Exploring the contribution of nature-based solutions for environmental challenges in the Netherlands.

Nature-based solutions (NbS) offer a promising and sustainable approach to addressing multiple environmental challenges, including climate change, pollution, and biodiversity loss. Despite the potential of NbS, their actual effectiveness in solving these challenges remains uncertain. Therefore, this study evaluates the contribution of NbS implemented in a nature-inclusive scenario for six environmental challenges and associated policy targets in the Netherlands. Fifteen different NbS were applied in the scenario in urban, agricultural, aquatic, and protected nature areas, with measures like flower field margins, green roofs, groundwater level management, and river restoration. The spatially-explicit Natural Capital Model was used to quantify the effectiveness of all applied NbS at a national-scale. Results show NbS significantly contribute to simultaneously solving all six assessed environmental challenges. The most significant impact was seen in improving the quality of water bodies (+34 %), making agriculture more sustainable (+24 %), and protecting and restoring biodiversity (+22 %). The contribution of NbS to address the quality of the living environment (+13 %), climate change (+10 %), and the energy transition was less effective (+2 %). Furthermore, NbS can help to achieve sectoral policy targets at the global, EU, and national levels, including those related to the Birds Habitats Directives, carbon emission, and pesticide reduction targets. This study highlights the potential of NbS to effectively address multiple environmental challenges, although they do not provide a complete solution, and suggests that future research could focus on identifying even more effective ways to implement NbS, and to mainstream their use in policy and practice.

Immunological signatures unveiled by integrative systems vaccinology characterization of dengue vaccination trials and natural infection.

Introduction: Dengue virus infection is a global health problem lacking specific therapy, requiring an improved understanding of DENV immunity and vaccine responses. Considering the recent emerging of new dengue vaccines, here we performed an integrative systems vaccinology characterization of molecular signatures triggered by the natural DENV infection (NDI) and attenuated dengue virus infection models (DVTs). Methods and results: We analyzed 955 samples of transcriptomic datasets of patients with NDI and attenuated dengue virus infection trials (DVT1, DVT2, and DVT3) using a systems vaccinology approach. Differential expression analysis identified 237 common differentially expressed genes (DEGs) between DVTs and NDI. Among them, 28 and 60 DEGs were up or downregulated by dengue vaccination during DVT2 and DVT3, respectively, with 20 DEGs intersecting across all three DVTs. Enriched biological processes of these genes included type I/II interferon signaling, cytokine regulation, apoptosis, and T-cell differentiation. Principal component analysis based on 20 common DEGs (overlapping between DVTs and our NDI validation dataset) distinguished dengue patients by disease severity, particularly in the late acute phase. Machine learning analysis ranked the ten most critical predictors of disease severity in NDI, crucial for the anti-viral immune response. Conclusion: This work provides insights into the NDI and vaccine-induced overlapping immune response and suggests molecular markers (e.g., IFIT5, ISG15, and HERC5) for anti-dengue-specific therapies and effective vaccination development.

Dirigent isoflavene-forming PsPTS2: 3D structure, stereochemical, and kinetic characterization comparison with pterocarpan-forming PsPTS1 homolog in pea.

