The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T‐cell‐mediated rejection (ACMR), while only tentatively ...addressing issues pertaining to antibody‐mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad‐based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor‐specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.
A multidisciplinary panel makes recommendations for the clinicopathological diagnosis of acute and chronic antibody mediated rejection in the pancreas and updates the Banff pancreas rejection grading schema published in 2008.
Background
Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS HIPEC) can offer significant survival advantage for select patients with colorectal peritoneal metastases (CRPM). ...Low socioeconomic status (SES) is implicated in disparities in access to care. We analyze the impact of SES on postoperative outcomes and survival at a high-volume tertiary CRS HIPEC center.
Patients and Methods
We conducted a retrospective cohort study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Patients were grouped according to SES. Baseline characteristics, perioperative outcomes, and survival were examined between groups.
Results
A total of 226 patients were analyzed, 107 (47%) low-SES and 119 (53%) high-SES patients. High-SES patients were younger (52 vs. 58 years,
p
= 0.01) and more likely to be White (95.0% vs. 91.6%,
p
= 0.06) and privately insured (83% vs. 57%,
p
< 0.001). They traveled significantly further for treatment and had lower burden of comorbidities and frailty (
p
= 0.01). Low-SES patients more often presented with synchronous peritoneal metastases (48% vs. 35%,
p
= 0.05). Following CRS HIPEC, low-SES patients had longer length of stay and higher burden of postoperative complications, 90-day readmission, and 30-day mortality. Median overall survival following CRS HIPEC was worse for low-SES patients (17.8 vs. 32.4 months,
p
= 0.02). This disparity persisted on multivariate survival analysis (low SES: HR = 1.46,
p
= 0.03).
Conclusions
Despite improving therapies for CRPM, low-SES patients remain at a significant disadvantage. Even patients who overcome barriers to care experience worse short- and long-term outcomes. Improving access and addressing these disparities is crucial to ensure equitable outcomes and improve patient care.
This study assessed whether circulating levels of adiponectin and leptin are associated with higher mortality in patients with RA.
Participants were adults from the Veterans Affairs RA Registry. ...Adipokines and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum at enrolment. Dates and causes of death were derived from the Corporate Data Warehouse and the National Death Index. Covariates were derived from medical record, biorepository and registry databases. Multivariable Cox proportional hazard models evaluated associations between biomarkers and all-cause and cause-specific mortality.
A total of 2583 participants were included. Higher adiponectin levels were associated with older age, male sex, white race, lower BMI, autoantibody seropositivity, radiographic damage, longer disease duration, prednisone use and osteoporosis. Higher adiponectin concentrations were also associated with higher levels of inflammatory cytokines but not higher disease activity at enrolment. Leptin was primarily associated with greater BMI and comorbidity. The highest quartile of adiponectin (vs lowest quartile) was associated with higher all-cause mortality hazard ratio (HR): 1.46 (95% CI: 1.11, 1.93), P = 0.009 and higher cardiovascular mortality HR: 1.85 (95% CI: 1.24, 2.75), P = 0.003, after accounting for covariates. Higher leptin levels were also associated with greater all-cause and cancer mortality.
Elevations in adipokines are associated with age, BMI, comorbidity and severe disease features in RA and independently predict early death. Associations between adiponectin and inflammatory cytokines support the hypothesis that chronic subclinical inflammation promotes metabolic changes that drive elevations in adipokines and yield adverse health outcomes.
Highlights • Inflammation promotes catecholamine-driven immune suppression. • COX-2 blockade prevents the induction of suppressive factors by epinephrine. • COX-2 blockade counteracts suppressive ...activity of epinephrine-treated macrophages. • Our data suggest that COX-2 blockade may reduce the immunosuppressive effects of psychologic stress.
Phys. Rev. Lett. 127, 062003 (2021) We describe an analysis comparing the $p\bar{p}$ elastic cross section as
measured by the D0 Collaboration at a center-of-mass energy of 1.96 TeV to that
in $pp$ ...collisions as measured by the TOTEM Collaboration at 2.76, 7, 8, and 13
TeV using a model-independent approach. The TOTEM cross sections extrapolated
to a center-of-mass energy of $\sqrt{s} =$ 1.96 TeV are compared with the D0
measurement in the region of the diffractive minimum and the second maximum of
the $pp$ cross section. The two data sets disagree at the 3.4$\sigma$ level and
thus provide evidence for the $t$-channel exchange of a colorless, $C$-odd
gluonic compound, also known as the odderon. We combine these results with a
TOTEM analysis of the same $C$-odd exchange based on the total cross section
and the ratio of the real to imaginary parts of the forward elastic scattering
amplitude in $pp$ scattering. The combined significance of these results is
larger than 5$\sigma$ and is interpreted as the first observation of the
exchange of a colorless, $C$-odd gluonic compound.
The fields of particle and nuclear physics have undertaken extensive programs to search for evidence of physics beyond that explained by current theories. The observation of the Higgs boson at the ...Large Hadron Collider completed the set of particles predicted by the Standard Model (SM), currently the best description of fundamental particles and forces. However, the theory's limitations include a failure to predict fundamental parameters and the inability to account for dark matter/energy, gravity, and the matter-antimater asymmetry in the universe, among other phenomena. Given the lack of additional particles found so far through direct searches in the post-Higgs era, indirect searches utilizing precise measurements of well predicted SM observables allow highly targeted alternative tests for physics beyond the SM. Indirect searches have the potential to reach mass/energy scales beyond those directly accessible by today's high-energy accelerators. The value of the weak charge of the proton Q_W^p is an example of such an indirect search, as it sets the strength of the proton's interaction with particles via the well-predicted neutral electroweak force. Parity violation (invariance under spatial inversion (x,y,z) -> (-x,-y,-z)) is violated only in the weak interaction, thus providing a unique tool to isolate the weak interaction in order to measure the proton's weak charge. Here we report Q_W^p=0.0719+-0.0045, as extracted from our measured parity-violating (PV) polarized electron-proton scattering asymmetry, A_ep=-226.5+-9.3 ppb. Our value of Q_W^p is in excellent agreement with the SM, and sets multi-TeV-scale constraints on any semi-leptonic PV physics not described within the SM.
Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require ...immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis.
Amyotrophic lateral sclerosis (ALS) is an untreatable, progressive, neurodegenerative disease specifically affecting motor neurons. Recently, the tyrosine kinase receptor EphA4 was directly ...implicated in ALS disease progression. We report that a long-lived mutated form of the EphA4 antagonist EphA4-Fc (mutEphA4-Fc), which blocks EphA4 binding to its ligands and inhibits its function, significantly improved functional performance in SOD1G93A ALS model mice, as assessed by rotarod and hind-limb grip strength tests. Further, heterozygous motor neuron-specific EphA4 gene deletion in SOD1G93A mice promoted significant improvement in functional performance during the disease course and a delay in disease onset relative to control mice. Importantly, mice in the heterozygous deletion group showed significantly improved survival of motor neurons and architecture of endplates of neuromuscular junctions compared with control and homozygous EphA4-deletion groups. Our novel results show that EphA4 signalling directly regulates motor neuron survival and that mutEphA4-Fc is a promising therapeutic candidate to slow disease progression in ALS.
A search is performed for the standard model Higgs boson in 5.2 fb{-1} of pp collisions at sqrts=1.96 TeV, collected with the D0 detector at the Fermilab Tevatron Collider. The final state considered ...is a pair of b jets and large missing transverse energy, as expected from pp-->ZH-->nunubb production. The search is also sensitive to the WH-->lnubb channel when the charged lepton is not identified. For a Higgs boson mass of 115 GeV, a limit is set at the 95% C.L. on the cross section multiplied by branching fraction for pp-->(Z/W)H(H-->bb) that is a factor of 3.7 larger than the standard model value, consistent with the factor of 4.6 expected.
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