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We present the analytic evaluation of the two-loop corrections to the amplitude for the scattering of four fermions in Quantum Electrodynamics, \\(f^- + f^+ + F^- + F^+ \\to 0\\), with \\(f\\) and \\(F\\) representing a massless and a massive lepton, respectively. Dimensional regularization is employed to evaluate the loop integrals. Ultraviolet divergences are removed by renormalizing the coupling constant in the \\({\\overline{\\text{MS}}}\\)-scheme, and the lepton mass as well as the external fields in the on-shell scheme. The analytic result for the renormalized amplitude is expressed as Laurent series around \\(d=4\\) space-time dimensions, and contains Generalized Polylogarithms with up to weight four. The structure of the residual infrared divergences of the virtual amplitude is in agreement with the prediction of the Soft Collinear Effective Theory. Our analytic results are an essential ingredient for the computation of the scattering cross section for massive fermion-pair production in massless fermion-pair annihilation, i.e. \\(f^- f^+ \\to F^- F^+\\), and crossing related processes such as the elastic scattering \\(f F \\to f F\\), with up to Next-to-Next to Leading Order accuracy.

The mini-proceedings of the STRONG2020 Virtual Workshop \"Space-like and Time-like determination of the Hadronic Leading Order contribution to the Muon \\(g-2\\)\", November 24--26 2021, are presented. This is the first workshop of the STRONG2020 WP21: JRA3-PrecisionSM: Precision Tests of the Standard Model (http://www.strong-2020.eu/joint-research-activity/jra3-precisionsm.html). The workshop was devoted to review of the working group activitity on: \\((\\it i)\\) Radiative Corrections and Monte Carlo tools for low-energy hadronic cross sections in \\(e^+ e^-\\) collisions; \\((\\it ii)\\) Annotated database for \\(e^+e^-\\) into hadrons processes at low energy; \\((\\it iii)\\) Radiative Corrections and Monte Carlo tools for \\(\\mu\\)-\\(e\\) elastic scattering.

To dissect the genotype-phenotype landscape of a cell, it is necessary to understand interactions between genes. Building on the digenic protein-protein interaction network, Kuzmin et al. created a trigenic landscape of yeast by using a synthetic genetic array (see the Perspective by Walhout). Triple-mutant analyses indicated that the majority of genes with trigenic associations functioned within the same biological processes. These converged on networks identified in the digenic interaction landscape. Although the overall effects were weaker for trigenic than for digenic interactions, trigenic interactions were more likely to bridge biological processes in the cell. Science , this issue p. eaao1729 ; see also p. 269 Trigenic interactions in yeast link bioprocesses are explored. To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic interaction network and tested for a genetic interaction with a third mutation. Trigenic interactions often occurred among functionally related genes, and essential genes were hubs on the trigenic network. Despite their functional enrichment, trigenic interactions tended to link genes in distant bioprocesses and displayed a weaker magnitude than digenic interactions. We estimate that the global trigenic interaction network is ~100 times as large as the global digenic network, highlighting the potential for complex genetic interactions to affect the biology of inheritance, including the genotype-to-phenotype relationship.

The genetic background of an organism can influence the overall effects of new genetic variants. Some mutations can amplify a deleterious phenotype, whereas others can suppress it. Starting with a literature survey and expanding into a genomewide assay, van Leeuwen et al. generated a large-scale suppression network in yeast. The data set reveals a set of general properties that can be used to predict suppression interactions. Furthermore, the study provides a template for extending suppression studies to other genes or to more complex organisms. Science , this issue p. 599 A large-scale study in yeast reveals how defects associated with a mutation in one gene can be compensated for by a second mutation in a suppressor gene. Genetic suppression occurs when the phenotypic defects caused by a mutation in a particular gene are rescued by a mutation in a second gene. To explore the principles of genetic suppression, we examined both literature-curated and unbiased experimental data, involving systematic genetic mapping and whole-genome sequencing, to generate a large-scale suppression network among yeast genes. Most suppression pairs identified novel relationships among functionally related genes, providing new insights into the functional wiring diagram of the cell. In addition to suppressor mutations, we identified frequent secondary mutations,in a subset of genes, that likely cause a delay in the onset of stationary phase, which appears to promote their enrichment within a propagating population. These findings allow us to formulate and quantify general mechanisms of genetic suppression.

