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BACKGROUND: Muscle-specific tyrosine kinase (MuSK) autoantibody-positive (Ab+) generalised myasthenia gravis (gMG) is a rare and frequently severe subtype of gMG. OBJECTIVES: To assess the efficacy and safety of rozanolixizumab in the subgroup of patients with MuSK Ab+ gMG in the MycarinG study. DESIGN: A randomised, double-blind, placebo-controlled phase III study. METHODS: Patients with acetylcholine receptor (AChR) Ab+ or MuSK Ab+ gMG (aged ⩾18 years, Myasthenia Gravis Foundation of America Disease Class II-IVa, Myasthenia Gravis Activities of Daily Living [MG-‍ADL] score ⩾3.0 [non-ocular symptoms], Quantitative Myasthenia Gravis score ⩾11.0) were randomly assigned (1:1:1) to receive once-weekly subcutaneous infusions of rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg or placebo for 6 weeks, followed by an 8-week observation period. Randomisation was stratified by AChR and MuSK autoantibody status. The primary study endpoint was change from baseline to Day 43 in MG-ADL score. Treatment-emergent adverse events (TEAEs) were also assessed. RESULTS: Overall, 200 patients were randomised, of whom 21 had MuSK Ab+ gMG and received rozanolixizumab 7 mg/kg (n = 5), 10 mg/kg (n = 8) or placebo (n = 8). In patients with MuSK Ab+ gMG, reductions from baseline to Day 43 in MG-ADL scores were observed: rozanolixizumab 7 mg/kg least squares mean (LSM) change (standard error), -7.28 (1.94); 10 mg/kg, -4.16 (1.78); and placebo, 2.28 (1.95). Rozanolixizumab 7 mg/kg LSM difference from placebo was -9.56 (97.5% confidence interval: -15.25, -3.87); 10 mg/kg, -6.45 (-11.03, -1.86). TEAEs were experienced by four (80.0%), five (62.5%) and three (37.5%) patients with MuSK Ab+ gMG receiving rozanolixizumab 7 mg/kg, 10 mg/kg and placebo, respectively. No patients experienced serious TEAEs. No deaths occurred. CONCLUSION: This subgroup analysis of adult patients with MuSK Ab+ gMG enrolled in the MycarinG study supports the use of rozanolixizumab as an effective treatment option for patients with gMG who have MuSK autoantibodies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03971422 (https://clinicaltrials.gov/study/NCT03971422); EU Clinical Trials Register: EudraCT 2019-000968-18 (https://www.clinicaltrials‌register.eu/ctr-search/trial/2019-000968-18/GB).

Abstract In the last two decades, an exponentially growing number of meta-analyses (MAs) synthesize thousands of peer-reviewed studies on the environmental impacts of farming practices (FPs). This paper describes the iMAP-FP evidence library, a comprehensive dataset on the effects of 34 categories of FPs (such as agronomic practices, cropping and livestock systems, land management options and mitigation techniques) on 34 impacts including climate mitigation, soil health, environmental pollution, water use, nutrients cycling, biodiversity, and agricultural productivity. Through systematic screening, 570 MAs published since 2000 were selected and categorized according to the type of FP. We assessed their impacts, the geographic regions covered, and their quality. We extracted 3,811 effects and their statistical significance associated with sustainable FPs (intervention) compared to a control (typically conventional agriculture) across 223 different intervention-control pairs. Our dataset is accompanied with an online free-access library, which includes a catalogue of synthetic reports summarizing the available evidence on each evaluated FP.

ABSTRACTProbiotics are exploited for adjuvant treatment in IBS, but reliable guidance for selecting the appropriate probiotic to adopt for different forms of IBS is lacking. We aimed to identify markers for recognizing non-constipated (NC) IBS patients that may show significant clinical improvements upon treatment with the probiotic strain Lacticaseibacillus paracasei DG (LDG). To this purpose, we performed a post-hoc analysis of samples collected during a multicenter, double-blind, parallel-group, placebo-controlled trial in which NC-IBS patients were randomized to receive at least 24 billion CFU LDG or placebo capsules b.i.d. for 12 weeks. The primary clinical endpoint was the composite response based on improved abdominal pain and fecal type. The fecal microbiome and serum markers of intestinal (PV1 and zonulin), liver, and kidney functions were investigated. We found that responders (R) in the probiotic arm (25%) differed from non-responders (NR) based on the abundance of 18 bacterial taxa, including the families Coriobacteriaceae, Dorea spp. and Collinsella aerofaciens, which were overrepresented in R patients. These taxa also distinguished R (but not NR) patients from healthy controls. Probiotic intervention significantly reduced the abundance of these bacteria in R, but not in NR. Analogous results emerged for C. aerofaciens from the analysis of data from a previous trial on IBS with the same probiotic. Finally, C. aerofaciens was positively correlated with the plasmalemmal vesicle associated protein-1 (PV-1) and the markers of liver function. In conclusion, LDG is effective on NC-IBS patients with NC-IBS with a greater abundance of potential pathobionts. Among these, C. aerofaciens has emerged as a potential predictor of probiotic efficacy.