Pea phytoalexins (-)-maackiain and (+)-pisatin have opposite C6a/C11a configurations, but biosynthetically how this occurs is unknown. Pea dirigent-protein (DP) PsPTS2 generates 7,2'-dihydroxy-4',5'-methylenedioxyisoflav-3-ene (DMDIF), and stereoselectivity toward four possible 7,2'-dihydroxy-4',5'-methylenedioxyisoflavan-4-ol (DMDI) stereoisomers was investigated. Stereoisomer configurations were determined using NMR spectroscopy, electronic circular dichroism, and molecular orbital analyses. PsPTS2 efficiently converted cis-(3R,4R)-DMDI into DMDIF 20-fold faster than the trans-(3R,4S)-isomer. The 4R-configured substrate's near ß-axial OH orientation significantly enhanced its leaving group abilities in generating A-ring mono-quinone methide (QM), whereas 4S-isomer's α-equatorial-OH was a poorer leaving group. Docking simulations indicated that the 4R-configured ß-axial OH was closest to Asp51, whereas 4S-isomer's α-equatorial OH was further away. Neither cis-(3S,4S)- nor trans-(3S,4R)-DMDIs were substrates, even with the former having C3/C4 stereochemistry as in (+)-pisatin. PsPTS2 used cis-(3R,4R)-7,2'-dihydroxy-4'-methoxyisoflavan-4-ol [cis-(3R,4R)-DMI] and C3/C4 stereoisomers to give 2',7-dihydroxy-4'-methoxyisoflav-3-ene (DMIF). DP homologs may exist in licorice (Glycyrrhiza pallidiflora) and tree legume Bolusanthus speciosus, as DMIF occurs in both species. PsPTS1 utilized cis-(3R,4R)-DMDI to give (-)-maackiain 2200-fold more efficiently than with cis-(3R,4R)-DMI to give (-)-medicarpin. PsPTS1 also slowly converted trans-(3S,4R)-DMDI into (+)-maackiain, reflecting the better 4R configured OH leaving group. PsPTS2 and PsPTS1 provisionally provide the means to enable differing C6a and C11a configurations in (+)-pisatin and (-)-maackiain, via identical DP-engendered mono-QM bound intermediate generation, which PsPTS2 either re-aromatizes to give DMDIF or PsPTS1 intramolecularly cyclizes to afford (-)-maackiain. Substrate docking simulations using PsPTS2 and PsPTS1 indicate cis-(3R,4R)-DMDI binds in the anti-configuration in PsPTS2 to afford DMDIF, and the syn-configuration in PsPTS1 to give maackiain.

Isoform-selective TGF-ß3 inhibition for systemic sclerosis.

BACKGROUND: Transforming growth factor ß (TGF-ß) is implicated as a key mediator of pathological fibrosis, but its pleiotropic activity in a range of homeostatic functions presents challenges to its safe and effective therapeutic targeting. There are three isoforms of TGF-ß, TGF-ß1, TGF-ß2, and TGF-ß3, which bind to a common receptor complex composed of TGF-ßR1 and TGF-ßR2 to induce similar intracellular signals in vitro. We have recently shown that the cellular expression patterns and activation thresholds of TGF-ß2 and TGF-ß3 are distinct from those of TGF-ß1 and that selective short-term TGF-ß2 and TGF-ß3 inhibition can attenuate fibrosis in vivo without promoting excessive inflammation. Isoform-selective inhibition of TGF-ß may therefore provide a therapeutic opportunity for patients with chronic fibrotic disorders. METHODS: Transcriptomic profiling of skin biopsies from patients with systemic sclerosis (SSc) from multiple clinical trials was performed to evaluate the role of TGF-ß3 in this disease. Antibody humanization, biochemical characterization, crystallization, and pre-clinical experiments were performed to further characterize an anti-TGF-ß3 antibody. FINDINGS: In the skin of patients with SSc, TGF-ß3 expression is uniquely correlated with biomarkers of TGF-ß signaling and disease severity. Crystallographic studies establish a structural basis for selective TGF-ß3 inhibition with a potent and selective monoclonal antibody that attenuates fibrosis effectively in vivo at clinically translatable exposures. Toxicology studies suggest that, as opposed to pan-TGF-ß inhibitors, this anti-TGF-ß3 antibody has a favorable safety profile for chronic administration. CONCLUSION: We establish a rationale for targeting TGF-ß3 in SSc with a favorable therapeutic index. FUNDING: This study was funded by Genentech, Inc.

Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

Relationship between dietary characteristics and heel quantitative ultrasound parameters in postmenopausal women from the OsteoLaus cohort.

