Sagittal plane assessment of manual concave rod bending for posterior correction in adolescents with idiopathic thoracic scoliosis (Lenke 1 and 3)

Objectives The objectives of this study were to evaluate the repeatability and reproducibility of a method for measuring freehand rod bending and to analyze the relationship between the rod's bend and the resulting sagittal correction. Materials and methods All the children who underwent correction by posterior translation using pedicle screws at all levels were included prospectively in 2018 and 2019. The rod's sagittal parameters were measured retrospectively by three independent surgeons on two separate occasions using the same protocol. After the rods were bent but before they were inserted, the surgeon traced the contours of the rods on a sheet of paper that was later scanned and analyzed semiautomatically. The spinal parameters were calculated based on biplanar radiographs taken preoperatively, postoperatively and at the final follow-up visit. Patients who had less than 10° thoracic kyphosis (T5–T12) made up the “Lenke N−” subgroup. Results Thirty patients were included (14 of whom were Lenke N−) who had a Cobb angle of 59.2 ± 11.3° preoperatively and 13.3 ± 8.4° postoperatively (p 0.9 (excellent). The mean kyphosis of the concave rod was 48.4 ± 5.7° (38.3–60.9°). The mean change in T5–T12 kyphosis was 9.7 ± 10.8° (−14.3–30.8°) (p < 0.0001) in the entire population, while it was 17.7 ± 7.1° (5.5–30.8°) (p < 0.0001) in the Lenke N− subgroup. The change in thoracic kyphosis was positively correlated with the kyphosis of the concave rod (rho = 0.52; p = 0.003). Conclusion This study found excellent reproducibility and repeatability of measuring freehand rod bending. The kyphosis applied to the concave rod is positively correlated to the change in the resulting kyphosis and made it possible to restore satisfactory thoracic kyphosis

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&nbsp;years old

Influence of Renal Function and Age on the Pharmacokinetics of Levofloxacin in Patients with Bone and Joint Infections

Despite its efficacy and toxicity being exposure-related, levofloxacin pharmacokinetics in patients with bone and joint infections has been poorly described to date, so the possible need for a dose adjustment is unknown in this population. A prospective population pharmacokinetic study was conducted in 59 patients to answer this question. The final model consisted of a one-compartment model with first-order absorption and elimination. Mean parameter estimates (% interindividual variability) were 0.895 h&minus;1 for the absorption rate constant (Ka), 6.10 L/h (40%) for the apparent clearance (CL/F), 90.6 L (25%) for the apparent distribution volume (V/F). Age and glomerular filtration rate (GFR), estimated by the modification of diet in renal disease formula, were related to CL/F by power models, and CL/F was found to increase for increasing GFR and decreasing age. For a similar GFR, the simulated area under the curve (AUC) was 55% higher in 70 years-old patients compared to 30 year-old patients. Based on this model, a 750 mg dose should provide an optimal exposure (AUC/ minimum inhibitory concentration (MIC) &ge;100), with the possible exception of patients older than 60 years and with GFR &lt;70 mL/min/m&sup2; who may necessitate a dose reduction, and patients with infections caused by bacteria with MIC close to 1 mg/L who may need an increase in the dose

A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1

International audienceRetinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms, 23 unrelated low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low penetrance mutations were studied. In families segregating the c.1981C>T mutation, we demonstrated, for the first time, a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher’s exact test: the probability of being unaffected is 90.3% and 32.5% when the mutation is inherited from the mother and the father, respectively (p-value = 7.10−7). Interestingly, a similar correlation was observed in families segregating other low penetrance alleles. Consequently, we investigated the putative involvement of an imprinted, modifier gene in low penetrance Rb. We first ruled out a MED4-driven mechanism by MED4 methylation and expression analyses. We then focused on the differentially methylated CpG85 island located in intron 2 of RB1 and showing parent-of-origin-specific DNA methylation. This differential methylation promotes expression of the maternal c.1981C>T allele. We propose that the maternally inherited c.1981C>T/p.Arg661Trp allele retains sufficient tumor suppressor activity to prevent retinoblastoma development. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and subsequently lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se but needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. We suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low penetrance Rb families

<i>RB1</i> allelic imbalance in family F5.

<p>The normalized SNaPshot cDNA ratio between the mutant and the wild type alleles are indicated below each carrier individual with corresponding SNaPshot results. The c.1981C>T/p.Arg661Trp mutant allele “T” is indicated in green and the wild type allele “C” is indicated in blue. Dotted symbols: unaffected carriers; half-blackened symbols: unilateral Rb.</p

Methylation analyses of <i>RB1</i> CpG islands using methylation array.

<p>X axis represents the position on chromosome 13. Y axis represents overall methylation level. CpG106 localizing in <i>RB1</i> promoter is shown in green, CpG42 is shown in pink and CpG85 is shown in blue. For each sample, multiple CpGs are located within an island and each dot represents a single result. A: Normal retina. CpG85 showing approximately 50% of methylation. B: Tumor sample. CpG85 displaying a hypermethylated profile.</p

Family F7 segregating the <i>RB1</i> c.1981C>T/p.Arg661Trp mutation.

<p>Genotype is provided for tested members as m/n for heterozygous carriers and n/n for homozygous wild-type. OC indicates obligate carriers. Blackened symbols: bilateral Rb; half-blackened symbols: unilateral Rb; dotted symbols: unaffected carriers; dashed symbols: deceased.</p

Expression imbalance in 20 carriers of the c.1981C>T/p.Arg661Trp mutation.

<p>Transmission in family F5 is detailed <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005888#pgen.1005888.g003" target="_blank">Fig 3</a>. First degree relatives are indicated for the other families. See text for ratio calculation. (*) See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005888#pgen.1005888.g003" target="_blank">Fig 3</a>.</p