Abstract In this paper we propose a physical derivation of a 4d conjectural duality for USp(2N) with an anti-symmetric rank-two tensor and fundamental flavors, in presence of a non-trivial superpotential. This duality has been conjectured as a consequence of an exact identity between the superconformal indices of the two phases, proved in the mathematical literature. Here we show that the duality can be derived by a combined sequence of known dualities, deconfinement of tensor matter, RG flow and Higgsing. Furthermore, by following these steps on the superconformal index, we provide an alternative derivation of the integral identity as well.

Abstract In this paper we give a field theory explanation of two confining dualities that have been proposed in the literature based on exact results from supersymmetric localization. The first confining model under investigation is 4d SU(N c + 1) SQCD with a conjugate rank-2 anti-symmetric tensor, N c + 3 anti-fundamentals, 2N c fundamentals and a superpotential that couples the anti-symmetric tensor and the fundamentals. The second confining model studied here is 3d N $$ \mathcal{N} $$ = 2 USp(4) gauge SQCD with two fundamentals, two rank-2 anti-symmetric tensors and vanishing superpotential. Here we prove that these models are confining by using the technique of deconfining the anti-symmetric tensors and then by flowing to the IR description by sequential dualities. As a bonus the analysis provides (alternative) proofs of the identities obtained from supersymmetric localization.

Abstract Background Since the beginning of the anti-COVID-19 vaccination campaign, it has become evident that vaccinated subjects exhibit considerable inter-individual variability in the response to the vaccine that could be partly explained by host genetic factors. A recent study reported that the immune response elicited by the Oxford-AstraZeneca vaccine in individuals from the United Kingdom was influenced by a specific allele of the human leukocyte antigen gene HLA-DQB1. Methods We carried out a genome-wide association study to investigate the genetic determinants of the antibody response to the Pfizer-BioNTech vaccine in an Italian cohort of 1351 subjects recruited in three centers. Linear regressions between normalized antibody levels and genotypes of more than 7 million variants was performed, using sex, age, centers, days between vaccination boost and serological test, and five principal components as covariates. We also analyzed the association between normalized antibody levels and 204 HLA alleles, with the same covariates as above. Results Our study confirms the involvement of the HLA locus and shows significant associations with variants in HLA-A, HLA-DQA1, and HLA-DQB1 genes. In particular, the HLA-A*03:01 allele is the most significantly associated with serum levels of anti-SARS-CoV-2 antibodies. Other alleles, from both major histocompatibility complex class I and II are significantly associated with antibody levels. Conclusions These results support the hypothesis that HLA genes modulate the response to Pfizer-BioNTech vaccine and highlight the need for genetic studies in diverse populations and for functional studies aimed to elucidate the relationship between HLA-A*03:01 and CD8+ cell response upon Pfizer-BioNTech vaccination.

In questo lavoro intendiamo presentare, almeno in parte, l’imponente intreccio di idee, tecniche e concetti che si è sviluppato intorno alla congettura di Poincaré, dalla sua formulazione agli inizi del secolo scorso fino alla soluzione data da Grisha Perelman agli inizi del nuovo millennio, portando a compimento il programma basato sullo studio del flusso di Ricci, delineato e sviluppato da Richard Hamilton dagli anni '80. Pur nei limiti e nelle possibilità di un articolo di rassegna, si è voluto presentare in modo matematicamente compiuto almeno alcune delle nozioni ed idee cruciali, a partire dalla formulazione stessa della congettura, disponendo soltanto di nozioni di base di algebra lineare, geometria e calcolo differenziale negli spazi euclidei, che si suppongono familiari al lettore. Ne risulterà probabilmente una lettura “impegnativa”, non necessariamente “ricreativa”, che però, almeno nelle intenzioni degli autori, dovrebbe ripagare il lettore con un'immagine piuttosto fedele di questi formidabili processi intellettuali, individuali e collettivi, che compongono una delle pagine più belle e profonde della storia della matematica.