The role of dietary patterns in the development of osteoporosis is unclear. The heel quantitative ultrasound (QUS) is a potential alternative to Dual X-Ray Absorptiometry. Nutrients, foods, dietary patterns and compliance to dietary guidelines were compared between the lowest and the highest tertiles of QUS parameters [Broadband Ultrasound Attenuation (BUA), Speed of Sound (SOS), Stiffness Index (SI)], using data from the OsteoLaus cohort. Participants in the highest tertiles of QUS parameters (385 for BUA, 397 for SOS, 386 for SI) were younger, of higher body weight, and had less major osteoporotic fractures. Women in the highest tertiles of SI and BUA consumed more fat (35.1 ± 0.4 vs 33.9 ± 0.4 and 34.9 ± 0.4 vs 33.8 ± 0.4 gr/day for SI and BUA, respectively, p < 0.05), and complied less frequently with dairy intake guidelines [odds ratio (95% confidence interval): 0.70 (0.53-0.92) and 0.72 (0.55-0.95) for SI and BUA, respectively, p < 0.05] than women in the lowest tertile. No differences were found regarding dietary patterns, healthy dietary scores, or compliance to dietary guidelines. Postmenopausal women in the highest QUS tertiles were younger, of higher weight and BMI, consumed more monounsaturated fatty acids and less dairy and calcium than women in the lowest tertiles. No differences were found between QUS tertiles regarding dietary patterns.

Comparison of a blind and an ultrasound-guided technique for Retrobulbar anesthesia in dogs undergoing unilateral subconjunctival enucleation.

OBJECTIVE: This study compared the quality of retrobulbar anesthesia using a blind inferior-temporal palpebral approach (ITP) with an ultrasound-guided supratemporal (ST) technique in dogs undergoing unilateral enucleation. ANIMAL STUDIED: Twenty-one client-owned dogs were undergoing enucleation. PROCEDURES: Dogs were randomly assigned to receive ITP (n = 10) or ST (n = 11) with 0.5% ropivacaine at 0.1 mL/cm of neurocranial length. The anesthetist was blinded to the technique. Intraoperative data included cardiopulmonary variables, inhalant anesthetics requirement, and requirement for rescue analgesia (intravenous fentanyl 2.5 mcg/kg). Postoperative data included pain scores, sedation scores, and need for intravenous hydromorphone (0.05 mg/kg). Treatments were compared using Wilcoxon's rank sum test or Fisher's exact test as appropriate. Comparison of variables over time were tested using a mixed effect linear model on rank. Significance was set at p = 0.05. RESULTS: Intraoperative cardiopulmonary variables and inhalant requirements were not different between groups. Dogs receiving ITP required median (interquartile range, IQR) 1.25 (0, 2.5) mcg/kg intraoperative fentanyl while those receiving ST required none (p < 0.01). Intraoperative fentanyl was required in 5/10 and 0/11 of dogs in the ITP and ST groups, respectively (p = 0.01). Postoperative analgesia requirements were not significantly different between groups; 2/10 and 1/10 dogs in the ITP and ST groups, respectively. Sedation score negatively affected pain score (p < 0.01). CONCLUSIONS: The ultrasound-guided ST technique was more effective at decreasing intraoperative opioid requirements than the blind ITP approach in dogs undergoing unilateral enucleation.

Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Sabatolimab is an immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), an immuno-myeloid regulator expressed on immune cells and leukaemic stem cells. In this trial, we compared the efficacy and safety of sabatolimab plus hypomethylating agent with placebo plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes. METHODS: STIMULUS-MDS1 was a multicentre, randomised, double-blind, placebo-controlled, phase 2 study done at 54 investigational sites in 17 countries. Adult patients (aged ≥18 years) with intermediate-risk, high-risk, and very high-risk myelodysplastic syndromes (according to Revised International Prognostic Scoring System criteria) who had not received previous treatment were included. Patients were randomly assigned (1:1) to intravenous sabatolimab (400 mg on day 8 and 22) or placebo plus a hypomethylating agent (intravenous decitabine 20 mg/m2 on day 1-5 or intravenous or subcutaneous azacitidine 75 mg/m2 on day 1-7 or day 1-5 and day 8 and 9) every 28 days until treatment discontinuation. The two primary endpoints were complete response rate and progression-free survival, assessed in the full analysis set, which included all randomly assigned patients. Complete response was analysed, as prespecified, 7 months after the last patient was randomly assigned. All other analyses presented, including progression-free survival, were done at the final data cutoff prespecified via a protocol amendment on Sept 2, 2021. Safety was assessed in in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03946670, and is ongoing. FINDINGS: Between July 29, 2019, and Aug 10, 2020, 127 patients were randomly assigned to sabatolimab plus a hypomethylating agent group (sabatolimab group; n=65) or placebo plus a hypomethylating agent (placebo group; n=62). The median age of participants was 73 years (IQR 69-77), of whom 86 (68%) of 127 patients were male and 77 (61%) were White. The primary endpoints were not met. Complete response (cutoff date of March 10, 2021) was achieved in 14 (22%; 95% CI 12·3-33·5) of 65 patients in the sabatolimab group vs 11 (18%; 9·2-29·5) of 62 patients in the placebo group (p=0·77). At the cutoff date of the final analysis (March 1, 2022), median follow-up for progression-free survival was 17·8 months (IQR 16·6-19·4) in the sabatolimab group and 19·2 months (17·7-22·3) in the placebo group, and the median progression-free survival was 11·1 months (95% CI 7·6-17·6) in the sabatolimab group vs 8·5 months (6·9-11·3) in the placebo group (hazard ratio 0·75 [95% CI 0·48-1·17]; p=0·1022). The most common adverse events of any grade were neutropenia (35 [56%] of 62 patients in the sabatolimab group vs 43 [68%] of 63 patients in the placebo group), thrombocytopenia (30 [48%] vs 32 [51%]), constipation (29 [47%] vs 24 [38%]), diarrhoea (27 [44%] vs 14 [22%]), anaemia (22 [35%] vs 34 [54%]), febrile neutropenia (22 [35%] vs 15 [24%]), and leukopenia (15 [24%] vs 20 [32%]). One patient developed a serious potential treatment-related immune-mediated adverse event in the sabatolimab group. There was one treatment-related death in the sabatolimab group due to pneumonitis. INTERPRETATION: The addition of sabatolimab to hypomethylating agents in this study did not result in a significant improvement in complete response rates or progression-free survival. Sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes. A randomised phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting. FUNDING: Novartis Pharmaceuticals.

Measurement of Henry's law constants of ethyl nitrate in deionized water, synthetic sea salt solutions, and n-octanol.

Ethyl nitrate (EN; C2H5ONO2) is an important component of atmospheric "odd nitrogen" (NOy) whose main source is marine emissions. To correctly describe its air-water transfer and model its global distribution, accurate values for its temperature- and salinity-dependent Henry's law solubility constants are needed. Here, we report Henry's law (HScp) constants for EN in deionized (DI) water, synthetic sea salt solutions (SSS), and n-octanol at temperatures between 278.2 K and 303.2 K. For DI water, HScp constants of (2.03 ± 0.06) M atm-1 at 293.2 K and (4.88 ± 0.13) M atm-1 at 278.2 K were observed (all stated uncertainties are at the 1σ level). The data are best described by ln(HScp(aq)/[Matm-1]) = -(16.2 ± 0.4)+(4.94 ± 0.11) × 103/T and ln(HScp(octanol)/[Matm-1]) = -(11.1 ± 1.9)+(4.15 ± 0.33) × 103/T, from which the octanol-water partition coefficient (KOW) was calculated. A temperature-independent salting-out factor of 1.25 ± 0.03 and Setschenow constant of KS = (0.33 ± 0.04) mol kg-1 were determined for SSS. Liquid-phase losses of EN were negligible in all solvents (kl < 1 × 10-4 s-1). The HScp(aq) values agree with results by Kames (1993) but are between 2% (at 303.2 K) and 19% (at 278.2 K) lower than the widely used parameterization by Kames and Schurath (1992), indicating a systemic bias in the EN literature and modelling of the Earth's nitrogen cycle.

