Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can ...progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the
of diagnosis, treatment and monitoring of HLH/MAS.
A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS.
The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance.
These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a ...monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in TH-MYCN-driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.
Objective
To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS‐C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests ...late in the course of SARS–CoV‐2 infection. Recommendations are also provided for children with hyperinflammation during COVID‐19, the acute, infectious phase of SARS–CoV‐2 infection.
Methods
The Task Force is composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS‐C and hyperinflammation in COVID‐19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9‐point scale was used to determine the appropriateness of each statement (median scores of 1–3 for inappropriate, 4–6 for uncertain, and 7–9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting.
Results
The guidance was approved in June 2020 and updated in November 2020 and October 2021, and consists of 41 final guidance statements accompanied by flow diagrams depicting the diagnostic pathway for MIS‐C and recommendations for initial immunomodulatory treatment of MIS‐C.
Conclusion
Our understanding of SARS–CoV‐2–related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.
Optimizing proton conduction in solids remains the most promising solution for achieving intermediate temperature (∼750–1000 K) solid oxide fuel cell devices, and enabling selective membranes for H2 ...separation. Proton conduction, a thermally activated process, exhibits its highest rates in yttrium (Y) acceptor doped BaZrO3 at an optimal doping level of 20% Y. The presence of extended defects such as grain boundaries has typically generated a wide variability in reported conductivity values. This has hindered a fundamental mechanistic understanding of how (acceptor) doping levels correlate with the activation energy of protons to produce an optimal doping level for fast proton transport. While isolated dopants have been suggested as the primary source of proton trapping, our results indicate that it is the local dopant-density that matters. Here, we show that increasing the local dopant density promotes localized lattice distortions in the presence of point defects such as oxygen-vacancies or proton interstitials. An increasing distortion amplitude traps the point defects more strongly in the form of polarons, forming defect-clusters at higher concentrations. This leads to a monotonic increase in the activation energy (and hence a decrease in proton mobility) as observed in our measurements. The optimum doping level can now be explained as a competition between increasing proton concentration with doping levels and increasing activation energy due to defect-clusters formed by defect-polarons. Based on our findings, we demonstrate how to improve proton conductivity in doped BaZrO3, by inhibiting this dopant-lattice polaronic interaction. This approach should be generally applicable for ionic conduction in perovskite oxides such as oxygen-ion conduction in solid-oxide fuel cells and alkali-ion conduction in solid-state batteries where carriers might get trapped as defect-polarons.
BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. ...Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.
Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can ...progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS.
A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS.
The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance.
These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
Most of the literature surrounding face transplantation focuses on technique, immunology, and psychology. Dental and skeletal outcomes remain persistently underreported. This study critically ...examined the worldwide face transplant experience to evaluate such outcomes.
A systematic review of all composite allografts containing midface and/or mandible was performed. Dental and skeletal complications were recorded. Formal imaging and photographs available in the literature were analyzed using skeletal measurements, soft-tissue cephalometrics, and the Angle classification. Outcomes of our face transplant patients, including condylar assessment and airway volume measurements, is also presented.
Twenty-five patients received allografts containing midface (n = 7) or mandible (n = 2), whereas 16 contained a double-jaw. All midface-only transplants developed skeletal deformity; 57 percent developed a palatal fistula. Both partial and full arch transplantation patients developed skeletal deformity. Among double-jaw transplants, 69 percent developed palatal fistula or floor-of-mouth dehiscence, 66 percent developed malocclusion, 50 percent developed trismus, and 31 percent required corrective orthognathic surgery. In 40 percent of patients, malocclusion recurred after corrective orthognathic surgery. Forty percent of all patients developed dental cavities or periodontal disease. All of our patients received midface and/or mandible. One patient required corrective orthognathic surgery. Midfacial segments showed clockwise rotation. Airway volumes decreased over time.
Skeletal and dental complications remain extremely common after facial allotransplantation involving either single- or double-jaw composites. Corrective orthognathic surgery and dental extraction is often necessitated. These data will aid face transplant teams during surgical planning and preoperative counseling.
Therapeutic, V.
