Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel

Andrew S Bomback1, James A Tumlin2, Joel Baranski3, James E Bourdeau4, Anatole Besarab5, Alice S Appel1, Jai Radhakrishnan1, Gerald B Appel11Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY, USA; 2Department of Internal Medicine, Division of Nephrology, University of Tennessee College of Medicine in Chattanooga, Chattanooga, TN, USA; 3Balboa Nephrology Medical Group, San Diego, CA, USA; 4Nephrology Specialists of Oklahoma, Tulsa, OK, USA; 5Department of Medicine, Division of Nephrology and Hypertension, Henry Ford Health System, Detroit, MI, USAPurpose: A synthetic adrenocorticotropin (ACTH) analog has shown efficacy in Europe as primary and secondary therapy for nephrotic syndrome, but there is no published experience using the natural, highly purified ACTH gel formulation, available in the United States, for nephrotic syndrome. We therefore investigated the use of ACTH gel for nephrotic syndrome in the United States.Patients and methods: Twenty-one patients with nephrotic syndrome treated with ACTH gel outside of research settings in the United States, with initiation of therapy by December 31, 2009, allowing a minimum 6 months follow-up. We defined complete remission as stable renal function with proteinuria falling to <500 mg/day, and partial remission as stable renal function with >50% reduction in proteinuria from 500 to 3500 mg/day.Results: Twenty-one patients with nephrotic syndrome were treated: 11 with idiopathic membranous nephropathy (iMN), 4 with membranoproliferative glomerulonephritis (MPGN), 1 with focal segmental glomerulosclerosis (FSGS), 1 with minimal change disease (MCD), 1 with immunoglobulin A (IgA) nephropathy, 1 with class V systemic lupus erythematosus (SLE) glomerulonephritis, 1 with monoclonal diffuse proliferative glomerulonephritis, and 1 with unbiopsied nephrotic syndrome. ACTH was used as primary therapy for 3 patients; the remaining patients had previously failed a mean 2.3 immunosuppressive regimens. Eleven patients achieved a complete or partial remission, with 4 (19%) in complete remission. Of the 11 patients who achieved remission, 9 had iMN, 1 had FSGS, and 1 had IgA nephropathy. Of the 11 patients with iMN, 3 (27%) achieved complete remission and 6 (55%) achieved partial remission despite having previously failed a mean 2.4 therapies. Five patients reported steroid-like adverse effects, but there were no severe infections. The limitations were retrospective data analysis with short-term follow-up.Conclusion: ACTH gel may be a viable treatment option for resistant nephrotic syndrome due to membranous nephropathy. Short-term data suggest that remission rates may approach 80%.Keywords: nephrotic syndrome, membranous nephropathy, chronic kidney diseas

GParareal: A time-parallel ODE solver using Gaussian process emulation

Sequential numerical methods for integrating initial value problems (IVPs) can be prohibitively expensive when high numerical accuracy is required over the entire interval of integration. One remedy is to integrate in a parallel fashion, "predicting" the solution serially using a cheap (coarse) solver and "correcting" these values using an expensive (fine) solver that runs in parallel on a number of temporal subintervals. In this work, we propose a time-parallel algorithm (GParareal) that solves IVPs by modelling the correction term, i.e. the difference between fine and coarse solutions, using a Gaussian process emulator. This approach compares favourably with the classic parareal algorithm and we demonstrate, on a number of IVPs, that GParareal can converge in fewer iterations than parareal, leading to an increase in parallel speed-up. GParareal also manages to locate solutions to certain IVPs where parareal fails and has the additional advantage of being able to use archives of legacy solutions, e.g. solutions from prior runs of the IVP for different initial conditions, to further accelerate convergence of the method -- something that existing time-parallel methods do not do

A dynamic magneto-optical trap for atom chips

We describe a dynamic magneto-optical trap (MOT) suitable for the use with vacuum systems in which optical access is limited to a single window. This technique facilitates the long-standing desire of producing integrated atom chips, many of which are likely to have severely restricted optical access compared with conventional vacuum chambers. This "switching-MOT" relies on the synchronized pulsing of optical and magnetic fields at audio frequencies. The trap's beam geometry is obtained using a planar mirror surface, and does not require a patterned substrate or bulky optics inside the vacuum chamber. Central to the design is a novel magnetic field geometry that requires no external quadrupole or bias coils which leads toward a very compact system. We have implemented the trap for 85Rb and shown that it is capable of capturing 2 million atoms and directly cooling below the Doppler temperature

Cardiac Biomarkers and Risk of Atrial Fibrillation in Chronic Kidney Disease: The CRIC Study.

