Engineering a "muco-trapping" ACE2-immunoglobulin hybrid with picomolar affinity as an inhaled, pan-variant immunotherapy for COVID-19.

Soluble angiotensin-converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a "muco-trapping" ACE2-Fc conjugate, termed ACE2-(G4S)6-Fc, comprised of the extracellular segment of ACE2 (lacking the C-terminal collectrin domain) that is linked to mucin-binding IgG1-Fc via an extended glycine-serine flexible linker. ACE2-(G4S)6-Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2-Fc decoys or similar truncated ACE2-Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2-(G4S)6-Fc effectively trapped fluorescent SARS-CoV-2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2-(G4S)6-Fc in hamsters as late as 2 days postinfection provided a 10-fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2-(G4S)6-Fc as an inhaled immunotherapy for COVID-19, as well as other emerging viruses that bind ACE2 for cellular entry.

Discussing on the Aortic Coverage in Type B Aortic Dissection Treatment: A Comprehensive Scoping Review.

OBJECTIVE: The objective of this study is to investigate and address the question surrounding the determination of the optimal endograft length of coverage during TEVAR for type B aortic dissection (TBAD), with a particular emphasis on the distal landing zone (DLZ). DATA SOURCES: MEDLINE, Scopus, and Web of Science databases were used. METHODS: The PRISMA-ScR statement was followed. RESULTS: Several variables can contribute to the length of coverage during TEVAR in TBAD patient. Baseline patient's characteristics, TBAD-related features, the type of endoprosthesis, and postoperative graft behaviour may contribute to the choice of coverage. CONCLUSIONS: No robust data have been published regarding the optimal length of TEVAR. Therefore, reporting the percentage of covered aorta and improving computational studies should be valorised to improve postoperative outcomes.

Right ventricular dysfunction and impaired right ventricular-pulmonary arterial coupling in paradoxical low-flow, low-gradient aortic stenosis.

AIMS: Paradoxical low-flow, low-gradient aortic stenosis (pLFLG AS) may represent a diagnostic challenge, and its pathophysiology is complex. While left ventricular (LV) systolic function is preserved, right ventricular dysfunction (RVD) and consecutive LV underfilling may contribute to low-flow and reduced stroke volume index, and to adverse outcomes following transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the potential role of RVD in pLFLG AS, and to assess the impact of pre-procedural RVD on clinical outcomes after TAVI in patients with pLFLG AS. METHODS AND RESULTS: Out of 2739 native AS patients, who received TAVI at the University of Cologne Heart Center between March 2013 and June 2021, 114 patients displayed pLFLG AS and were included in this study. Right ventricular (RV) function was assessed by transthoracic echocardiography, and a fractional area change (FAC) ≤35% and/or a tricuspid annular plane systolic excursion (TAPSE) <18 mm determined RVD. In addition, the TAPSE/systolic pulmonary artery pressure ratio (TAPSE/sPAP) was monitored as a measure of RV-pulmonary arterial (PA) coupling. An impaired FAC and TAPSE was present in 21.9% and 45.6% of patients, respectively, identifying RVD in 50.0%. RVD (p = 0.016), reduced FAC (p = 0.049), reduced TAPSE (p = 0.035) and impaired RV-PA coupling (TAPSE/sPAP ratio <0.31 mm/mmHg; p = 0.009) were associated with significantly higher all-cause mortality compared to patients with normal RV function. After adjustment for sex, age, body mass index, EuroSCORE II, previous myocardial infarction and mitral regurgitation, independent predictors for all-cause mortality were FAC, sPAP, TAPSE/sPAP ratio, right atrial area, RV diameter and tricuspid regurgitation. CONCLUSIONS: Adverse RV remodelling, RVD and impaired RV-PA coupling provide an explanation for low-flow and reduced stroke volume index in a subset of patients with pLFLG AS, and are associated with excess mortality after TAVI.