BackgroundPrimary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes. Evaluation of podocyte B7-1 expression and treatment with abatacept (a B7-1 antagonist) has shown promise but remains controversial.MethodsFrom 2012 to 2020, twelve patients developed post-KT FSGS with nephrotic range proteinuria, failed conventional therapy, and were treated with abatacept. Nine/twelve (< 21 years old) experienced recurrent FSGS; three adults developed de novo FSGS, occurring from immediately, up to 8 years after KT. KT biopsies were stained for B7-1.ResultsNine KTRs (75%) responded to abatacept. Seven of nine KTRs were B7-1 positive and responded with improvement/resolution of proteinuria. Two patients with rFSGS without biopsies resolved proteinuria after abatacept. Pre-treatment UPCR was 27.0 ± 20.4 (median 13, range 8–56); follow-up UPCR was 0.8 ± 1.3 (median 0.2, range 0.07–3.9, p < 0.004). Two patients who were B7-1 negative on multiple KT biopsies did not respond to abatacept and lost graft function. One patient developed proteinuria while receiving belatacept, stained B7-1 positive, but did not respond to abatacept.ConclusionsPodocyte B7-1 staining in biopsies of KTRs with post-transplant FSGS identifies a subset of patients who may benefit from abatacept.A higher resolution version of the Graphical abstract is available as Supplementary information

We generated a global genetic interaction network for Saccharomyces cerevisiae , constructing more than 23 million double mutants, identifying about 550,000 negative and about 350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell.

More favorable clinical outcomes with medium‐term follow‐up have been reported among kidney transplant recipients receiving maintenance therapy consisting of “reduced‐tacrolimus (TAC) dosing,” mycophenolate mofetil (MMF), and low‐dose corticosteroids. However, it is not clear whether long‐term maintenance therapy with reduced‐calcineurin inhibitor (CNI) dosing still leads to reduced renal function. A prospectively followed cohort of 150 kidney transplant recipients randomized to receive TAC/sirolimus (SRL) versus TAC/MMF versus cyclosporine microemulsion (CSA)/SRL, plus low‐dose maintenance corticosteroids, now has 20 years of post‐transplant follow‐up. Average CNI trough levels over time among patients who were still alive with functioning grafts at 60, 120, and 180 months post‐transplant were determined and ranked from smallest‐to‐largest for both TAC and CSA. Stepwise linear regression was used to determine whether these ranked average trough levels were associated with the patient's estimated glomerular filtration rate (eGFR) at those times, particularly after controlling for other significant multivariable predictors. Experiencing biopsy‐proven acute rejection (BPAR) and older donor age were the two most significant multivariable predictors of poorer eGFR at 60, 120, and 180 months post‐transplant ( p < 000001 and 0.000003 for older donor age at 60 and 120 months; p = 0.00008 and <0.000001 for previous BPAR at 60 and 120 months). Assignment to CSA also implied a significantly poorer eGFR (but with less magnitudes of effect) in multivariable analysis at 60 and 120 months ( p = 0.01 and 0.002). Higher ranked average CNI trough levels had no association with eGFR at any timepoint in either univariable or multivariable analysis ( p > 0.70). Long‐term maintenance therapy with reduced‐CNI dosing does not appear to cause reduced renal function.