Neuroimmunology of rabies: New insights into an ancient disease.

Rabies is an ancient neuroinvasive viral (genus Lyssavirus, family Rhabdoviridae) disease affecting approximately 59,000 people worldwide. The central nervous system (CNS) is targeted, and rabies has a case fatality rate of almost 100% in humans and animals. Rabies is entirely preventable through proper vaccination, and thus, the highest incidence is typically observed in developing countries, mainly in Africa and Asia. However, there are still cases in European countries and the United States. Recently, demographic, increasing income levels, and the coronavirus disease 2019 (COVID-19) pandemic have caused a massive raising in the animal population, enhancing the need for preventive measures (e.g., vaccination, surveillance, and animal control programs), postexposure prophylaxis, and a better understanding of rabies pathophysiology to identify therapeutic targets, since there is no effective treatment after the onset of clinical manifestations. Here, we review the neuroimmune biology and mechanisms of rabies. Its pathogenesis involves a complex and poorly understood modulation of immune and brain functions associated with metabolic, synaptic, and neuronal impairments, resulting in fatal outcomes without significant histopathological lesions in the CNS. In this context, the neuroimmunological and neurochemical aspects of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are likely related to the clinical manifestations of rabies infection. Uncovering new links between immunopathological mechanisms and neurochemical imbalance will be essential to identify novel potential therapeutic targets to reduce rabies morbidity and mortality.

Building the Bridge From Pediatric to Adult Neurological Care.

In this brief communication, we discuss the current landscape and unmet needs of pediatric to adult transition care in neurology. Optimizing transition care is a priority for patients, families, and providers with growing discussion in neurology. We also introduce the activities of the University of Toronto Pediatric-Adult Transition Working Group - a collaborative interdivisional and inter-subspeciality group of faculty, advanced-practice providers, trainees, and patient-family advisors pursuing collaboration with patients, families, and universities from across Canada. We envision that these efforts will result in a national neurology transition strategy that will inform designation of health authority attention and funding.

Global Perceptions on ERAS® in Pancreatoduodenectomy.

BACKGROUND: Uptake of ERAS® pathways for pancreatic surgery have been slow and impacted by low compliance. OBJECTIVE: To explore global awareness, perceptions and practice of ERAS® peri-pancreatoduodenectomy (PD). METHODS: A structured, web-based survey (EPSILON) was administered through the ERAS® society and IHPBA membership. RESULTS: The 140 respondents included predominantly males (86.4%), from Europe (45%), practicing surgery (95%) at academic/teaching hospitals (63.6%) over a period of 10-20 years (38.6%). Most respondents identified themselves as general surgeons (68.6%) with 40.7% reporting an annual PD volume of 20-50 cases, practicing post-PD clinical pathways (37.9%), with 31.4% of respondents auditing their outcomes annually. Reduced medical complications, cost and hospital length of stay, and improved patient satisfaction were perceived benefits of compliance to enhancing-recovery. Multidisciplinary co-ordination was considered the most important factor in the implementation and sustainability of peri-PD ERAS® pathways, while reluctance to change among health care practitioners, difficulties in data collection and audit, lack of administrative support, and recruitment of an ERAS® dedicated nurse were reported to be important barriers. CONCLUSIONS: The EPSILON survey highlighted global clinician perceptions regarding the benefits of compliance to peri-PD ERAS®, the importance of individual components, perceived facilitators and barriers, to the implementation and sustainability of these pathways.

Immunological Evaluation of Pediatric Patients with Polyautoimmunity.