Ultra-Early and Short-Term Tranexamic Acid Treatment in Patients With Good- and Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: The results of the ULTRA trial showed that ultra-early and short-term treatment with tranexamic acid (TXA) does not improve clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Possibly, the lack of a beneficial effect in all patients with aSAH is masked by antagonistic effects of TXA in certain subgroups. In this post hoc subgroup analysis, we investigated the effect of TXA on clinical outcome in patients with good-grade and poor-grade aSAH. METHODS: The ULTRA trial was a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment. Participants received ultra-early and short-term TXA in addition to usual care or usual care only. This post hoc subgroup analysis included only ULTRA participants with confirmed aSAH and available World Federation of Neurosurgical Societies (WFNS) grade on admission. Patients were categorized into those with good-grade (WFNS 1-3) and poor-grade (WFNS 4-5) aSAH. The primary outcome was clinical outcome assessed by the modified Rankin scale (mRS). Odds ratios (ORs) and adjusted ORs (aORs) with 95% CIs were calculated using ordinal regression analyses. Analyses were performed using the as-treated principle. In all patients with aSAH, no significant effect modification of TXA on clinical outcome was observed for admission WFNS grade (p = 0.10). RESULTS: Of the 812 ULTRA participants, 473 patients had (58%; N = 232 TXA, N = 241 usual care) good-grade and 339 (42%; N = 162 TXA, N = 176 usual care) patients had poor-grade aSAH. In patients with good-grade aSAH, the TXA group had worse clinical outcomes (OR: 0.67, 95% CI 0.48-0.94, aOR 0.68, 95% CI 0.48-0.94) compared with the usual care group. In patients with poor-grade aSAH, clinical outcomes were comparable between treatment groups (OR: 1.04, 95% CI 0.70-1.55, aOR 1.05, 95% CI 0.70-1.56). DISCUSSION: This post hoc subgroup analysis provides another important argument against the use of TXA treatment in patients with aSAH, by showing worse clinical outcomes in patients with good-grade aSAH treated with TXA and no clinical benefit of TXA in patients with poor-grade aSAH, compared with patients treated with usual care. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid, given for <24 hours within the first 24 hours, does not improve the 6-month outcome in good-grade or poor initial-grade aneurysmal SAH.

Effectiveness and safety of immunoadsorption as a rescue treatment of inflammatory myopathies: report of three cases and literature review.

Idiopathic inflammatory myopathy (IIM) summarizes rare, systemic autoimmune conditions primarily characterized by inflammatory damage to the skeletal muscle. Although primary damage occurs to the muscle, these IIM-related conditions involve other organs, including the skin, lungs, upper gastrointestinal tract, joints, and heart. While many patients have an adequate response to immunosuppressive treatment, some patients develop rapidly progressive and treatment-resistant life-threatening courses. Treatment-resistant IIM is challenging for the treating physician and requires interdisciplinary and individualized treatment approaches. Extracorporeal therapy is one option for rescue therapy, with immunoadsorption (IA) having proven more effective than plasma exchange regarding the removal of circulating antibodies. Despite its efficacy and desirable safety profile, the clinical value of IA use in IIM is understudied with no controlled trials reported. Here, we present a review of the current knowledge regarding the management of treatment-resistant IIM and the cases of three patients with treatment-resistant IIM (two with dermatomyositis and one with immune-mediated necrotizing myopathy) who have successfully been treated with IA. All patients responded well to the therapy and experienced no IA-related complications. Taken together, we found IA to be a safe and effective treatment option in treatment-resistant IIM.

Accurate placement of thoracolumbar pedicle screws using a handheld iOS-based navigation device: a prospective intra-patient agreement study.

