True PD Research Articles

Close accord on partial discharge diagnosis during voltage harmonics in electric motors fed by variable frequency drives

AbstractPartial discharge (PD) diagnostics test is a reliable solution for estimating insulation health conditions in power system components. During laboratory PD diagnostics, the effect of harmonic components in the voltage waveform generated by variable frequency drives (VFD) fed electric motors (EMs) is often overlooked. As VFD‐fed EMs operate at low speeds, the harmonic concentration in the voltage increases. It has been found that PD activity in VFD‐fed EM is significantly affected by the addition of harmonic components in the voltage, thus making it necessary to consider their impact when performing true PD diagnostics. This paper investigates the influence of voltage harmonic distortion produced in VFD‐fed EM on PD severity and the subsequent insulation degradation. Eight VFD‐fed EM are used to study the PD behaviour under different levels of harmonic pollution. The PD characteristics, such as inception voltage, pulse repetition rate, accumulated apparent charge, average discharge current, discharge power, and quadratic rate, are determined. Using probability distribution functions, PD activity and severity at various voltage harmonic levels are estimated. The proposed technique can be used to plan the maintenance activities that ensure the reliability for industrial applications dealing with the voltage harmonic distortion.

Atypical response patterns in Chinese patients with cancer with immune checkpoint blockade.

e14631 Background: As specific patterns of progression, atypical responses, including pseudoprogression (PsPD) and dissociated response (DR), have been recently described. The purpose of the present study was to evaluate the frequency and prognosis of PsPD and DR in Chinese cancer patients treated with immune checkpoint inhibitors. Methods: We retrospectively reviewed patients with advanced cancer who received PD-1/PD-L1 inhibitor alone or combination therapy in a single center between December 2019 and January 2022. We evaluated all measurable lesions in each organ to identify PsPD and DR independently of RECIST 1.1. PsPD was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and DR as concomitant decrease in some lesions and increase in others or emerging new lesions at a same timepoint. Progression‐free survival (PFS) and overall survival (OS) was compared between patients with atypical responses and those with true response (CR/PR) or nonresponse (SD/PD) using Cox proportional hazards models. Results: The present study included 178 patients aged 18-81 years (median: 63 years). The overall response rate was 18.5%. PsPD and DR were observed in 12 (6.7%) and 7 (3.9%) patients, respectively, and were not associated with any patient’s baseline characteristics. Median PFS (10.9 vs. 5.3 months; p=0.041) and OS (24.1 vs. 13.2 months; p=0.010) was significantly longer in patients with atypical response versus nonresponse, but shorter versus true responses (PFS: 10.9 vs. 35.4 months; p=0.009; OS: 24.1 vs. NR months; p=0.047). Patients with DR had a longer median PFS (10.1 vs. 1.5 months; p<0.0001) and OS (23.9 vs. 5.6 months; p=0.0001) than those with true PD. All patients with PsPD or DR were administrated with continuing ICIs. Among patients who experienced an initial progression (excluding patients with PsPD and DR), the continuing ICIs treatment cohort (n=20) still had a significantly longer median OS (7.5 vs. 3.1 months; p=0.004) than discontinuing ICIs treatment cohort (n=11). Conclusions: PsPD and DR are uncommon patterns of disease progression. Patients with DR exhibited a relatively favorable clinical outcome. Prognosis or biomarkers are needed to identify early patients with atypical responses who will benefit from immunotherapy.

Pilot Evaluation of Telemetered Cardiac Hemodynamics in the Setting of Fully‐Implanted Programmable Drug Delivery in Rats: A New Tool for Cardiovascular Drug Discovery?