BACKGROUND: Autoimmunity can be the first or predominant manifestation in patients with primary immunodeficiency disorder, also referred to as inborn errors of immunity (IEI). This study aims to evaluate the immune status of pediatric patients with polyautoimmunity to identify those with underlying immune defects. METHODS: In this cross-sectional study, pediatric patients with polyautoimmunity including at least one confirmed autoimmune endocrine disease were enrolled. Demographic and clinical data were collected using a questionnaire based on medical records and direct family interviews. For each patient, a basic immunologic evaluation was performed. The clinical diagnosis was established according to the criteria of the European Society for Immunodeficiencies (ESID). Based on the presence or absence of a history of severe and/or recurrent infections, patients were divided into two groups for comparison. RESULTS: Thirty-nine patients, 18 males (46.2%) and 21 females (53.8%), were included. Fourteen patients (35.9%) had consanguineous parents. Fifteen patients (38.5%) had a history of severe and/or recurrent infections. The median (interquartile range: IQR) age of our patients at the time of evaluation was 11.1 (9-16) years. The median (IQR) age at the onset of infections and autoimmunities were 3 (1-10.8) and 5 (2.6-8) years, respectively. The most common infectious complications reported were pneumonia and candidiasis, each in 12.8% of the patients. The most prevalent autoimmune disorders were type 1 diabetes (74.3%) and autoimmune thyroiditis (58.9%). IEI was diagnosed in six patients (15.38%), five of which were from the group with severe or recurrent infections: three with selective IgA deficiency, two with common variable immunodeficiency (CVID), and one with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), but without a history of infections. CONCLUSION: The occurrence of early onset polyautoimmunity in association with severe and/or recurrent infections or in patients with a positive family history should be a warning sign for physicians to initiate an evaluation for possible immunodeficiency disorders to prevent complications through early treatment.

CD5 B-Cell Predominant Primary Immunodeficiency: Part of the Spectrum of MAGT1 Deficiency.

Background: Selective anti-polysaccharide antibody deficiency (SPAD) with CD5 B-cell predominance and autoimmune phenomena was identified in a male cohort first reported by Antall et al in 1999. The phenotypically likewise and genotypically identical X-linked immunodeficiency with magnesium defect, Epstein-Barr Virus infection, and neoplasia (XMEN) disease was defined as a novel primary immunodeficiency (PID) in 2011. Recent studies of the magnesium transporter 1 (MAGT1) gene mutation reveal glycosylation defects contributing to more phenotypic variance than the "XMEN" title pathologies. The updated title, "X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect," was proposed in 2020. Objectives: To reflect the patient population more accurately, a prospective classification update may consider MAGT1 glycobiological errors contributing to phenotypic variance but also pre-genetic testing era reports with CD5 B-cell predominance. Methods: Patient 1 from Antall et al presented at 28 years of age for further immunological evaluation of his CD5/CD19 B-cell predominance diagnosed at 5 years old. Design: Immune re-evaluation done through flow cytometry and next-generation sequencing. Results: Flow cytometry B-cell phenotyping revealed persistent CD5+CD19+ (93%). Flow cytometric histogram quantified reduced activator CD16+CD56+ natural killer and CD8+ T-cell receptor, Group 2, Member D (NKG2D) glycoprotein expression. A c.923-1_934 deletion loss of function mutation was identified in the MAGT1 gene. Conclusion: We suggest the novel PID XMEN, based on its CD5 B-cell predominance, had been discovered and reported over a decade earlier as CD5+ PID based on the MAGT1 mutation found in the same. We encourage consideration of combining these labels and recent findings to offer the most accurate classification of this disease.

Symptom and Treatment Satisfaction in Members of the US and Canadian GBS/CIDP Foundations with a Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy.

