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

BackgroundWe previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases. MethodsWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. ResultsNo 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=1.1x10-4), in analyses restricted to 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=2.1x10-4). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P=3.4x10-3). When these 14 loci and TLR7 were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P=4.7x10-7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P=0.02). Finally, the patients with pLOF or 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=1.68x10-5). ConclusionsRare 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.

Salvataje de fracturas laterales de cadera con clavo-placa de 95º (AO/ASIF) / Lateral hip fracture salvage with 95º blade plate (AO/ASIF)

Introducción: Con las técnicas contemporáneas de reducción y osteosíntesis, la mayoría de las fracturas intertrocantéricas de cadera y de cuello femoral suelen consolidar sin problemas. La mayoría de estas fracturas se tratan mediante reducción cerrada y fijación interna con excelentes resultados. El fracaso terapéutico, por lo general, conduce a dolor y discapacidad funcional. En estos casos, los posibles tratamientos se reducen a dos, si se exceptúa el manejo conservador para pacientes críticos, una opción es una nueva osteosíntesis o la artroplastia total de cadera. La valguización de la falla de las fracturas tiene como objetivo transformar las fuerzas de cizallamiento de la zona de seudoartrosis en fuerzas compresivas, estimulando así la consolidación de las fracturas. Materiales y Métodos: Se evaluó retrospectivamente a 14 pacientes con seudoartrosis de fracturas intertrocantéricas de cadera, entre enero de 2010 y febrero de 2014, operados en nuestra institución. Todos fueron sometidos a una revisión con el objetivo de lograr una posición en valgo del fragmento proximal fijado siempre con clavo-placa de 95º (AO/ASIF). El objetivo de este estudio fue evaluar los resultados clínicos y radiológicos de seudoartrosis de fracturas intertrocantéricas de cadera. Resultados: Se logró la consolidación de la fractura en los 14 pacientes. El tiempo de consolidación promedio varió de tres a seis meses. El puntaje de Harris promedio para la valoración subjetiva fue de 82,65. En ningún caso, se extrajo el material luego de la consolidación de la fractura. Conclusión: El clavo-placa de 95º (AO/ASIF) sigue siendo una muy buena opción en los casos de seudoartrosis de fémur proximal, siempre que la planificación preoperatoria y la técnica quirúrgica sean correctas, y el posoperatorio sea adecuado.

Introduction: Contemporary techniques for reduction and internal fixation make most femoral neck and intertrochanteric hip fractures heal without problems. Most of these fractures are treated with closed reduction and internal fixation achieving excellent results. Treatment failure of hip fractures usually leads to pain and disability. Therapeutic alternatives can be limited to two options, with the exception of the conservative non-operative treatment in critical patients: a new fixation system or an arthroplasty. The valgus osteotomy aims to transform the shear forces in the area of nonunion into compressive forces, thereby stimulating fracture healing. Methods: Fourteen patients with intertrochanteric hip fracture nonunion were retrospectively evaluated between January 2010 and February 2014. All patients underwent revision surgery in order to achieve a valgus position of the proximal fragment, using a 95º blade plate (AO/ASIF). The objective of this study was to evaluate the clinical and radiographic results of intertrochanteric hip fracture nonunion treated with this method. Results: Fracture healing was achieved in all 14 patients. Average healing time ranged from three to six months. The Harris score averaged 82.65. Hardware removal was not performed after fracture healing. Conclusion: The 95° blade plate is still a very good option in cases of proximal femur nonunion, provided the preoperative planning and the surgical technique are correct and the postoperative care is adequate.