Guidelines on cost modelling: Economic policies and methods of determining the costs of services related to national telecommunication/ICT networks

These final guidelines on cost modelling were elaborated under ITU-D Question 4/1 on economic policies and methods of determining the costs of services related to national telecommunication/ICT networks, including next-generation networks

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

H017 Time dependent activation of AKT-GSK3beta and calcineurin signaling pathways during the development of TAC-induced left ventricular hypertrophy in B6D2/F1 mice

Left ventricular hypertrophy (LVH) is an adaptive response to chronic biomechanical stress that later progresses to maladaptive hypertrophy and heart failure. To better understand the mechanisms responsible for LVH development, we studied the activation of two major kinases, protein kinase B (Akt/PKB) and glycogen synthase kinase3b (GSK3b) and of a phosphatase, calcineurin (Cn) in an experimental model of thoracic aorta constriction (TAC).Methods4 week-old B6D2/F1 male, Sham-operated (Sham) and TAC mice were studied 3, 7, 15, 30 and 60 days post-TAC. Gene expression and activation of signalling pathways was studied by PCR and Western Blot.ResultsTAC-induced LVH (10 – 51 % at days 3-60, respectively) was associated with: 1) fetal gene reexpression characterised by an increase in mRNA levels of BNP (1.7-3 fold) and a-SK (2-4 fold), an a- to b-MHC switch seen at day 30 only ; 2) a significant increase in SERCA2a (1.7 fold), PLB, and NCX (3.6 fold) protein levels at day 7. 3) a 2 fold increase in P-Akt at day 3 and a decrease at day 15 while Akt was increased at days 7 and 15 ; 4) an increase in P-GSK3b at day 15 (1.5 fold), whereas no change in Akt and GSK3b protein levels were seen at days 30 and 60 ; 5) a significant decrease in CnAb at day 15 (2 fold).ConclusionLVH develops progressively from day 3 in response to TAC, accompanied by re-expression of the fetal gene program. The alpha to beta-MHC mRNA switch occurs late, associated with the transition to HF, which occurs progressively with time. At days 3 and 15, P-Akt acts as an upstream regulator of GSK3b which may favour the development of LVH. 7 days post-TAC, a SERCA2a and NCX increase might contribute to decrease free cytosolic calcium level. At day 15, a further increase in LVH is associated with an increase in Cn activity and an increase GSK3b, which may counteract the hypertrophic response. Taken together, our data suggest a time-dependent cross-talk between Cn and GSK3b to modulate cardiac hypertrophic response to pressure overload

Immediate vs. deferred switching from a boosted protease inhibitor (PI/r) based regimen to a Dolutegravir (DTG) based regimen in virologically suppressed patients with high cardiovascular risk or Age =50 years: final 96 weeks results of NEAT 022 study

Background Both immediate and deferred switching from a ritonavir-boosted protease inhibitor (PI/r)–based regimen to a dolutegravir (DTG)–based regimen may improve lipid profile. Methods European Network for AIDS Treatment 022 Study (NEAT022) is a European, open-label, randomized trial. Human immunodeficiency virus (HIV)–infected adults aged =50 years or with a Framingham score =10% were eligible if HIV RNA was <50 copies/mL. Patients were randomized to switch from PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D). Week 96 endpoints were proportion of patients with HIV RNA <50 copies/mL, percentage change of lipid fractions, and adverse events (AEs). Results Four hundred fifteen patients were randomized: 205 to DTG-I and 210 DTG-D. The primary objective of noninferiority at week 48 was met. At week 96, treatment success rate was 92.2% in the DTG-I arm and 87% in the DTG-D arm (difference, 5.2% [95% confidence interval, –.6% to 11%]). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AEs or treatment-modifying AEs. Total cholesterol and other lipid fractions (except high-density lipoprotein) significantly (P < .001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV-infected patients =50 years old or with a Framingham score =10% was highly efficacious and well tolerated, and improved the lipid profile