BACKGROUND: Accurate pedicle screw placement is a challenge with reported misplacement rates of 10% and higher. A handheld navigation device (HND) may provide accuracy equal to CT-based navigation (CT-Nav) but without the cost and complexity. OBJECTIVE: To study the accuracy of a handheld navigation device for pedicle screw placement. STUDY DESIGN: This prospective cross-sectional study with consistently applied reference standard enrolled 20 patients undergoing 92 pedicle screw placements. PATIENTS: Patients who underwent pedicle screw placement between May 2022 and September 2022. OUTCOME MEASURES: Pedicle screw placement accuracy per Gertzbein-Robbins. METHODS: Once the screw pilot hole was established, the proposed trajectory of the HND was compared with that proposed by CT-Nav. Postoperatively, screw accuracy was graded according to Gertzbein-Robbins by a blinded radiologist based on CT scans. Accuracy was compared between the two systems and published control for fluoroscopy assisted and CT-Nav placement using Bayesian posterior distribution. RESULTS: The trajectory proposed by the HND and CT-Nav were in agreement in 98.9% (95% Exact CI; 94.09%-99.97%). The HND accuracy was 98.9% with 91 screws rated "A" and 1 rated "C". Non-inferiority to fluoroscopic placement was achieved because the one-sided normal-approximation 95% CI Lower Bound (LB) of 95.3% is greater than the Performance Goal (PG) of 83.4%. Post-hoc analysis demonstrated that the probability of superiority of the HND relative to the historical accuracy rate of 91.5% for fluoroscopy assisted procedures is >0.999 and that the HND's accuracy rate is within 4.5% of CT-Nav of 95.5% is >0.999. No adverse events or intra-operative complications associated with HND were observed. There was 1 (1.1%) intra-operative repositioning and no re-operations for any reason. CONCLUSIONS: The accuracy rate of the HND was 98.9%, and the proposed trajectory matched with CT-Nav in 98.9% of the time. This is superior to the historical published accuracy rate for fluoroscopy-assisted procedures and equivalent to the historical published accuracy rate for CT-Nav. CLINICAL TRIAL REGISTRATION NUMBER: Dutch trial register NL74268.058.20.

[Fever in rheumatological diseases]. / Fieber bei rheumatologischen Erkrankungen.

Fever is a frequent and important symptom in patients with rheumatological diseases and can be an expression of activity of the underlying rheumatological disease. There is great variability in the incidence of fever as a symptom of the disease between individual diseases. The growing understanding of the molecular signatures of the diseases can help to explain these discrepancies: A genetic overactivation of potently pyrogenic cytokines is the reason why fever is nearly always present in autoinflammatory syndromes. In contrast, fever is less common in polyarthritis and myositis and mostly limited to severe courses of disease. In the diagnostic work-up of fever, frequent differential diagnoses, such as infections, malignancies, side effects of drugs and hypersensitivity reactions should be considered. This article provides an overview of the physiology of the development of fever, describes the relevance of fever in individual rheumatological diseases and proposes a workflow for the clinical clarification of rheumatological patients who present with fever.

Development of Pan-Anti-SARS-CoV-2 Agents through Allosteric Inhibition of nsp14/nsp10 Complex.

SARS-CoV-2 nsp14 functions both as an exoribonuclease (ExoN) together with its critical cofactor nsp10 and as an S-adenosyl methionine-dependent (guanine-N7) methyltransferase (MTase), which makes it an attractive target for the development of pan-anti-SARS-CoV-2 drugs. Herein, we screened a panel of compounds (and drugs) and found that certain compounds, especially Bi(III)-based compounds, could allosterically inhibit both MTase and ExoN activities of nsp14 potently. We further demonstrated that Bi(III) binds to both nsp14 and nsp10, resulting in the release of Zn(II) ions from the enzymes as well as alternation of protein quaternary structures. The in vitro activities of the compounds were also validated in SARS-CoV-2-infected mammalian cells. Importantly, we showed that nsp14 serves as an authentic target of Bi(III)-based antivirals in SARS-CoV-2-infected mammalian cells by quantification of both the protein and inhibitor. This study highlights the importance of nsp14/nsp10 as a potential target for the development of pan-antivirals against SARS-CoV-2 infection.

Successful Rescue Therapy With Daratumumab in Rapidly Progressive Interstitial Lung Disease Caused by MDA5-Positive Dermatomyositis.

Melanoma differentiation-associated gene 5 (MDA5) positive dermatomyositis is a rare systemic autoimmune disease that is associated with life-threatening rapidly progressive interstitial lung disease. We report the case of a 19-year-old male patient with a life-threatening disease course caused by rapidly progressive interstitial lung disease that caused respiratory failure despite intensive immunosuppression with multiple agents (steroids, IV immunoglobulins, tofacitinib, cyclophosphamide, mycophenolate mofetil, ciclosporin and rituximab). Rescue therapy with daratumumab, an anti-CD38-antibody, was initiated. Significant pulmonary improvement was noticed after 4 weekly injections of 1,800 mg. After 6 months of follow up, stable disease remission with significant pulmonary improvement and persistent depletion of CD38+ plasma cells and MDA5-antibody titers were seen. This is the first report of the successful use of daratumumab in dermatomyositis. It highlights the potential of CD38 targeted therapies for severe antibody-mediated autoimmune diseases such as dermatomyositis.