Cosmic strings are topological defects which can be formed in grand unified theory scale phase transitions in the early universe. They are also predicted to form in the context of string theory. The ...main mechanism for a network of Nambu-Goto cosmic strings to lose energy is through the production of loops and the subsequent emission of gravitational waves, thus offering an experimental signature for the existence of cosmic strings. Here we report on the analysis conducted to specifically search for gravitational-wave bursts from cosmic string loops in the data of Advanced LIGO 2015-2016 observing run (O1). No evidence of such signals was found in the data, and as a result we set upper limits on the cosmic string parameters for three recent loop distribution models. In this paper, we initially derive constraints on the string tension Gμ and the intercommutation probability, using not only the burst analysis performed on the O1 data set but also results from the previously published LIGO stochastic O1 analysis, pulsar timing arrays, cosmic microwave background and big-bang nucleosynthesis experiments. We show that these data sets are complementary in that they probe gravitational waves produced by cosmic string loops during very different epochs. Finally, we show that the data sets exclude large parts of the parameter space of the three loop distribution models we consider.
Several albumin solutions are available for volume expansion. Hyper-oncotic solutions (≥ 20%) are more effective than hypo-oncotic (≤ 5%) as they recruit endogenous extracellular fluid into blood ...vessels rather than adding volume. The latter may cause volume overload, with several associated complications. This systematic review aimed to evaluate evidence on the efficacy and safety of hyper-oncotic vs. hypo-oncotic albumin solutions across different clinical settings. The review was conducted according to PRISMA guidelines. Ninety articles were retained (58 randomized controlled trials). Four studies directly compared albumin solutions. SWIPE showed that cumulative fluid balance at 48 h was significantly lower with 20% vs. 5% albumin (mean − 576 mL;
P
= 0.01). Twenty percent albumin was also associated with decreased chloride load vs. 4% albumin in critically ill patients. All 10 pre-/intraoperative studies evaluated 4–5% solutions; 14 studies evaluated 4–5% albumin in postoperative patients. Renal injury was reported in some studies; however, hydroxyethyl starch was associated with higher incidence vs. albumin. Importantly, 20% albumin preserved cumulative organ function in liver transplantation, and 25% albumin was more beneficial than saline in cardiac surgery patients. Thirty-two studies were performed in critically ill patients. Several studies reported increased risk of positive fluid balance and chloride load with hypo-oncotic albumin, whereas multiple benefits were associated with 20% albumin, including improved endothelial function and perfusion. Of 18 pediatric studies that evaluated ≤ 10% albumin, benefits such as correction of hypotension and improved cardiac output were noted. In conclusion, hyper-oncotic albumin solutions should be more routinely used to avoid potential risks associated with hypo-oncotic solutions.
Purpose To study the functional results after Aptis-Scheker distal radioulnar joint (DRUJ) replacement in young patients. Methods We performed a retrospective study selecting all patients under age ...40 years, with a clinical and radiological follow-up longer than 2 years, who underwent DRUJ replacement. Patients’ charts were reviewed and age at surgery, profession, hobbies, comorbidities, diagnosis, previous procedures, and complications were recorded. Preoperative and postoperative Disabilities of Arm, Shoulder, and Hand and Patient-Rated Wrist Evaluation scores, visual analog scale score, grip strength, lifting capacity, and wrist range of motion were recorded. Functional results and characteristics of the patients were correlated with linear regression. A Kaplan-Meier curve was plotted. Results We performed 46 arthroplasties. Average patient age was 32 years. Forty-one arthroplasties were performed for pain and 5 for pain and instability. Average follow-up was 61 months. Thirty-seven patients underwent multiple procedures before DRUJ replacement (1.7 ± 1.2 procedures). Extensor carpi ulnaris release with implant coverage using a local adipofascial flap (5) or dermal-fat graft (4) was the most common procedure performed after implantation of the prosthesis. Thirty surgeries were undertaken to address complications after DRUJ replacement in 15 wrists. A total of 36 procedures not related to DRUJ replacement were performed in 15 wrists after the arthroplasty. Grip, lifting, Disabilities of Arm, Shoulder, and Hand and Patient-Rated Wrist Evaluation scores, visual analog scale score, and supination showed statistically significant improvement after surgery. Functional results were comparable in patients who received the implant with either a standard or extended stem. Patient age and number of the previous procedures did not correlate with functional results. The 5-year survival of the implant was 96%. Conclusions In this group of young patients, the implant improved the functional status of the extremity. The most frequent complication was extensor carpi ulnaris tendonitis, which was addressed by interposition of an adipofascial flap. Type of study/level of evidence Therapeutic IV.
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