Solid Organ Transplant (SOT) recipients are at significant higher risk for COVID-19 and due to immunosuppressive medication, the immunogenicity after vaccination is suboptimal. In the previous studies, booster method showed significant benefit in this population. In the current study, we compared using a mix-and-match method vs. same vaccine as a third dose in SOT recipients. This was a patient-blinded, single center, randomized controlled trial comparing BNT162b2 vs. JNJ-78436735 vaccine as the third dose after two doses of BNT162b2 vaccine. We included adult SOT recipients with functional graft who had received two doses of BNT162b2 vaccine. Participants were randomly assigned to receive either BNT162b2 or JNJ-78436735 in one-to-one ratio. Primary outcome was SARS-CoV-2 IgG positivity at 1 month after the third dose. Sixty SOT recipients, including 36 kidney, 12 liver, 2 lung, 3 heart, and 5 combined transplants, were enrolled, and 57 recipients were analyzed per protocol. There were no statistically significant differences between the two vaccine protocols for IgG positivity (83.3% vs. 85.2% for BNT162b2 and JNJ-78436735, respectively, p = 0.85, Odds Ratio 0.95, 95% Confidence Interval 0.23–4.00). Comparison of the geometric mean titer demonstrated a higher trend with BNT162b2 ( p = 0.09). In this pilot randomized controlled trial comparing mix and match method vs. uniform vaccination in SOT recipients, both vaccines were safely used. Since this was a small sample sized study, there was no statistically significant difference in immunogenicity; though, the mix and match method showed relatively lower geometric mean titer, as compared to uniform vaccine. Further studies need to be conducted to determine duration of this immunogenicity. Clinical Trial Registration : https://clinicaltrials.gov/ct2/show/NCT05047640?term=20210641&draw=2&rank=1 , identifier 20210641.

ObjectiveTo compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses.MethodsFrom the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression.ResultsOf 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an ‘early’ second IVIg course (1–2 weeks after start of the first IVIg course) and 18 patients a ‘late’ second IVIg course (2–4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course.ConclusionsThis observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.

Aims/hypothesis To better understand the implications of new-onset diabetes after transplant (NODAT), we used our prospectively followed cohort of 628 adult primary kidney transplant recipients to determine the prognostic impact of pretransplant diabetes and NODAT. Methods The study cohort consisted of all participants in four randomised immunosuppression trials performed at our centre since May 2000. For each cause-specific hazard analysed, Cox stepwise regression was used to determine a multivariable model of significant baseline predictors; the multivariable influence of having pretransplant diabetes and NODAT (t) (the latter defined as a zero-one, time-dependent covariate) was subsequently tested. Similar analyses of estimated glomerular filtration rate (eGFR) at 36 and 60 months post transplant were performed using stepwise linear regression. Finally, a repeated measures analysis of mean HbA 1c as a function of diabetes category (pretransplant diabetes vs NODAT) and randomised trial (first to fourth) was performed. Results Median follow-up was 56 months post transplant. Patients with pretransplant diabetes comprised 23.4% (147/628), and 22.5% (108/481) of the remaining patients developed NODAT. Pretransplant diabetes had no prognostic influence on first biopsy-proven acute rejection and death-censored graft failure hazard rates, nor on eGFR, but was associated with significantly higher rates of death with a functioning graft (DWFG) ( p  = 0.003), DWFG due to a cardiovascular event ( p  = 0.005) and infection that required hospitalisation ( p  = 0.03). NODAT (t) had no unfavourable impact on any of these hazard rates nor on eGFR, with actuarial freedom from DWFG remaining at over 90% among patients in pre- and post-NODAT states at 72 months post transplant/NODAT. Mean HbA 1c for patients in the first to fourth randomised trials, averaged across diabetes category, decreased by trial (7.28%, 6.92%, 6.87% and 6.64% [56.1, 52.1, 51.6 and 49.1 mmol/mol], respectively; p  = 0.02). Conclusions/interpretation Less-than-expected post-NODAT risk for graft loss and death may exist in the current climate of tighter glucose monitoring post transplant.