Comparative analysis of SARS-CoV-2 Omicron BA.2.12.1 and BA.5.2 variants.

The initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants, BA.1 and BA.2, are being progressively displaced by BA.5 in many countries. To provide insight on the replacement of BA.2 by BA.5 as the dominant SARS-CoV-2 variant, we performed a comparative analysis of Omicron BA.2.12.1 and BA.5.2 variants in cell culture and hamster models. We found that BA.5.2 exhibited enhanced replicative kinetics over BA.2.12.1 in vitro and in vivo, which is evidenced by the dominant BA.5.2 viral genome detected at different time points, regardless of immune selection pressure with vaccine-induced serum antibodies. Utilizing reverse genetics, we constructed a mutant SARS-CoV-2 carrying spike F486V substitution, which is an uncharacterized mutation that concurrently discriminates Omicron BA.5.2 from BA.2.12.1 variant. We noticed that the 486th residue does not confer viral replication advantage to the virus. We also found that 486V displayed generally reduced immune evasion capacity when compared with its predecessor, 486F. However, the surge of fitness in BA.5.2 over BA.2.12.1 was not due to stand-alone F486V substitution but as a result of the combination of multiple mutations. Our study upholds the urgency for continuous monitoring of SARS-CoV-2 Omicron variants with enhanced replication fitness.

Granulovacuolar degeneration bodies are independently induced by tau and α-synuclein pathology.

BACKGROUND: Granulovacuolar degeneration bodies (GVBs) are intracellular vesicular structures that commonly accompany pathological tau accumulations in neurons of patients with tauopathies. Recently, we developed the first model for GVBs in primary neurons, that requires exogenous tau seeds to elicit tau aggregation. This model allowed the identification of GVBs as proteolytically active lysosomes induced by tau pathology. GVBs selectively accumulate cargo in a dense core, that shows differential and inconsistent immunopositivity for (phosphorylated) tau epitopes. Despite the strong evidence connecting GVBs to tau pathology, these structures have been reported in neurons without apparent pathology in brain tissue of tauopathy patients. Additionally, GVBs and putative GVBs have also been reported in the brain of patients with non-tau proteinopathies. Here, we investigated the connection between pathological protein assemblies and GVBs in more detail. METHODS: This study combined newly developed primary neuron models for tau and α-synuclein pathology with observations in human brain tissue from tauopathy and Parkinson's disease patients. Immunolabeling and imaging techniques were employed for extensive characterisation of pathological proteins and GVBs. Quantitative data were obtained by high-content automated microscopy as well as single-cell analysis of confocal images. RESULTS: Employing a novel seed-independent neuronal tau/GVB model, we show that in the context of tauopathy, GVBs are inseparably associated with the presence of cytosolic pathological tau and that intracellular tau aggregation precedes GVB formation, strengthening the causal relationship between pathological accumulation of tau and GVBs. We also report that GVBs are inseparably associated with pathological tau at the single-cell level in the hippocampus of tauopathy patients. Paradoxically, we demonstrate the presence of GVBs in the substantia nigra of Parkinson's disease patients and in a primary neuron model for α-synuclein pathology. GVBs in this newly developed α-synuclein/GVB model are induced in the absence of cytosolic pathological tau accumulations. GVBs in the context of tau or α-synuclein pathology showed similar immunoreactivity for different phosphorylated tau epitopes. The phosphorylated tau immunoreactivity signature of GVBs is therefore independent of the presence of cytosolic tau pathology. CONCLUSION: Our data identify the emergence of GVBs as a more generalised response to cytosolic protein pathology.

Resectability of bilobar liver tumours after simultaneous portal and hepatic vein embolization versus portal vein embolization alone: meta-analysis.