IntroductionThe mechanistic understanding of pharmacokinetics–pharmacodynamics (PK/PD) relationships is a key component of modern cardiovascular drug discovery. However, given that both PK properties and/or experimental techniques (such as anesthesia) can alter auto‐regulatory/autonomic control in vivo (thus masking true PD responses), tools permitting the determination of translationally‐relevant PK/PD relationships for cardio‐active agents are limited. This pilot study established the feasibility of combining implantable programable infusion pumps and telemetered cardiac hemodynamic monitoring for the assessment PK‐independent PD responses in untethered conscious rats.MethodsHealthy Sprague‐Dawley rats (n = 7) were chronically instrumented with both a digital telemetered micro‐manometer catheter (HD‐S21, Data Sciences International) in the LV, and with a fully‐implanted programmable/refillable infusion pump in a femoral vein (iPRECIO® SMP‐200). The pumps were programmed, a priori, to perform (after a 21‐day recovery period) a two‐arm drug delivery protocol, consisting (each arm) of a 72h active period (ON, @12.5μL/hr) followed by a 96h washout (OFF period, on patency mode @1μL/hr); prior to each active period the pumps were loaded with either vehicle (CTRL) or a novel pure negative inotrope (MYK‐581), while normal saline was loaded prior to OFF periods. Left‐ventricular pressures (LVP) and derived functional indices were evaluated continuously (via telemetry) before/during active periods, while cardiac function/geometry were assessed (via echocardiography) prior to the end of the active period.ResultsFully implanted conscious rats had normal cardiac hemodynamics (HR: 339 ± 8 bpm, LVPmax: 119±3 mmHg) and cardiac function (EF: 76 ± 2%, FS: 47± 1%, and dLVP/dtmax: 9275 ± 369 mmHg/s), showing normal circadian oscillations. Similar observations were made during vehicle administration (e.g., EF: 77 ± 1%, and dLVP/dtmax: 9585 ± 891 mmHg/s), while marked reductions in both echocardiographic (EF: 45 ± 8.7%, FS: 24 ± 6%, P < 0.05 vs. VEH) and LVP‐derived (dLVP/dtmax: −21 ± 6%, or 7313 ± 819 mmHg/s, P < 0.05 vs. VEH) functional indices were observed during the MYK‐treatment period.ConclusionsTaken together, these data demonstrate that telemetered hemodynamics and fully‐implanted programmable/refillable infusion pump technologies can be successfully integrated in vivo in order to generate translationally‐relevant PK‐independent pharmacodynamics data in untethered conscious rats.Support or Funding InformationThese studies were supported by MyoKardia

1382. Acid-Fast Bacilli Testing Trends at 43 In- and Outpatient Facilities and Nontuberculous Mycobacterial Pulmonary Isolation Rate, United States, 2009–2015

BackgroundThe prevalence of nontuberculous mycobacterial pulmonary disease (NTM PD) is increasing in the United States and globally. The reasons for this increase are not clear but could be related to both gained awareness leading to increased mycobacterial testing, or to a true NTM PD increase. To further examine the role of testing rates in the observed increase, we studied trends in Acid-Fast Bacteria (AFB) testing and NTM isolation positivity using a large Electronic Health Record (EHR) dataset in the United States.MethodsUsing the Cerner Health Facts EHR dataset, we extracted microbiologic, demographic, and clinical data for patient encounters (inpatient or outpatient), with ≥1 orders for AFB respiratory cultures. The analysis was limited to the 43 facilities reporting continuously for the period 2009–2015. A patient with at least one AFB test was considered tested (AFB) and a patient with at least one pathogenic NTM respiratory isolate was considered positive. Trends in AFB testing and NTM positivity were estimated using log-linked Poisson regression (P < 0.05).ResultsFrom 2009 through 2015, of 14.8 million patients, 65,010 had 142,315 AFB tests, averaging 2.2 AFB tests/patient, for an overall testing prevalence of 0.43%; the annual testing prevalence remained unchanged during the study period (P = 0.44) (Figure 1). Of the 65,010 patients with AFB tests, 3,942 (6.1%) had ≥1 pathogenic NTM species, for an overall pulmonary NTM isolation prevalence of 2.7/10,000 patients represented in Cerner Health Facts dataset. Of the patients that had at least one pathogenic NTM, 3,094 (78%) had M. avium complex, and 265 (7%) had M. abscessus/chelonae, (Figure 2). Among patients with at least 1 NTM-positive culture, 138 patients had concomitant growth of M. tuberculosis.ConclusionIncreases in NTM PD are not explained by increases in AFB testing, which remained constant in the population represented here. This study was funded in part by the Division of Intramural Research, NIAID, NIH. Disclosures All authors: No reported disclosures.