Background: Muscle-specific tyrosine kinase (MuSK) autoantibody-positive (Ab+) generalised myasthenia gravis (gMG) is a rare and frequently severe subtype of gMG. Objectives: To assess the efficacy and safety of rozanolixizumab in the subgroup of patients with MuSK Ab+ gMG in the MycarinG study. Design: A randomised, double-blind, placebo-controlled phase III study. Methods: Patients with acetylcholine receptor (AChR) Ab+ or MuSK Ab+ gMG (aged ⩾18 years, Myasthenia Gravis Foundation of America Disease Class II–IVa, Myasthenia Gravis Activities of Daily Living [MG-‍ADL] score ⩾3.0 [non-ocular symptoms], Quantitative Myasthenia Gravis score ⩾11.0) were randomly assigned (1:1:1) to receive once-weekly subcutaneous infusions of rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg or placebo for 6 weeks, followed by an 8-week observation period. Randomisation was stratified by AChR and MuSK autoantibody status. The primary study endpoint was change from baseline to Day 43 in MG-ADL score. Treatment-emergent adverse events (TEAEs) were also assessed. Results: Overall, 200 patients were randomised, of whom 21 had MuSK Ab+ gMG and received rozanolixizumab 7 mg/kg ( n = 5), 10 mg/kg ( n = 8) or placebo ( n = 8). In patients with MuSK Ab+ gMG, reductions from baseline to Day 43 in MG-ADL scores were observed: rozanolixizumab 7 mg/kg least squares mean (LSM) change (standard error), –7.28 (1.94); 10 mg/kg, –4.16 (1.78); and placebo, 2.28 (1.95). Rozanolixizumab 7 mg/kg LSM difference from placebo was −9.56 (97.5% confidence interval: −15.25, −3.87); 10 mg/kg, −6.45 (−11.03, –1.86). TEAEs were experienced by four (80.0%), five (62.5%) and three (37.5%) patients with MuSK Ab+ gMG receiving rozanolixizumab 7 mg/kg, 10 mg/kg and placebo, respectively. No patients experienced serious TEAEs. No deaths occurred. Conclusion: This subgroup analysis of adult patients with MuSK Ab+ gMG enrolled in the MycarinG study supports the use of rozanolixizumab as an effective treatment option for patients with gMG who have MuSK autoantibodies. Trial registration: ClinicalTrials.gov: NCT03971422 ( https://clinicaltrials.gov/study/NCT03971422 ); EU Clinical Trials Register: EudraCT 2019-000968-18 ( https://www.clinicaltrials‌register.eu/ctr-search/trial/2019-000968-18/GB ).

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22–3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Anna Schwesinger,1,* Li-Tang Tsai,1,* Wei Lang,1 Noemi Mantegazza,1 Robert Bauernschmitt,2 Markus Johannes Wilhelm,2 Heike Annette Bischoff-Ferrari,1,3,4 Michael Gagesch1,5,6 1Center on Aging and Mobility, University of Zurich, Zurich, Switzerland; 2Clinic for Cardiac Surgery, University Hospital Zurich, Zurich, Switzerland; 3Department of Geriatrics and Aging Research, University of Zurich, Zurich, Switzerland; 4IHU HealthAge, University Hospital Toulouse and University Toulouse III Paul Sabatier, Toulouse, France; 5Department of Aging Medicine, University Hospital Zurich, Zurich, Switzerland; 6University Clinic of Aging Medicine, Zurich City Hospital, Zurich, Switzerland*These authors contributed equally to this workCorrespondence: Michael Gagesch, University Clinic for Aging Medicine, Zurich City Hospital, Tièchestrasse 99, 8037 Zürich, Switzerland, Tel +41 44 417 31 98, Email michael.gagesch@stadtspital.chPurpose: Postoperative delirium (POD) after transcatheter aortic valve implantation (TAVI) is frequent in older adults and associated with multiple negative outcomes including a higher mortality. We aimed to investigate whether a comprehensive geriatric assessment (CGA) prior to TAVI reduces the odds of POD and results in a positive change in self-care ability, intended to lay a foundation for future geriatric comanagement.Patients and methods: We used a retrospective, single-center study with a quasi-experimental design enrolling patients aged 70 years and older undergoing CGA before elective TAVI, and a nonrandomized comparison group without preoperative CGA. Data on POD occurrence during the first 5 days after TAVI (primary outcome) and change in self-care ability index (SPI) between admission and discharge (secondary outcome) were collected from electronic health records and CGA data (exposure) by clinical assessment. To explore associations between (1) CGA and POD, and (2) CGA and SPI, multivariate logistic regression and linear regression models were applied adjusting for age, sex, BMI, and number of medications.Results: Among 435 patients (mean age 81.0 ± 5.6 years, 43.6% women, median [IQR] SPI at baseline 40 [39, 40] points), POD incidence was 14.3% in the CGA group vs 18.8% in the non-CGA group (P 0.219). Undergoing CGA before TAVI was not associated with the odds for POD (OR: 1.15; 95%CI: 0.65– 2.04) or improved SPI (P 0.073).Conclusion: We observed no association of CGA prior to TAVI with POD incidence or postoperative self-care, highlighting the need for additional studies investigating the effect of POD preventive measures in older TAVI patients integrated into a comprehensive geriatric comanagement program.Keywords: POPS, frail older adults, perioperative care, aortic stenosis, TAVI, delirium