BACKGROUND: Many patients with bi-lobar liver tumours are not eligible for liver resection due to an insufficient future liver remnant (FLR). To reduce the risk of posthepatectomy liver failure and the primary cause of death, regenerative procedures intent to increase the FLR before surgery. The aim of this systematic review is to provide an overview of the available literature and outcomes on the effectiveness of simultaneous portal and hepatic vein embolization (PVE/HVE) versus portal vein embolization (PVE) alone. METHODS: A systematic literature search was conducted in PubMed, Web of Science, and Embase up to September 2022. The primary outcome was resectability and the secondary outcome was the FLR volume increase. RESULTS: Eight studies comparing PVE/HVE with PVE and six retrospective PVE/HVE case series were included. Pooled resectability within the comparative studies was 75 per cent in the PVE group (n = 252) versus 87 per cent in the PVE/HVE group (n = 166, OR 1.92 (95% c.i., 1.13-3.25)) favouring PVE/HVE (P = 0.015). After PVE, FLR hypertrophy between 12 per cent and 48 per cent (after a median of 21-30 days) was observed, whereas growth between 36 per cent and 67 per cent was reported after PVE/HVE (after a median of 17-31 days). In the comparative studies, 90-day primary cause of death was similar between groups (2.5 per cent after PVE versus 2.2 per cent after PVE/HVE), but a higher 90-day primary cause of death was reported in single-arm PVE/HVE cohort studies (6.9 per cent, 12 of 175 patients). CONCLUSION: Based on moderate/weak evidence, PVE/HVE seems to increase resectability of bi-lobar liver tumours with a comparable safety profile. Additionally, PVE/HVE resulted in faster and more pronounced hypertrophy compared with PVE alone.

Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial.

BACKGROUND AND OBJECTIVES: The ULTRA-trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at six months. An expected proportion of the included patients had non-aneurysmal subarachnoid hemorrhage In this post-hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at six months. METHODS: The ULTRA-trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013 and January 20, 2020. After confirmation of subarachnoid hemorrhage on non-contrast computer tomography, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care, or usual care only. In this post-hoc analysis, we included all ULTRA-participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at six months, assessed by the modified Rankin Scale, dichotomized into good (0-3) and poor (4-6) outcome. RESULTS: Of the 813 ULTRA-trial patients who had an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio (aOR) 0·92; 95% confidence interval (C.I.) 0·69 to 1·24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) aOR 0.76, 95% C.I. 0.57-1.03, all-cause mortality at 30 days aOR 0.91, 95% C.I. 0.65-1.28), all-cause mortality at six months aOR 1.10 (95% C.I. 0.80-1.52). DISCUSSION: Ultra-early and short-term tranexamic acid treatment did not improve clinical outcome at six months in patients with aneurysmal subarachnoid hemorrhage and therefore, cannot be recommended. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24th, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.

Rare, rarer, lung involvement in adult-onset Still's disease: A mini-review.

Adult-onset Still's disease (AOSD) is a polygenic systemic autoinflammatory disease which is associated with increased morbidity and mortality. Pulmonary involvement is a rare, but serious complication of AOSD. As in AOSD, IL-1b, IL-18, and IL-6 dominate the molecular pathogenesis, which mediate a type 1 and type 3 inflammatory signature of the adaptive immune system. This is evidenced by the success of IL-1- and IL-6 inhibition in the management of AOSD. However, anaphylactic reactions to treatment with IL-1- or IL-6-inhibitors is currently being discussed as a potential trigger for lung involvement inf AOSD, while genetic risk factors have also been identified. Clinically, pulmonary involvement in AOSD can manifest in many different forms. Parenchymal inflammation with peripheral consolidations is the most frequent form while PAH is less common, but often very difficult to manage. This mini-review provides an overview of the pathophysiology as well as the clinical presentation and the diagnostic features of pulmonary involvement in AOSD.

Improved Parameterization for the Size Distribution of Emitted Dust Aerosols Reduces Model Underestimation of Super Coarse Dust.

