Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Nanoparticle-Catalyzed Transamination under Tumor Microenvironment Conditions: A Novel Tool to Disrupt the Pool of Amino Acids and GSSG in Cancer Cells.

Catalytic cancer therapy targets cancer cells by exploiting the specific characteristics of the tumor microenvironment (TME). TME-based catalytic strategies rely on the use of molecules already present in the TME. Amino groups seem to be a suitable target, given the abundance of proteins and peptides in biological environments. Here we show that catalytic CuFe2O4 nanoparticles are able to foster transaminations with different amino acids and pyruvate, another key molecule present in the TME. We observed a significant in cellulo decrease in glutamine and alanine levels up to 48 h after treatment. In addition, we found that di- and tripeptides also undergo catalytic transamination, thereby extending the range of the effects to other molecules such as glutathione disulfide (GSSG). Mechanistic calculations for GSSG transamination revealed the formation of an imine between the oxo group of pyruvate and the free -NH2 group of GSSG. Our results highlight transamination as alternative to the existing toolbox of catalytic therapies.

Extremity high-grade sarcomas in elderly patients, are they candidates for surgery? Experience in a sarcoma referral center.

The number of elderly patients diagnosed with cancer is increasing. However, knowledge regarding cancer in elderly patients is very scarce. The aim of this study is to analyze the differences in management and outcomes of high-grade extremity sarcomas between elderly and middle-aged patients. Two cohorts were made (> 70 and 30/50 years old) among patients treated in a multidisciplinary unit of a national reference center between 2011 and 2017 with a minimum of 2 years of follow-up. The management and outcomes between these two cohorts were compared. Seventy patients were included, 34 young patients and 36 elderly patients. The only difference between the treatment schemes was the chemotherapy used, 67.6% of the young patients received chemotherapy versus 16.7% of the elderly patients (p = 0.000015). There were no differences either in the overall survival or the progression-free survival between groups at 1 and 2-year follow-up. Deceases for other causes were nearly exclusive of elderly patients at a median of 45.57 months. Surgery is the treatment of choice for sarcomas in both elderly and young patients having similar results in terms of progression-free survival, overall survival, and surgery outcomes. The use of chemotherapy is the only difference in the treatment schemes between both groups. In the elderly patient with minimal or no comorbidity and good functional reserve, surgical curative treatment should be chosen. As for frail elderly patients, the therapeutic objectives must be focused mainly on quality of life and palliation of symptoms.

Is a greater degree of constraint really harmful? Clinical biomechanical comparative study between condylar constrained knee and rotating hinge prosthesis.

BACKGROUND: The real degree of constraint of rotating hinge knee and condylar constrained prostheses is a matter of discussion in revision knee arthroplasty. The objective of this study is to compare the tibial rotation between implants in the clinical settings. METHODS: An investigator blinded experimental study was designed including 20 patients: in 10 of them a rotating hinge knee prosthesis (Endomodel®, LINK) was implanted and in the remaining 10 a constrained condylar knee prosthesis (LCCK®, Zimmer) was used. A medial parapatellar approach was performed and implantation was performed according to conventional surgical technique. Tibial rotation was measured with two accelerometers in full extension and at 30°, 60° and 90° of flexion. Pre and postoperative Knee Injury and Osteoarthritis Outcome Score was recorded. FINDINGS: Both groups were homogenous in age (73.4 years in rotating hinge knee prosthesis vs 74 years in constrained condylar knee group), sex, laterality and preoperative Knee Injury and Osteoarthritis Outcome Score (p > 0.05). The postoperative Knee Injury and Osteoarthritis Outcome Score was significantly higher in the rotating hinge knee prosthesis group (80.98 vs 76.28). The degrees of tibial rotation measured by inertial sensors in the rotating hinge knee prosthesis group were also significantly higher than those measured in the constrained condylar knee group (5.66° vs 2.1°) with p = 0.001. INTERPRETATION: Rotating hinge knee prosthesis appears to represent a lower rotational constraint degree than constrained condylar knee systems in clinical practice and it may increase the clinical satisfaction. The clinical significance: Rotating hinge knee prosthesis appears to represent a lower constraint degree than constrained condylar knee systems in clinical practice.

Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease.

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.

Design and Processing as Ultrathin Films of a Sublimable Iron(II) Spin Crossover Material Exhibiting Efficient and Fast Light-Induced Spin Transition.

Materials based on spin crossover (SCO) molecules have centered the attention in molecular magnetism for more than 40 years as they provide unique examples of multifunctional and stimuli-responsive materials, which can be then integrated into electronic devices to exploit their molecular bistability. This process often requires the preparation of thermally stable SCO molecules that can sublime and remain intact in contact with surfaces. However, the number of robust sublimable SCO molecules is still very scarce. Here, we report a novel example of this kind. It is based on a neutral iron(II) coordination complex formulated as [Fe(neoim)2], where neoimH is the ionogenic ligand 2-(1H-imidazol-2-yl)-9-methyl-1,10-phenanthroline. In the first part, a comprehensive study, which covers the synthesis and magnetostructural characterization of the [Fe(neoim)2] complex as a bulk microcrystalline material, is reported. Then, in the second part, we investigate the suitability of this material to form thin films through high-vacuum sublimation. Finally, the retainment of all present SCO capabilities in the bulk when the material is processed is thoroughly studied by means of X-ray absorption spectroscopy. In particular, a very efficient and fast light-induced spin transition (LIESST effect) has been observed, even for ultrathin films of 15 nm.

Estimating overdiagnosis in giant cell arteritis diagnostic pathways using genetic data: genetic association study.

OBJECTIVES: Giant cell arteritis (GCA) may be confirmed by temporal artery biopsy (TAB) but false negatives can occur. GCA may be overdiagnosed in TAB-negative cases, or if neither TAB nor imaging is done. We used Human Leucocyte Antigen (HLA) genetic association of TAB-positive GCA as an "unbiased umpire" test to estimate historic overdiagnosis of GCA. METHODS: Patients diagnosed with GCA between 1990-2014 were genotyped. During this era, vascular imaging alone was rarely used to diagnose GCA. HLA region variants were jointly imputed from genome-wide genotypic data of cases and controls. Per-allele frequencies across all HLA variants with p< 1.0x1 0 -5 were compared with population control data to estimate overdiagnosis rates in cases without a positive TAB. RESULTS: Genetic data from 663 GCA patients were compared with data from 2619 population controls. TAB-negative GCA (n = 147) and GCA without TAB result (n = 160) had variant frequencies intermediate between TAB-positive GCA (n = 356) and population controls. For example, the allele frequency of HLA-DRB1*04 was 32% for TAB-positive GCA, 29% for GCA without TAB result, 27% for TAB-negative GCA and 20% in population controls. Making several strong assumptions, we estimated that around two-thirds of TAB-negative cases and one-third of cases without TAB result may have been overdiagnosed. From these data, TAB sensitivity is estimated as 88%. CONCLUSIONS: Conservatively assuming 95% specificity, TAB has a negative likelihood ratio of around 0.12. Our method for utilising standard genotyping data as an "unbiased umpire" might be used as a way of comparing the accuracy of different diagnostic pathways.

Glycosylation of polyphenolic compounds: Design of a self-sufficient biocatalyst by co-immobilization of a glycosyltransferase, a sucrose synthase and the cofactor UDP.

Glycosyltransferases catalyze the regioselective glycosylation of polyphenolic compounds, increasing their solubility without altering their antioxidant properties. Leloir-type glycosyltransferases require UDP-glucose as a cofactor to glycosylate a hydroxyl of the polyphenol, which is expensive and unstable. To simplify these processes for industrial implementation, the preparation of self-sufficient heterogeneous biocatalysts is needed. In this study, a glycosyltransferase and a sucrose synthase (as an UDP-regenerating enzyme) were co-immobilized onto porous agarose-based supports coated with polycationic polymers: polyethylenimine and polyallylamine. In addition, the UDP cofactor was strongly ionically adsorbed and co-immobilized with the enzymes, eliminating the need to add it separately. Thus, the optimal self-sufficient heterogeneous biocatalyst was able to catalyze the glycosylation of three polyphenolic compounds (piceid, phloretin and quercetin) with in situ regeneration of the UDP-glucose, allowing multiple consecutive reaction cycles without the addition of exogenous cofactor. A TTN value of 50 (theoretical maximum) was obtained in the reaction of piceid glycosylation, after 5 reaction cycles, using the self-sufficient biocatalyst based on an improved sucrose synthase variant. This result was 5-fold higher than the obtained using soluble cofactor and the co-immobilized enzymes, and much higher than those reported in the literature for similar processes.

The complex HLA-E-nonapeptide in Behçet disease.

Introduction: The knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules. Objective: This study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD. Methods: We analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism. Discussion: Our results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.

Bloqueos Nerviosos. Bases Anatómicas del Dolor Somático Abdomino-Pélvico / Nerve Blocks. Anatomy of the Somatic Innervation of the Abdomino-Pelvic Cavity

El dolor abdominal es una de las sintomatologías que afectan con frecuencia la cavidad abdomino-pélvica. Dicha cavidad posee una inervación somática en la que intervienen del séptimo a doceavo nervios intercostales, ramos colaterales y terminales del plexo lumbar y el nervio pudendo; siendo objetivo de este trabajo la descripción anatómica del dolor abdominopélvico a través del plexo lumbar, nervios intercostales y nervio pudendo, sus diferentes patrones y variaciones de conformación, y las implicancias de éstas últimas en las distintas maniobras clínico-quirúrgicas. Se realizó un estudio descriptivo, observacional y morfométrico de la inervación somática de la cavidad abdomino-pélvica, en 50 preparaciones cadavéricas, fijadas en solución de formaldehído, de la Tercera Cátedra de Anatomía, Facultad de Medicina, Universidad de Buenos Aires, entre Agosto/2017-Diciembre/2019. La descripción clásica del plexo lumbar se encontró en 35 casos; la presencia del nervio femoral accesorio en ningún caso; así como también la ausencia del nervio iliohipogástrico en ningún caso; el nervio obturador accesorio se halló en 2 casos; el nervio genitofemoral dividiéndose dentro de la masa muscular del psoas mayor en 6 casos; el nervio cutáneo femoral lateral emergiendo únicamente de la segunda raíz lumbar en 6 casos y por último se encontró la presencia de un ramo del nervio obturador uniéndose al tronco lumbosacro en un caso. Los nervios intercostales y el nervio pudendo presentaron una disposición clásica en todos los casos analizados. Es esencial un adecuado conocimiento y descripción del plexo lumbar, nervios intercostales y nervio pudendo para un adecuado abordaje de la cavidad abdomino-pélvica en los bloqueos nerviosos.

SUMMARY: Abdominal pain is one of the symptoms that affect the abdominal-pelvic cavity. The abdominal-pelvic cavity has a somatic innervation involving the seventh to twelfth intercostal nerves, collateral and terminal branches of the lumbar plexus and the pudendal nerve. The objective of this work is the description of the lumbar plexus, intercostal nerves and pudendal nerve, its different patterns and structure variations, as well as its implications during pain management in patients. A descriptive, observational, and morphometric study of patterns and structure variations of the lumbar plexus, intercostal nerves and pudendal nerve was conducted in 50 formalin-fixed cadaveric dissections of the Third Chair of Anatomy at the School of Medicine in the Universidad de Buenos Aires from August 2017 to December/2019. The standard description of the lumbar plexus was found in 35 cases; accessory femoral nerve was not present in any of the cases; absence of the iliohipogastric nerve was also not found in any case, while the accessory obturating nerve was found in 2 cases; genitofemoral nerve dividing within the muscle mass of psoas in 6 cases; lateral femoral cutaneous nerve emerging only from the second lumbar root in 6 cases and finally, presence of a branch of the obturating nerve was found joining the lumbosacral trunk in one case. The pudendal and intercostal nerve patterns presented a typical pathway in all cases. Adequate knowledge and description of the lumbar plexus, intercostal nerves and pudendal nerve is essential for an adequate approach of the abdominal-pelvic cavity in nerve blocks.

Validation of a Pathological Score for the Assessment of Bronchial Biopsies in Severe Uncontrolled Asthma: Beyond Blood Eosinophils.

BACKGROUND: Blood eosinophil count (BEC) is currently used as a surrogate marker of T2 inflammation in severe asthma but its relationship with tissue T2-related changes is elusive. Bronchial biopsy could add reliable information but lacks standardization. OBJECTIVES: To validate a systematic assessment of the bronchial biopsy for the evaluation of severe uncontrolled asthma (SUA) by standardizing a pathological score. METHODS: A systematic assessment of submucosal inflammation, tissue eosinophilic count/field (TEC), goblet cells hyperplasia, epithelial changes, basement membrane thickening, prominent airway smooth muscle and submucosal mucous glands was initially agreed and validated in representative bronchial biopsies of 12 patients with SUA by 8 independent pathologists. In a second phase, 62 patients with SUA who were divided according to BEC≥300cells/mm3 or less underwent bronchoscopy with bronchial biopsies and the correlations between the pathological findings and the clinical characteristics were investigated. RESULTS: The score yielded good agreement among pathologists regarding submucosal eosinophilia, TEC, goblet cells hyperplasia and mucosal glands (ICC=0.85, 0.81, 0.85 and 0.87 respectively). There was a statistically significant correlation between BEC and TEC (r=0.393, p=0.005) that disappeared after correction by oral corticosteroids (OCS) use (r=0.170, p=0.307). However, there was statistically significant correlation between FeNO and TEC (r=0.481, p=0.006) that was maintained after correction to OCS use (r=0.419, p=0.021). 82.4% of low-BEC had submucosal eosinophilia, 50% of them moderate to severe. CONCLUSION: A standardized assessment of endobronchial biopsy is feasible and could be useful for a better phenotyping of SUA especially in those receiving OCS.

Asymptomatic immunodeficiency-associated vaccine-derived poliovirus infections in two UK children.

Increasing detections of vaccine-derived poliovirus (VDPV) globally, including in countries previously declared polio free, is a public health emergency of international concern. Individuals with primary immunodeficiency (PID) can excrete polioviruses for prolonged periods, which could act as a source of cryptic transmission of viruses with potential to cause neurological disease. Here, we report on the detection of immunodeficiency-associated VDPVs (iVDPV) from two asymptomatic male PID children in the UK in 2019. The first child cleared poliovirus with increased doses of intravenous immunoglobulin, the second child following haematopoetic stem cell transplantation. We perform genetic and phenotypic characterisation of the infecting strains, demonstrating intra-host evolution and a neurovirulent phenotype in transgenic mice. Our findings highlight a pressing need to strengthen polio surveillance. Systematic collection of stool from asymptomatic PID patients who are at high risk for poliovirus excretion could improve the ability to detect and contain iVDPVs.

Prevalence and risk factors for silicosis among a large cohort of stone benchtop industry workers.

OBJECTIVES: High silica content artificial stone has been found to be associated with silicosis among stone benchtop industry (SBI) workers. The objectives of this study were to determine the prevalence of and risk factors for silicosis among a large cohort of screened SBI workers, and determine the reliability of respiratory function testing (RFT) and chest x-ray (CXR) as screening tests in this industry. METHODS: Subjects were recruited from a health screening programme available to all SBI workers in Victoria, Australia. Workers undertook primary screening, including an International Labour Office (ILO) classified CXR, and subject to prespecified criteria, also underwent secondary screening including high-resolution CT (HRCT) chest and respiratory physician assessment. RESULTS: Among 544 SBI workers screened, 95% worked with artificial stone and 86.2% were exposed to dry processing of stone. Seventy-six per cent (414) required secondary screening, among whom 117 (28.2%) were diagnosed with silicosis (median age at diagnosis 42.1 years (IQR 34.8-49.7)), and all were male. In secondary screening, silicosis was associated with longer SBI career duration (12 vs 8 years), older age, lower body mass index and smoking. In those with silicosis, forced vital capacity was below the lower limit of normal in only 14% and diffusion capacity for carbon monoxide in 13%. Thirty-six (39.6%) of those with simple silicosis on chest HRCT had an ILO category 0 CXR. CONCLUSION: Screening this large cohort of SBI workers identified exposure to dry processing of stone was common and the prevalence of silicosis was high. Compared with HRCT chest, CXR and RFTs had limited value in screening this high-risk population.

Morbidity and Mortality Analysis in the Treatment of Intertrochanteric Hip Fracture with Two Fixation Systems: Dynamic Hip Screw (DHS) or Trochanteric Fixation Nail Advance (TFNA).

BACKGROUND: The aim of this study was to compare the clinical outcomes, complications, and mortality of patients with intertrochanteric hip fracture treated with dynamic hip screw (DHS) vs. trochanteric fixation nail advance (TFNA). METHODS: We evaluated 152 patients with intertrochanteric fractures concerning age, sex, comorbidity, Charlson Index, preoperative gait, OTA/AO classification, time from fracture to surgery, blood loss, amount of blood replacement, changes in gait, full weight-bearing at hospital discharge, complications, and mortality. The final indicators encompassed the adverse effects linked to implants, postoperative complications, clinical healing or bone healing duration, and functional score. RESULTS: The study included a total of 152 patients, out of which 78 (51%) received DHS treatment and 74 (49%) received TFNA treatment. The results of this study show that the TFNA group demonstrated superiority (p < 0.001). However, it should be noted that the TFNA group had a higher frequency of the most unstable fractures (AO 31 A3, p < 0.005). Full weight-bearing at discharge also decreased in patients with more unstable fractures (p = 0.005) and severe dementia (p = 0.027). Mortality was higher in the DHS group; however, a longer time from diagnosis to surgery was also observed in this group (p < 0.005). CONCLUSIONS: The TFNA group has shown a higher success rate in achieving full weight-bearing at hospital discharge when treating trochanteric hip fractures. This makes it the preferred choice for treating unstable fractures in this region of the hip. Additionally, it is important to note that a longer time to surgery is associated with increased mortality in patients with hip fractures.

Accuracy of computer-aided static and dynamic navigation systems in the placement of zygomatic dental implants.

BACKGROUND: Zygomatic implants are widely used in the rehabilitation of severely atrophic maxillae, but implant placement is not without risks, and it can potentially cause damage to related anatomical structures. The aim of this study was to perform a comparative analysis of the accuracy of static navigation systems in placing zygomatic dental implants in comparison to dynamic navigation systems. METHODS: Sixty zygomatic dental implants were randomly allocated to one of three study groups, categorized by which implant placement strategy was used: A: computer-aided static navigation system (n = 20) (GI); B: computer-aided dynamic navigation system (n = 20) (NI); or C: free-hand technique (n = 20) (FHI). For the computer-aided study groups, a preoperative cone-beam computed tomography (CBCT) scan of the existing situation was performed in order to plan the approach to be used during surgery. Four zygomatic dental implants were inserted in each of fifteen polyurethane stereolithographic models (n = 15), with a postoperative CBCT scan taken after the intervention. The pre- and postoperative CBCT scans were then uploaded to a software program used in dental implantology to analyze the angular deviations, apical end point, and coronal entry point. Student's t-test was used to analyze the results. RESULTS: The results found statistically significant differences in apical end-point deviations between the FHI and NI (p = 0.0053) and FHI and GI (p = 0.0004) groups. There were also statistically significant differences between the angular deviations of the FHI and GI groups (p = 0.0043). CONCLUSIONS: The manual free-hand technique may enable more accurate placement of zygomatic dental implants than computer-assisted surgical techniques due to the different learning curves required for each zygomatic dental implant placement techniques.

Cranial and extracranial giant cell arteritis do not exhibit differences in the IL6 -174 G/C gene polymorphism.

OBJECTIVES: Since interleukin-6 (IL-6) is a pivotal proinflammatory cytokine implicated in the pathogenesis of giant cell arteritis (GCA), we aimed to determine the potential association of the functional IL6 -174 G/C polymorphism with GCA as well as if the single base change variation at the promoter region in the human IL-6 gene may account for differences in the clinical spectrum of GCA between cranial and extracranial large vessel vasculitis (LVV)-GCA. METHODS: The IL6 -174 G/C polymorphism (rs1800795) was genotyped in 191 patients with biopsy-proven GCA who had typical cranial manifestations of the disease, 109 patients with extracranial LVV-GCA, without cranial ischaemic manifestations of GCA, and 877 ethnically matched unaffected controls. A comparative study was carried out between patients with cranial and extracranial LVV-GCA and controls. RESULTS: No significant differences in genotype and allele frequencies of IL6 -174 G/C polymorphism were found between the whole cohort of GCA patients and healthy controls. It was also the case when cranial and extracranial LVV-GCA were compared or when each of these subgroups was compared to controls. Moreover, no significant results in genotype and allele frequencies of IL6 -174 G/C polymorphism were disclosed when the whole cohort of GCA patients were stratified according to the presence of polymyalgia rheumatica, severe ischaemic manifestations, including permanent visual loss and peripheral arteriopathy, and HLA-DRB1*04:01 status. CONCLUSIONS: Our results show that the IL6 -174 G/C polymorphism does not influence the phenotypic expression of GCA.

Case report: Clearance of longstanding, immune-deficiency-associated, vaccine-derived polio virus infection following remdesivir therapy for chronic SARS-CoV-2 infection.

The global polio eradication campaign has had remarkable success in reducing wild-type poliovirus infection, largely built upon the live attenuated Sabin oral poliovirus vaccine. Whilst rare, vaccine poliovirus strains may cause infection and subsequently revert to a neurovirulent type, termed vaccine-derived poliovirus (VDPV). Persistent, vaccine derived infection may occur in an immunocompromised host (iVDPV), where it is a recognised complication following receipt of the Sabin vaccine. This has significant implications for the global polio eradication campaign and there is currently no agreed global strategy to manage such patients.Here we describe a case of a 50-year-old man with common variable immune deficiency, persistently infected with a neurovirulent vaccine-derived type 2 poliovirus following vaccination in childhood. iVDPV infection had proven resistant to multiple prior attempts at treatment with human breast milk, ribavirin and oral administration of a normal human pooled immunoglobulin product. His iVDPV infection subsequently resolved after 12 days treatment with remdesivir, an adenosine analogue prodrug that is an inhibitor of viral RNA-dependent RNA polymerase, administered as treatment for a prolonged, moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. iVDPV from the patient, isolated prior to treatment, was subsequently demonstrated to be sensitive to remdesivir in vitro. Based on the observations made in this case, and the mechanistic rationale for use with iVDPV, there is strong justification for further clinical studies of remdesivir treatment as a potentially curative intervention in patients with iVDPV infection.

Cranial and extracranial large-vessel giant cell arteritis share a genetic pattern of interferon-gamma pathway.

OBJECTIVES: Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. METHODS: Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. CONCLUSIONS: Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.

Ultrasound-Guided A1 Pulley Release Versus Classic Open Surgery for Trigger Digit: A Randomized Clinical Trial.

OBJECTIVES: We compared an ultra-minimally invasive ultrasound-guided percutaneous A1 pulley release and a classic open surgery for trigger digit. METHODS: We designed a single-center randomized control trial. All cases had clinical signs of primary grade III trigger digit. Concealed allocation (1:1) was used for assigning patients to each group and data collectors were blinded. The Quick-Disabilities of the Arm, Shoulder, and Hand (Quick-DASH) questionnaire was our primary variable. Quick-DASH, two-point discrimination, grip strength, time until stopping analgesics, having full digital range of motion and restarting everyday activities were registered on the 1st, 3rd, and 6th weeks, 3rd and 6th months, and 1st year after the procedure. RESULTS: We randomized 84 patients to ultrasound-guided release and classic open surgery. Quick-DASH scores significantly favored the percutaneous technique until the 3rd month: 7.6 ± 1.2 versus 15.3 ± 2.4 (mean ± standard error of the mean). The percutaneous group obtained significantly better results in all the variables studied: time until stopping analgesics, achieving full range of motion and restarting everyday activities. Grip strength was significantly better in the percutaneous group for the 1st week only. Five cases of moderate local pain were observed in the open technique. There was one case of transient nerve numbness per group. CONCLUSIONS: The ultra-minimally invasive ultrasound-guided A1 pulley release was clinically superior to the classic open surgery in functional recovery with a lower complication rate.