Analysis of circulating tumor DNA (ctDNA) in pseudoprogression in anti-PD1 treated metastatic melanoma (MM).

9546 Background: We have previously shown that undetectable ctDNA either at baseline or during therapy predicted response in mm patients (pts) treated with anti-PD1 antibodies (aPD1). Pseudoprogression, defined as radiological progression prior to response, occurs in 8% of pts treated with aPD1. We sought to determine if ctDNA could differentiate pseudoprogression from true progression, defined as continued clinical or radiological disease progression. Methods: Between July 2014 and May 2016, pts receiving aPD1 had serial bloods for ctDNA. Included pts either had RECIST PD at first restaging or early clinical progression. Those with untreated brain metastases were excluded from the analysis. ctDNA was quantified using digital droplet PCR for mutations (BRAF/NRAS) at baseline and during the first 12 wks of treatment. Based on our prior studies, ctDNA results were grouped in to ‘favorable’ and ‘unfavorable’ ctDNA profiles (see Table), and these were compared in pts with true and pseudoprogression. Results: 29 pts were included, 28 with RECIST PD at first restaging and one with early clinical progression. 9 (31%) pts had a subsequent RECIST PR or SD and were considered pseudoprogression and 20 (69%) had true progression. Of the pseudoprogressors, 7/9 pts remained in response with a median follow-up of 20 months (mths). 2/9 pts had disease progression at 7 and 18 mths, with ctDNA that remained detectable with a &gt; 10-fold decrease during treatment in both patients. Of those with true progression and a favourable profile, 1 had a &gt; 10-fold decrease in ctDNA by wk 12 and was switched to MAPK therapy prior to further imaging, and the other had an undetectable ctDNA at wk 6 which increased again at wk 12. The latter pt had a new lesion on first restaging CT scan despite PR in all existing lesions with true PD on second restaging at wk 24. Conclusions: ctDNA in patients with mm at baseline and early on aPD1 treatment differentiates pseudo from true progression. [Table: see text]

Non-parametric regression in clustered multistate current status data with informative cluster size.

Datasets examining periodontal disease records current (disease) status information of tooth-sites, whose stochastic behavior can be attributed to a multistate system with state occupation determined at a single inspection time. In addition, the tooth-sites remain clustered within a subject, and the number of available tooth-sites may be representative of the true PD status of that subject, leading to an 'informative cluster size' scenario. To provide insulation against incorrect model assumptions, we propose a nonparametric regression framework to estimate state occupation probabilities at a given time and state exit/entry distributions, utilizing weighted monotonic regression and smoothing techniques. We demonstrate the superior performance of our proposed weighted estimators over the un-weighted counterparts via. a simulation study, and illustrate the methodology using a dataset on periodontal disease.

Dementia associated with Parkinson’s disease: Applying the Movement Disorder Society Task Force criteria

BackgroundDiagnostic criteria and procedures for dementia in Parkinson’s disease (PDD) have been proposed by a Movement Disorders Society Task Force (MDS-TF). The objective of this study was to explore the utility of the new MDS-TF criteria and procedures in clinical practice. MethodsTwo hundred ninety nine PD patients (36.5% with PDD as per MDFS-TF criteria; 33.1% according the DSM-IV) were included in the study. A variety of standardized motor, cognitive, psychiatric, and global severity measures were administered. A multivariate logistic regression model was built to determine the variables producing discrepancy between the MDS-TF and DSM-IV criteria for PDD and the clinical features that distinguished false negative cases. ResultsAgreement between MDS-TF and DSM-IV criteria was substantial (87.3%; kappa = 0.72), but the DSM-IV criteria failed to identify 22% of patients fulfilling MDS-TF criteria. False negative cases were older and had more severe motor symptoms but less psychosis than those true non-demented PD. False positives had less severe motor symptoms than true PDD, although the difference did not reach statistical significance. ConclusionsOur findings suggest that the MDS-TF criteria are more sensitive than the DSM-IV for a diagnosis of PDD. Old age, absence of psychiatric symptoms, and severe motor impairment can hinder the diagnosis of PDD.