Aircraft measurement campaigns have revealed that super coarse dust (diameter >10 µm) surprisingly accounts for approximately a quarter of aerosols by mass in the atmosphere. However, most global aerosol models either underestimate or do not include super coarse dust abundance. To address this problem, we use brittle fragmentation theory to develop a parameterization for the emitted dust size distribution that includes emission of super coarse dust. We implement this parameterization in the Community Earth System Model (CESM) and find that it brings the model in good agreement with aircraft measurements of super coarse dust close to dust source regions. However, the CESM still underestimates super coarse dust in dust outflow regions. Thus, we conclude that the model underestimation of super coarse atmospheric dust is in part due to the underestimation of super coarse dust emission and likely in part due to errors in deposition processes.

Severity of SARS-CoV-2 Omicron BA.2 infection in unvaccinated hospitalized children: comparison to influenza and parainfluenza infections.

There has been a rapid surge of hospitalization due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants globally. The severity of Omicron BA.2 in unexposed, unvaccinated, hospitalized children is unknown. We investigated the severity and clinical outcomes of COVID-19 infection during the Omicron wave in uninfected, unvaccinated hospitalized children and in comparison with influenza and parainfluenza viral infections. This population-based study retrieved data from the HK territory-wide CDARS database of hospitalisations in all public hospitals and compared severe outcomes for the Omicron BA.2-dominant fifth wave (5-28 February 2022, n = 1144), and influenza and parainfluenza viruses (1 January 2015-31 December 2019, n = 32212 and n = 16423, respectively) in children 0-11 years old. Two deaths (0.2%) out of 1144 cases during the initial Omicron wave were recorded. Twenty-one (1.8%) required PICU admission, and the relative risk was higher for Omicron than influenza virus (n = 254, 0.8%, adjusted RR = 2.1, 95%CI 1.3-3.3, p = 0.001). The proportion with neurological complications was 15.0% (n = 171) for Omicron, which was higher than influenza and parainfluenza viruses (n = 2707, 8.4%, adjusted RR = 1.6, 95%CI 1.4-1.9 and n = 1258, 7.7%, adjusted RR = 1.9, 95%CI 1.6-2.2, p < 0.001 for both, respectively). Croup occurred for Omicron (n = 61, 5.3%) more than influenza virus (n = 601, 1.9%, adjusted RR = 2.0, 95%CI 1.5-2.6, p < 0.001) but not parainfluenza virus (n = 889, 5.4%). Our findings showed that for hospitalized children who had no past COVID-19 or vaccination, Omicron BA.2 was not mild. Omicron BA.2 appeared to be more neuropathogenic than influenza and parainfluenza viruses. It targeted the upper airways more than influenza virus.

[Immunoglobulin-G4-related disease]. / Immunglobulin-G4-assoziierte Erkrankung.

After years of confusion about apparently distinct clinical disease symptoms, the term IgG4-related disease (IgG4-RD) has been coined in 2001, uniting these fibroinflammatory clinical entities with a tendency for tumorous enlargement and tissue fibrosis. Over the past two decades, experimental and clinical studies could make astounding progress in the understanding of this elusive disease. By now, we have a reasonable idea of the pathophysiological mechanisms, which opens up new avenues for therapeutic approaches. It seems like a dense lymphoplasmacytic cell infiltrate, consisting of B­cells, IgG4+ plasma cells, follicular T­helper cells, CD4+ cytotoxic T­cells and M2 macrophages induces a smoldering inflammatory reaction with a fibrogenic cytokine milieu. This stimulates fibroblasts to secrete extracellular matrix components, leading to the histopathologically characteristic storiform fibrosis and obliterative phlebitis. Macroscopically, this reaction results in diffuse organ swelling and tumorous lesions. The macroscopic and histological differentiation from conditions mimicking IgG4-RD can be challenging. This is especially true for granulomatous diseases, such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The situation is further complicated by the fact that ANCAs can be positive in IgG4-RD and, vice versa IgG4 antibodies can be elevated in numerous differential diagnoses, such as infections, AAV, sarcoidosis, and malignancies. This article provides an overview of the multifaceted clinical condition of IgG4-RD with respect to the pathophysiology, diagnostic steps and treatment. Furthermore, an overview of the differential diagnoses is discussed especially with respect to granulomatous diseases.

An antibody class with a common CDRH3 motif broadly neutralizes sarbecoviruses.

The devastation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)-directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses, suggesting that 10-40 is a promising agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses but also uncovered a distinct antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine.