Planck pre-launch status : The Planck mission

Peer reviewe

Planck early results I : The Planck mission

Peer reviewe

Extensive study of human insulin immunoassays: promises and pitfalls for insulin analogue detection and quantification:

BACKGROUND: Over the last few decades, new synthetic insulin analogues have been developed. Their measurement is of prime importance in the investigation of hypoglycaemia, but their quantification is hampered by variable cross-reactivity with many insulin assays. For clinical analysis, it has now become essential to know the potential cross-reactivity of analogues of interest. METHODS: In this work, we performed an extensive study of insulin analogue cross-reactivity using numerous human insulin immunoassays. We investigated the cross-reactivity of five analogues (lispro, aspart, glulisine, glargine, detemir) and two glargine metabolites (M1 and M2) with 16 commercial human insulin immunoassays as a function of concentration. RESULTS: The cross-reactivity values for insulin analogues or glargine metabolites ranged from 0% to 264%. Four assays were more specific to human insulin, resulting in negligible cross-reactivity with the analogues. However, none of the 16 assays was completely free of cross-reactivity with analogues or metabolites. The results show that analogue cross-reactivity, which varies to a large degree, is far from negligible, and should not be overlooked in clinical investigations. CONCLUSIONS: This study has established the cross-reactivity of five insulin analogues and two glargine metabolites using 16 immunoassays to facilitate the choice of the immunoassay(s) and to provide sensitive and specific analyses in clinical routine or investigation

The development of descending projections from the brainstem to the spinal cord in the fetal sheep

<p>Abstract</p> <p>Background</p> <p>Although the fetal sheep is a favoured model for studying the ontogeny of physiological control systems, there are no descriptions of the timing of arrival of the projections of supraspinal origin that regulate somatic and visceral function. In the early development of birds and mammals, spontaneous motor activity is generated within spinal circuits, but as development proceeds, a distinct change occurs in spontaneous motor patterns that is dependent on the presence of intact, descending inputs to the spinal cord. In the fetal sheep, this change occurs at approximately 65 days gestation (G65), so we therefore hypothesised that spinally-projecting axons from the neurons responsible for transforming fetal behaviour must arrive at the spinal cord level shortly before G65. Accordingly we aimed to identify the brainstem neurons that send projections to the spinal cord in the mature sheep fetus at G140 (term = G147) with retrograde tracing, and thus to establish whether any projections from the brainstem were absent from the spinal cord at G55, an age prior to the marked change in fetal motor activity has occurred.</p> <p>Results</p> <p>At G140, CTB labelled cells were found within and around nuclei in the reticular formation of the medulla and pons, within the vestibular nucleus, raphe complex, red nucleus, and the nucleus of the solitary tract. This pattern of labelling is similar to that previously reported in other species. The distribution of CTB labelled neurons in the G55 fetus was similar to that of the G140 fetus.</p> <p>Conclusion</p> <p>The brainstem nuclei that contain neurons which project axons to the spinal cord in the fetal sheep are the same as in other mammalian species. All projections present in the mature fetus at G140 have already arrived at the spinal cord by approximately one third of the way through gestation. The demonstration that the neurons responsible for transforming fetal behaviour in early ontogeny have already reached the spinal cord by G55, an age well before the change in motor behaviour occurs, suggests that the projections do not become fully functional until well after their arrival at the spinal cord.</p

International consensus statement on routine blood testing in primary ciliary dyskinesia

Background Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by dysfunction of motile cilia. Symptoms include recurrent and chronic airway infections which can lead to deteriorating lung function and inflammatory destructive lung disease in the form of persistent atelectasis and bronchiectasis. Routine blood testing may be used as a tool for disease monitoring and management. However, currently there are no consensus-based guidelines within the field of PCD. BEAT-PCD together with the ERN-LUNG PCD-Clinical Trial Network aimed to develop an international expert consensus statement on which routine blood tests should be conducted in patients with PCD. Methods An international panel of 33 PCD experts from 17 countries was established to generate consensus on routine blood testing in PCD. A modified Delphi technique with three e-survey rounds was used to reach consensus, which was defined as ≥80% agreement for each statement. Two patient representatives were included in the consensus process. Results The expert panel reached consensus on 51 out of 101 statements (50%) on routine blood testing in children and adults with PCD to be performed at diagnosis, annually and on exacerbation. The statements include biomarkers for inflammation, haemoglobin, iron status, vitamin D, immune function, inhalant allergies, liver and kidney function, and allergic bronchopulmonary aspergillosis. Conclusions This is the first international consensus on routine blood testing in PCD. It highlights blood tests that may be relevant to perform at diagnosis, annually and on exacerbation in people with PCD. Further research on the clinical usefulness of routine blood testing in PCD is needed

Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials

Background The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor–tezacaftor–deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor–tezacaftor–deutivacaftor compared with standard of care elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older. Methods In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor–tezacaftor–ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor–tezacaftor–deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was –3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete. Findings In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor–tezacaftor–ivacaftor (n=202) or vanzacaftor–tezacaftor–deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6–38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor–tezacaftor–ivacaftor (n=289) or vanzacaftor–tezacaftor–deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5–42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor–tezacaftor–deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor–tezacaftor–ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI –0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor–tezacaftor–deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor–tezacaftor–ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI –0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor–tezacaftor–deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor–tezacaftor–ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]). Interpretation Vanzacaftor–tezacaftor–deutivacaftor is non-inferior to elexacaftor–tezacaftor–ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor–tezacaftor–deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators. Funding Vertex Pharmaceuticals

Le syndrome ASIA associé aux implants mammaires : lien de causalité ou association fortuite ?

International audienceObjective: The "Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants" (ASIA syndrome) described in 2011 by Shoenfeld and Agmon-Levin is believed to be the consequence of several immunological dysfunctions triggered by exposure to an adjuvant. Controversies regarding the existence of this syndrome and its possible link to silicone breast implants (SBI) have been growing via social networks and patient groups. The objective of our review was to identify all published cases of ASIA syndromes in SBI carriers to determine the circumstances of onset, key characteristics, and possible biases.Method: A literature search of the Pubmed database selecting only original articles written in English between 2011 and 2019 found 126 cases of ASIA syndromes, defined according to the criteria of Shoenfeld and Agmon-Levin, associated with SBI.Results: This syndrome was diagnosed in nearly ¾ cases in a context of prosthetic complications (rupture, effusion, peri-prosthetic shell, infection) with a median time interval of 4 years between SBI implantation and the onset of symptoms. Explantation of the SBI led to an improvement in symptoms in about half of the cases. However, animal, biological and histological studies have provided conflicting results on the links between silicone and dysimmune syndromes.Conclusion: Women should be clearly, fairly and appropriately informed of our uncertainties about ASIA syndrome. Mandatory reporting of dysimmune syndromes occurring in silicone MI carriers would increase our knowledge of this still poorly understood condition, for which a genetic predisposition is being investigated