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF ("AF event") was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease

Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis

BACKGROUND AND OBJECTIVES: In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results. METHODS: Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 10 RESULTS: The Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of -2.7 points per the ALS Functional Rating Scale-Revised, whereas the other 2 changed by an average of -10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group. DISCUSSION: Treg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS

Highly non-Gaussian states created via cross-Kerr nonlinearity

We propose a feasible scheme for generation of strongly non-Gaussian states using the cross-Kerr nonlinearity. The resultant states are highly non-classical states of electromagnetic field and exhibit negativity of their Wigner function, sub-Poissonian photon statistics, and amplitude squeezing. Furthermore, the Wigner function has a distinctly pronounced ``banana'' or ``crescent'' shape specific for the Kerr-type interactions, which so far was not demonstrated experimentally. We show that creating and detecting such states should be possible with the present technology using electromagnetically induced transparency in a four-level atomic system in N-configuration.Comment: 12 pages, 7 figure

Research-based versus clinical serum creatinine measurements and the association of acute kidney injury with subsequent kidney function: findings from the Chronic Renal Insufficiency Cohort study.

Background:Observational studies relying on clinically obtained data have shown that acute kidney injury (AKI) is linked to accelerated chronic kidney disease (CKD) progression. However, prior reports lacked uniform collection of important confounders such as proteinuria and pre-AKI kidney function trajectory, and may be susceptible to ascertainment bias, as patients may be more likely to undergo kidney function testing after AKI. Methods:We studied 444 adults with CKD who participated in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study and were concurrent members of a large integrated healthcare delivery system. We estimated glomerular filtration rate (eGFR) trajectories using serum creatinine measurements from (i) the CRIC research protocol (yearly) and (ii) routine clinical care. We used linear mixed effects models to evaluate the associations of AKI with acute absolute change in eGFR and post-AKI eGFR slope, and explored whether these varied by source of creatinine results. Models were adjusted for demographic characteristics, diabetes status and albuminuria. Results:During median follow-up of 8.5 years, mean rate of eGFR loss was -0.31 mL/min/1.73 m2/year overall, and 73 individuals experienced AKI (55% Stage 1). A significant interaction existed between AKI and source of serum creatinine for acute absolute change in eGFR level after discharge; in contrast, AKI was independently associated with a faster rate of eGFR decline (mean additional loss of -0.67 mL/min/1.73 m2/year), which was not impacted by source of serum creatinine. Conclusions:AKI is independently associated with subsequent steeper eGFR decline regardless of the serum creatinine source used, but the strength of association is smaller than observed in prior studies after taking into account key confounders such as pre-AKI eGFR slope and albuminuria

Results from the Atacama B-mode Search (ABS) Experiment

The Atacama B-mode Search (ABS) is an experiment designed to measure cosmic microwave background (CMB) polarization at large angular scales ($\ell>40$). It operated from the ACT site at 5190~m elevation in northern Chile at 145 GHz with a net sensitivity (NEQ) of 41 $\mu$K$\sqrt{\rm s}$. It employed an ambient-temperature sapphire half-wave plate rotating at 2.55 Hz to modulate the incident polarization signal and reduce systematic effects. We report here on the analysis of data from a 2400 deg$^2$ patch of sky centered at declination $-42^\circ$ and right ascension $25^\circ$. We perform a blind analysis. After unblinding, we find agreement with the Planck TE and EE measurements on the same region of sky. We marginally detect polarized dust emission and give an upper limit on the tensor-to-scalar ratio of $r<2.3$ (95% cl) with the equivalent of 100 on-sky days of observation. We also present a new measurement of the polarization of Tau A and introduce new methods associated with HWP-based observations.Comment: 38 pages, 11 figure