Tofacitinib for the Treatment of Refractory Immune Checkpoint Inhibitor-Associated Immune Nephritis

Immune checkpoint inhibitor (ICI)-associated immune nephritis or acute interstitial nephritis (AIN) is one of the rare but known complication of ICI therapy. Guidelines recommend treatment of ICI-associated AIN with steroids, then TNF-alpha inhibitor infliximab. However, some cases are refractory to these therapies, potentially due to insufficient cytokine blockade. This is the first case where a 65-year-old female with metastatic lung adenocarcinoma, requiring high maintenance doses of steroids for immune nephritis was treated with tofacitinib, an oral Janus kinase (JAK) inhibitor. Tofacitinib enabled successful steroid tapering and might be a therapy option for refractory immune nephritis

Membranous Nephropathy in Chronic Lymphocytic Leukemia Responsive to Ibrutinib: A Case Report

Membranous nephropathy (MN) is an uncommon renal presentation in patients with chronic lymphocytic leukemia (CLL), and as such, there is no standard therapy for these patients. A few cases of MN in CLL have been described with varying success in MN treatment involving alkylating agents and fludarabine. Here we report the first case of MN in a patient with CLL treated with ibrutinib with complete renal response. This presentation underlines the importance of recognizing rare glomerular diseases that may occur with CLL and offers a new therapeutic avenue to the treatment of CLL-associated MN

Perceived barriers to pediatrician and family practitioner participation in pediatric clinical trials: Findings from the Clinical Trials Transformation Initiative.

Despite legislation to stimulate pediatric drug development through clinical trials, enrolling children in trials continues to be challenging. Non-investigator (those who have never served as a clinical trial investigator) providers are essential to recruitment of pediatric patients, but little is known regarding the specific barriers that limit pediatric providers from participating in and referring their patients to clinical trials. We conducted an online survey of pediatric providers from a wide variety of practice types across the United States to evaluate their attitudes and awareness of pediatric clinical trials. Using a 4-point Likert scale, providers described their perception of potential barriers to their practice serving as a site for pediatric clinical trials. Of the 136 providers surveyed, 52/136 (38%) had previously referred a pediatric patient to a trial, and only 17/136 (12%) had ever been an investigator for a pediatric trial. Lack of awareness of existing pediatric trials was a major barrier to patient referral by providers, in addition to consideration of trial risks, distance to the site, and time needed to discuss trial participation with parents. Overall, providers perceived greater challenges related to parental concerns and parent or child logistical barriers than study implementation and ethics or regulatory barriers as barriers to their practice serving as a trial site. Providers who had previously been an investigator for a pediatric trial were less likely to be concerned with potential barriers than non-investigators. Understanding the barriers that limit pediatric providers from collaboration or inhibit their participation is key to designing effective interventions to optimize pediatric trial participation

Urinary T Cells Are Detected in Patients With Immune Checkpoint Inhibitor-Associated Immune Nephritis That Are Clonotypically Identical to Kidney T Cell Infiltrates

Acute kidney injury (AKI) occurs in ~20% of patients receiving immune checkpoint inhibitor (ICI) therapy; however, only 2-5% will develop ICI-mediated immune nephritis. Conventional tests are nonspecific in diagnosing disease pathology and invasive procedures (i.e. kidney biopsy) may not be feasible. In other autoimmune renal diseases, urinary immune cells correlated with the pathology or were predictive of disease activity. Corresponding evidence and analysis are absent for ICI-mediated immune nephritis. We report the first investigation analyzing immune cell profiles of matched kidney biopsies and urine of patients with ICI-AKI. We demonstrated the presence of urinary T cells in patients with immune nephritis by flow cytometry analysis. Clonotype analysis of T cell receptor (TCR) sequences confirmed enrichment of kidney TCRs in urine. As ICI therapies become standard of care for more cancers, noninvasively assessing urinary immune cells of ICI therapy recipients can facilitate clinical management and an opportunity to tailor ICI-nephritis treatment

Interpreting the Global Enteric Multicenter Study (GEMS) Findings on Sanitation, Hygiene, and Diarrhea

Sanitation and hygiene are global concerns, as reflected in international development and human rights policy . The Sustainable Development Goals (SDGs) include target 6.2: to “achieve access to adequate and equitable sanitation and hygiene for all and end open defecation”. Globally, about 2.5 billion people do not use improved sanitation, of whom 1 billion defecate in the open. Fecal contamination of the environment and poor handwashing are responsible for an estimated 577,000 deaths annually. This is likely an underestimation: there is emerging evidence that poor sanitation and hygiene contribute to undernutrition and could be responsible for approximately half of all child stunting. Much of the health impact of inadequate sanitation and hygiene is attributed to diarrheal disease and its secondary effects. However, diarrhea is difficult to measure, and sanitation and hygiene are difficult to link to health outcomes

CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence

The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A–HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a “lock and key” interaction is typical of innate receptor–ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors

Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma

BackgroundDiagnosing immune checkpoint inhibitor (ICI)-associated nephritis can be challenging since it is a rare complication of therapy, associated with a spectrum of immune-mediated pathologies, and can present months after ICI therapy discontinuation (i.e., late-onset). ICIs are increasingly administered in combination with other cancer therapies with associated nephrotoxicity, further obfuscating the diagnosis of ICI-associated nephritis. In this report, we describe the first suspected case of late-onset ICI-associated membranous nephropathy (MN) in a patient with metastatic clear cell renal cell carcinoma (RCC) who had discontinued ICI therapy 6 months prior to presentation. Prompt recognition of the suspected late-onset immune-related adverse event (irAE) resulted in the successful treatment of MN and continuation of RCC therapy.Case presentationA 57-year-old man with metastatic clear cell RCC was responsive to third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor) when he presented with nephrotic range proteinuria and acute kidney injury (AKI). His kidney biopsy revealed probable secondary MN with subendothelial and mesangial immune complex deposits and negative staining for both phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). While a diagnosis of paraneoplastic MN could not be excluded, the patient was responding to cancer therapy and had tumor regression. However, 6 months prior to presentation, the patient had received pembrolizumab, an ICI, with his first-line RCC treatment. Due to concern that the patient may be presenting with late-onset ICI-associated MN, he was effectively treated with rituximab, which allowed for his continued RCC therapy.ConclusionThis report highlights the first case of suspected late-onset ICI-associated MN and the increasing complexity of recognizing renal irAEs. With the growing indications for the use of ICIs in combination with other cancer therapies, recognizing the various presentations of ICI-immune nephritis can help guide patient management and treatment

An approach to addressing subpopulation considerations in systematic reviews: the experience of reviewers supporting the U.S. Preventive Services Task Force

Abstract Background Guideline developers and other users of systematic reviews need information about whether a medical or preventive intervention is likely to benefit or harm some patients more (or less) than the average in order to make clinical practice recommendations tailored to these populations. However, guidance is lacking on how to include patient subpopulation considerations into the systematic reviews upon which guidelines are often based. In this article, we describe methods developed to consistently consider the evidence for relevant subpopulations in systematic reviews conducted to support primary care clinical preventive service recommendations made by the U.S. Preventive Services Task Force (USPSTF). Proposed approach Our approach is grounded in our experience conducting systematic reviews for the USPSTF and informed by a review of existing guidance on subgroup analysis and subpopulation issues. We developed and refined our approach based on feedback from the Subpopulation Workgroup of the USPSTF and pilot testing on reviews being conducted for the USPSTF. This paper provides processes and tools for incorporating evidence-based identification of important sources of potential heterogeneity of intervention effects into all phases of systematic reviews. Key components of our proposed approach include targeted literature searches and key informant interviews to identify the most important subpopulations a priori during topic scoping, a framework for assessing the credibility of subgroup analyses reported in studies, and structured investigation of sources of heterogeneity of intervention effects. Conclusions Further testing and evaluation are necessary to refine this proposed approach and demonstrate its utility to the producers and users of systematic reviews beyond the context of the USPSTF. Gaps in the evidence on important subpopulations identified by routinely applying this process in systematic reviews will also inform future research needs

Enhancing Optical Up-Conversion Through Electrodynamic Coupling with Ancillary Chromophores

In lanthanide-based optical materials, control over the relevant operating characteristics–for example transmission wavelength, phase and quantum efficiency–is generally achieved through the modification of parameters such as dopant/host combination, chromophore concentration and lattice structure. An alternative avenue for the control of optical response is through the introduction of secondary, codoped chromophores. Here, such secondary centers act as mediators, commonly bridging the transfer of energy between primary absorbers of externally sourced optical input and other sites of frequency-converted emission. Utilizing theoretical models based on experimentally feasible, three-dimensional crystal lattice structures; a fully quantized theoretical framework provides insights into the locally modified mechanisms that can be implemented within such systems. This leads to a discussion of how such effects might be deployed to either enhance, or potentially diminish, the efficiency of frequency up-conversion

The Heavy Metal Survey: Star Formation Constraints and Dynamical Masses of 21 Massive Quiescent Galaxies at z~1.4-2.2

In this paper, we present the Heavy Metal Survey, which obtained ultra-deep medium-resolution spectra of 21 massive quiescent galaxies at $1.4\lesssim z\lesssim 2.2$ with Keck/LRIS and MOSFIRE. With integration times of up to 16 hrs per band per galaxy, we observe numerous Balmer and metal absorption lines in atmospheric windows. We successfully derive spectroscopic redshifts for all 21 galaxies and for 19 we also measure stellar velocity dispersions ($\sigma_v$), ages, and elemental abundances, as detailed in an accompanying paper. Except for one emission-line AGN, all galaxies are confirmed as quiescent through their faint or absent H$\alpha$ emission and evolved stellar spectra. For most galaxies exhibiting faint H$\alpha$, elevated [NII]/H$\alpha$ suggests a non-star-forming origin. We calculate dynamical masses ($M_{\rm dyn}$) by combining $\sigma_v$ with structural parameters obtained from HST/COSMOS(-DASH), and compare them with stellar masses ($M_*$) derived using spectrophotometric modeling, considering various assumptions. For a fixed initial mass function (IMF), we observe a strong correlation between $M_{\rm dyn}/M_*$ and $\sigma_v$. This correlation may suggest that a varying IMF, with high-$\sigma_v$ galaxies being more bottom-heavy, was already in place at $z\sim2$. When implementing the $\sigma_v$-dependent IMF found in the cores of nearby early-type galaxies and correcting for biases in our stellar mass and size measurements, we find a low scatter in $M_{\rm dyn}/M_*$ of 0.14 dex. However, these assumptions result in unphysical stellar masses, which exceed the dynamical masses by 34%. This tension suggests that distant quiescent galaxies do not simply grow inside-out into today's massive early-type galaxies and the evolution is more complicated.Comment: Submitted to ApJ (25 pages, 11 figures