Summary
Autoimmune diabetes mellitus is a rare but significant side effect of treatment with immune checkpoint inhibitors. Immune checkpoint inhibitor‐induced diabetes mellitus (CPI‐DM) is ...characterized by acute onset of dramatic hyperglycemia with severe insulin deficiency and occurrence following exposure to programmed cell death‐1/programmed cell death ligand‐1 (PD‐1/PD‐L1) inhibitors rather than cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4) inhibitors. As a growing number of patients undergo immunotherapy, further understanding of the characteristics of CPI‐DM patients is needed for improved prognostic and diagnostic application in order to reduce overall morbidity for this already at‐risk population. Additionally, understanding of the features and mechanisms of CPI‐DM may contribute to understanding mechanisms of spontaneous type I diabetes mellitus (T1DM). Here, we summarize the clinical features of CPI‐DM and interrogate the genetic and cellular mechanisms that may contribute to the disease, as well as the clinical challenges for predicting and treating these patients as increasing cancer immunotherapies reach clinical utility.
Immune checkpoint inhibitor‐induced diabetes mellitus (CPI‐DM) is characterized by acute onset of dramatic hyperglycemia with severe insulin deficiency and occurrence following exposure to PD‐1/PD‐L1 inhibitors rather than CTLA‐4 inhibitors. Genetic predisposition is likely to play a role, as is a second trigger. Improved understanding of CPI‐DM is needed clinically to reduce overall morbidity and may also contribute to understanding mechanisms of spontaneous T1DM.
Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. ...Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 37%), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.
Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens ...providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.
BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in ...preventing COVID-19.sup.1. Here we extend a previous phase-I/II trial report.sup.2 by presenting data on the immune response induced by BNT162b2 prime-boost vaccination from an additional phase-I/II trial in healthy adults (18-55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNgamma.sup.+ or IL-2.sup.+ CD8.sup.+ and CD4.sup.+ T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide-MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8.sup.+ T cells of the early-differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8.sup.+ T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses.
Intravenous alteplase improves functional outcome after acute ischemic stroke. However, little is known about the effects on self-reported health-related quality of life (HRQoL).
WAKE-UP was a ...multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in stroke with unknown onset time. HRQoL was assessed using the EuroQol five-dimensional questionnaire (EQ-5D) at 90 days, comprising the EQ-5D index and the EQ visual analogue scale (VAS). Functional outcome was assessed by the modified Rankin Scale (mRS). We calculated the effect of treatment on EQ-5D index and EQ VAS using multiple linear regression models. Mediation analysis was performed on stroke survivors to explore the extent to which the effect of alteplase on HRQoL was mediated by functional outcome.
Among 490 stroke survivors, the EQ-5D index was available for 452 (92.2%), of whom 226 (50%) were assigned to treatment with alteplase and 226 (50%) to placebo. At 90 days, mean EQ-5D index was higher, reflecting a better health state, in patients randomized to treatment with alteplase than with placebo (0.75 vs 0.67) with an adjusted mean difference of 0.07 (95% CI 0.02-0.12,
= 0.005). In addition, mean EQ VAS was higher with alteplase than with placebo (72.6 vs 64.9), with an adjusted mean difference of 7.6 (95% CI 3.9-11.8,
< 0.001). Eighty-five percent of the total treatment effect of alteplase on the EQ-5D index was mediated using the mRS score while there was no significant direct effect. By contrast, the treatment effect on the EQ VAS was mainly through the direct pathway (60%), whereas 40% was mediated by the mRS.
Assessment of patient-reported outcome measures reveals a potential benefit of intravenous alteplase for HRQoL beyond improvement of functional outcome.
ClinicalTrials.gov number, NCT01525290; EudraCT number, 2011-005906-32.
During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe ...complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke).
We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE.
Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 95% CI, 0.21-0.61,
<0.001). Higher age (
=0.04) and male sex (
=0.01) were predictors for the occurrence of SAE.
SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.
This commentary paper critically discusses the recent debate paper by Petry et
al. (2014) that argued there was now an international consensus for assessing Internet
Gaming Disorder (IGD). Our ...collective opinions vary considerably regarding many different
aspects of online gaming. However, we contend that the paper by Petry and colleagues does
not provide a true and representative international community of researchers in this area.
This paper critically discusses and provides commentary on (i) the representativeness of
the international group that wrote the ‘consensus’ paper, and (ii) each of
the IGD criteria. The paper also includes a brief discussion on initiatives that could be
taken to move the field towards consensus. It is hoped that this paper will foster debate
in the IGD field and lead to improved theory, better methodologically designed studies,
and more robust empirical evidence as regards problematic gaming and its psychosocial
consequences and impact.
Phylogenetic relationships among the four major lineages of land plants (liverworts, mosses, hornworts, and vascular plants) remain vigorously contested; their resolution is essential to our ...understanding of the origin and early evolution of land plants. We analyzed three different complementary data sets: a multigene supermatrix, a genomic structural character matrix, and a chloroplast genome sequence matrix, using maximum likelihood, maximum parsimony, and compatibility methods. Analyses of all three data sets strongly supported liverworts as the sister to all other land plants, and analyses of the multigene and chloroplast genome matrices provided moderate to strong support for hornworts as the sister to vascular plants. These results highlight the important roles of liverworts and hornworts in two major events of plant evolution: the water-to-land transition and the change from a haploid gametophyte generation-dominant life cycle in bryophytes to a diploid sporophyte generation-dominant life cycle in vascular plants. This study also demonstrates the importance of using a multifaceted approach to resolve difficult nodes in the tree of life. In particular, it is shown here that densely sampled taxon trees built with multiple genes provide an indispensable test of taxon-sparse trees inferred from genome sequences.
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