 10(-4) & PLUSMN; 0.8 x 10(-4) vs. 3.1 x 10(-4) & PLUSMN; 0.8 x 10(-4), P = 0.0003), peaking between Day 2 and 5. Molnupiravir drives the emergence of more G-A and C-T transitions than other mutations (P = 0.031). SARS-CoV-2 selective evolution under Molnupiravir pressure does not differ from that under Paxlovid or no-drug pressure, except for orf8 (dN > dS, P = 0.001); few amino acid mutations are enriched at specific sites. No RNA-dependent RNA polymerase (RdRp) or main proteases (Mpro) mutations conferring resistance to Molnupiravir or Paxlovid are found. This proof-of-concept study defines the SARS-CoV-2 within-host evolution during antiviral treatment, confirming higher in vivo variability induced by Molnupiravir compared to Paxlovid and drug-naive, albeit not resulting in apparent mutation selection

General Practitioners as partners for a shared management of chronic HIV infection: An insight into the perspectives of Italian People Living with HIV

Is it possible to achieve a collaboration between Infectious Diseases (ID) Specialists and General Practitioners (GPs) in the management of chronic HIV infection? A cross sectional survey was conducted among People Living with HIV (PLWHIV) attending the outpatient services of four Italian Infectious Diseases Centers to understand to which extent patients trust their GPs and involve them in the management of their chronic condition. Information about level of communication with GPs, subjective perception of the disease, and presence of co-medications were collected and matched with socio-demographic data using \u3c72statistics. A p<0.05 was considered statistically significant. From December 2019 to February 2020, 672 patients completed the survey, 59% males and 56% >50 years. Overall, 508 patients (76%) had informed GPs about HIV-positivity. Communication of diagnosis was significantly associated with age >50years, lower education level, history of disease >10 years and residency in Northern Italy. The "Undetectable = Untrasmittable" (U = U) concept was investigated as an indirect measure of perceived stigma. 23% of subjects was unaware of its meaning. Despite undetectable status, 50% of PLWHIV found difficult to communicate their condition to GPs, especially married (52% vs 48% of unmarried, p = 0.003), well-educated patients (51% vs 48, p = 0.007), living in Southern vs Northern Italy (52% vs 46%, p< 0.001). More than 75% of the participants consulted the ID specialist for co-medications and DDIs management, often complaining a lack of communication of the former with GPs. Overall, a good level of communication between PLWHIV and GPs was outlined, even if a wider involvement of the latter in HIV care is desirable

Piezo1 activation augments sickling propensity and the adhesive properties of sickle red blood cells in a calcium‐dependent manner

International audienceSummary Haemoglobin S polymerization in the red blood cells (RBCs) of individuals with sickle cell anaemia (SCA) can cause RBC sickling and cellular alterations. Piezo1 is a mechanosensitive protein that modulates intracellular calcium (Ca 2+ ) influx, and its activation has been associated with increased RBC surface membrane phosphatidylserine (PS) exposure. Hypothesizing that Piezo1 activation, and ensuing Gárdos channel activity, alter sickle RBC properties, RBCs from patients with SCA were incubated with the Piezo1 agonist, Yoda1 (0.1–10 μM). Oxygen‐gradient ektacytometry and membrane potential measurement showed that Piezo1 activation significantly decreased sickle RBC deformability, augmented sickling propensity, and triggered pronounced membrane hyperpolarization, in association with Gárdos channel activation and Ca 2+ influx. Yoda1 induced Ca 2+ ‐dependent adhesion of sickle RBCs to laminin, in microfluidic assays, mediated by increased BCAM binding affinity. Furthermore, RBCs from SCA patients that were homo−/heterozygous for the rs59446030 gain‐of‐function Piezo1 variant demonstrated enhanced sickling under deoxygenation and increased PS exposure. Thus, Piezo1 stimulation decreases sickle RBC deformability, and increases the propensities of these cells to sickle upon deoxygenation and adhere to laminin. Results support a role of Piezo1 in some of the RBC properties that contribute to SCA vaso‐occlusion, indicating that Piezo1 may represent a potential therapeutic target molecule for this disease