INTRODUCTION: Current guidelines for defining good outcomes in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) are predominately defined by experts. At present, we do not have a patient-anchored definition of what constitutes a "good" outcome. Our study aimed to assess the symptom burden of people living with CIDP, as well as satisfaction with treatments and clinical outcomes. METHODS: We conducted an online-survey in CIDP patients registered with the US and Canadian GBS/CIDP foundations. Respondents answered general demographic and clinical questions, as well as satisfaction with current symptom burden and treatments, plus validated outcome measures. RESULTS: A total of 318 individuals with self-reported CIDP completed the online survey, of whom 128 (40%) considered their current disease burden as satisfactory while 190 (60%) did not. Of 305 patients who answered the treatment satisfaction question, 222(74%) were satisfied with their treatments. Patients who were satisfied with their current symptoms had, on average, better scores in quality of life and disease severity scales, although regression modeling showed that only ability to walk, stable symptoms, and health utility scores were associated with symptom satisfaction. Treatment satisfaction was associated with stable symptoms, use of IVIG, and use of one versus no medication. CONCLUSIONS: A high proportion of members of the US and Canadian GBS/CIDP Foundations reporting a diagnosis of CIDP were unsatisfied with current symptoms, despite a high level of overall satisfaction with treatments. There is an unmet need for improving long-term outcomes in people with a diagnosis of CIDP, and for studying patient-centered long-term treatment goals.

Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: a systems biology approach.

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) severity due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, and chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health and disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 severity (71 mild, 61 moderate, and 27 with severe symptoms) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multiple linear regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid ß peptide, ß catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition and hierarchical clustering analysis based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe COVID-19 patients ≥50 years of age. Follow-up analysis using binomial logistic regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies significantly increased the likelihood of developing a severe COVID-19 phenotype with aging. These findings provide key insights to explain why aging increases the chance of developing more severe COVID-19 phenotypes.

Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Recurarization with magnesium sulfate administered after two minutes sugammadex reversal: A randomized, double-blind, controlled trial.

STUDY OBJECTIVE: The current study tested the hypothesis that magnesium sulfate after reversal with sugammadex causes recurarization. DESIGN: A single-center, prospective, randomized, double-blind, controlled trial. SETTING: Terciary care hospital in Rio de Janeiro, Brazil. PATIENTS: Included 60 patients undergoing for elective otolaryngological surgery. INTERVENTIONS: All patients received total intravenous anesthesia and a single dose of rocuronium (0.6 mg/kg). In 30 patients, the neuromuscular blockade was reversed with sugammadex (4 mg/kg) at the reappearance of one or two posttetanic counts (deep-blockade series). In 30 other patients, sugammadex (2 mg/kg) was administered at the reappearance of the second twitch of the train-of-four (moderate-blockade series). After the normalized train-of-four ratio recovered to ≥0.9, the patients in each series were randomized to receive intravenous magnesium sulfate (60 mg/kg) or placebo for 10 min. Neuromuscular function was measured by acceleromyography. MEASUREMENTS: The primary outcome was the number of patients who exhibited recurarization (normalized train-of-four ratio < 0.9). The secondary outcome was rescue with an additional dose of sugammadex after 60 min. MAIN RESULTS: In the deep-blockade series, a normalized train-of-four ratio < 0.9 occurred in 9/14 (64%) patients receiving magnesium sulfate and 1/14 (7%) receiving placebo, RR 9.0 (95% CI: 62-1.30), and (p = 0.002), with four rescues with sugammadex. In the moderate-blockade series, neuromuscular blockade recurred in 11/15 (73%) patients receiving magnesium sulfate and in 0/14 (0%) receiving placebo (p < 0.001), with two rescues. The absolute differences in recurarization were 57% and 73% in the deep-blockade and moderate-blockade, respectively. CONCLUSIONS: Single-dose magnesium sulfate led to a normalized train-of-four ratio < 0.9, 2 min after recovery from rocuronium-induced deep and moderate neuromuscular blockade using sugammadex. Additional sugammadex reversed prolonged recurarization.

Enhanced Recovery After Surgery and Elderly Patients: Advances.

Enhanced recovery after surgery (ERAS) is a new way of working where evidence-based care elements are assembled to form a care pathway involving the patient's entire journey through surgery. Many elements included in ERAS have stress-reducing effects on the body or helps avoid side effects associated with alternative treatment options. This leads to less overall stress from the injury caused by the operation and helps facilitate recovery. In old, frail patients with concomitant diseases and less physical reserves, this may help explain why the ERAS care is reported to be beneficial for this specific patient group.