FLAIR, T1 contrast enhancement, MR perfusion, and FDG PET following hypofractionated stereotactic radiotherapy (HFSRT), bevacizumab (BEV), and temozolomide (TMZ) for glioblastoma (GBM).

2048 Background: In GBM, VEGF inhibition decreases vascular permeability and MRI contrast enhancement (CE), which may or may not reflect meaningful anti-tumor activity. We sought to evaluate the relationships between different imaging modalities and anti-tumor activity in a prospective phase II trial of BEV, TMZ and HFSRT in GBM. Methods: Newly diagnosed GBM pts (N=40) received HFSRT with concomitant/ adjuvant BEV and TMZ. All pts underwent dynamic susceptibility contrast MR perfusion (DSC) at baseline, after HFSRT and every 2m. An FDG-PET scan was done at cycle 6. McDonald and RANO response criteria were applied. Results: DSC showed early/progressive decreases in relative cerebral blood volume (rCBV): baseline mean rCBV: 2.77; 6 weeks: 1.65 (p=0.014); 2m: 1.07 (p<0.001); 4m: 0.98 (p<0.001). Conversely, the extent of FLAIR hypersignal progressively increased (mean diameter product: 953, 1165, 1145, 1384 at 6 wks, 2m, 4m and 6m). Response rates per McDonald vs RANO were: complete response (27 vs 10%), partial (63 vs 63%), stable disease (3% vs 20%), progression (7 vs 7%). Because progressive FLAIR occurred within the RT port, time to radiographic progression per McDonald and RANO were identical: median 13m. Residual hypermetabolism seen at the 6m PET (N=6/31) predicted poor survival (p<0.001). Three pts with progressive FLAIR but not CE underwent re-resection; two had true PD and one had mainly radionecrosis. Conclusions: As treatment failure was mostly local, RANO criteria did not shorten time to progression compared to McDonald. DSC depicted early changes in rCBV linked to VEGF modulation, validating DSC as a reliable tool to evaluate anti-VEGF properties of new drugs in vivo. However, VEGF modulation was not predictive of durable anti-tumor activity. A positive PET at 6m predicted poor survival, indicating treatment failure even if other imaging modalities suggested otherwise. However, tumor progression may still be present despite negative PET and DSC, particularly in the setting of increasing non-enhancing FLAIR within the RT port. New imaging tools and improved response criteria are needed to guide management of these pts.

Through-Space Intramolecular Palladium Rearrangement in Substituted Aryl Complexes: Theoretical Study of the Aryl to Alkylpalladium Migration Process

DFT/B3LYP calculations have been carried out to study intramolecular 1,n palladium shifts (n = 3-5) between sp2 and sp3 carbon atoms in alkylarylpalladium systems. Such shifts, which also involve a concomitant exchange with a hydrogen atom of the alkylaryl ligand, are quite often a pivotal step of several organic transformations mediated by palladium complexes. We show that the intimate mechanism for the 1,3 shift corresponds to a Pd(IV) pathway, whereas a Pd(II) pathway is favored in the case of 1,5 migrations. In the case of 1,4 migrations, both mechanisms are competitive. The Pd(IV) pathway can involve either a true Pd(IV) intermediate (oxidative addition/reductive elimination mechanism) or a Pd(IV) transition state (oxidative hydrogen migration mechanism). The energy barrier is very high for the 1,3 palladium shift, making this process very unlikely, in contrast to the other ones which have enthalpy barriers ranging between 22.8 kcal mol-1 (for the 1,5 shift) and 31.9 kcal mol-1 (for the least favorable 1,4 shift studied here). All of these results are in line with our previous results for palladium shifts between two sp2 carbon atoms. In addition, the sp2 to sp3 shifts have been found to be rather exothermic owing to the possibility for the alkylaryl ligand in the product to achieve a eta3 coordination mode. This eta3 coordination mode results either from the shift itself (1,3 case) or from a subsequent rearrangement that comprises a chain-running mechanism within the alkyl chain bound to the metal (for n > 3).

Intramolecular 1,n Palladium Migrations in Polycyclic Aromatic Hydrocarbons. Palladium(II) versus Palladium(IV) Mechanisms: A Theoretical Study

DFT/B3LYP calculations have been carried out to study intramolecular 1,n aryl-to-aryl palladium shifts (n = 3−6) in polyaryl systems. Such rearrangements, which are associated with a concomitant shift of a hydrogen atom, have been found experimentally to be a pivotal step of several organic transformations mediated by palladium complexes. From the calculations of the various transition states and intermediates involved in the process, the intimate mechanism for the 1,3 shift is shown to correspond to a Pd(IV) pathway, whereas a Pd(II) pathway is favored in the case of 1,5 and 1,6 migrations. In the case of 1,4 migrations, both mechanisms become competitive. The Pd(IV) pathway can involve either a true Pd(IV) intermediate (oxidative addition mechanism) or a Pd(IV) transition state (oxidative hydrogen migration mechanism). The energy barrier is very high for the 1,3 palladium shift, making this process very unlikely, in contrast to the other ones, which have enthalpy barriers ranging between 17.8 and 27.5 k...

New synthetic applications of water-soluble acetate Pd/TPPTS catalyst generated in Situ. evidence for a true Pd(0) species intermediate

Studies on the sp-sp intermolecular coupling reactions with the palladium water-soluble catalyst prepared in situ from palladium(II) acetate and sulfonated triphenylphosphine P(C6H4-m-SO3Na)(3) (TPPTS) in a homogeneous acetonitrile-water system, without Cu(I) promotor, afford diynes with moderate yields (45-65%). Under the same conditions, the sp(2)-sp coupling of 2-iodophenols or 2-iodoanilines and terminal alkynes followed by intramolecular cyclization gives indolic and furanic products in good yields (60-99%). Under these aqueous conditions, an efficient and short synthesis of eutypine illustrated the synthetic potentiality of the coupling. Furthermore, through a series of kinetic and P-31 NMR experiments, we have demonstrated that a mixture of Pd(OAc)(2) and TPPTS affords spontaneously a palladium(0) complex, through formation of bivalent complex Pd(OAc)(2)-(TPPTS)(2). A detailed mechanism of the reaction has been investigated thoroughly and the pertinent rate constants measured. The resulting palladium(0) complex reacts with phenyl iodide via an oxidative addition. This complex is considerably less reactive than the corresponding complex generated from PPh(3), probably due to steric effects.

Low-potential potentiostatic oxidation of aluminium in pore forming electrolytes

Steady-state porous anodization of a high purity aluminium electrode in sulphuric and propanedioic acid solutions by means of the potentiostatic technique and in the 1.00–10.0 V vs sce potential range has been studied. Palibroda's equation for the steady-state j-V data at high potentials has been transformed to account for the true pd across the oxide film. At potentials much lower than the critical one, a linear function of the steady-state current density with the potential is predicted. The experimental results are in agreement with this linear law, although the current density in stationary conditions greatly depends on the nature of the electrolyte used. For propanedioic acid solutions, steady-state current density values are in the range 20–70 μA cm −2 and for pH = 1.0 H 2SO 4, in the range 200–800 μA cm −2. From the linear equation, the potential of zero film thickness has been calculated, the results being consistent with recent data in the literature.